supplement supplemental table 1supplement supplemental table 1: clinical parameters of...

Supplement Supplemental Table 1: Clinical parameters of non-QT-prolonging drugs, including mode of action, regulatory status, molecular weight (MW), human plasma protein binding (PPB) percentage, and unbound effective therapeutic plasma concentration (ETPCfree). Many of these drugs are viewed as safe, not regulated by the United States Food and Drug Administration (FDA), and are available over the counter (OTC). Where necessary, ETPCfree was calculated from reported maximum plasma concentrations using MW and PPB. Where multiple reports of PPB were available, the minimum value was used in calculations.

Compound Indication FDA Approval

Status MW PPB ETPCfree

Range [M] References

Acetaminophen analgesic and antipyretic OTC 151.2 77.5 1.5E-05 7.4E-05 (1-3)

Ascorbic Acid antioxidant OTC 176.1 0.0 2.3E-05 1.0E-04 (4; 5)

Aspirin analgesic and antipyretic OTC 180.2 55.0 3.7E-04 7.5E-04 (6; 7)

Caffeine stimulant and diuretic OTC 194.2 17.0 2.1E-05 1.7E-04 (8)

Ceftriaxone antibiotic 1984 554.6 83.3 1.5E-07 9.0E-05 (6; 9)

Cilostazol phosphodiesterase inhibitor 1999 369.5 95.0 1.1E-07 1.8E-07 (10-12)

Ciprofloxacin antibiotic 2004 311.3 20.0 5.1E-06 1.3E-05 (13-15)

Clozapine antipsychotic 1989 326.8 94.5 3.8E-09 4.6E-08 (16-19)

Desvenlafaxine antidepressant 2008 263.4 30.0 4.3E-07 6.2E-07 (20; 21)

Diltiazem vasodilator (calcium channel blocker) 1982 414.5 80.0 3.5E-08 7.3E-08 (22-24)

Duloxetine Oxalate antidepressant 2004 297.4 95.0 5.9E-09 1.5E-08 (25-27)

Eltrombopag hematopoietic 2008 564.7 99.0 3.0E-09 1.9E-08 (28)

Famotidine antihistamine 1998 337.4 15.0 1.5E-07 4.5E-07 (29-32)

Fluconazole antifungal 1990 306.3 11.0 7.6E-06 4.1E-05 (16; 33)

Fluoxetine antidepressant 1987 309.3 94.5 2.3E-09 1.3E-08 (25; 34-36)

Fluvoxamine antipsychotic 1994 434.4 80.0 4.1E-08 2.5E-07 (37)

Lamivudine antiviral 1995 229.3 36.0 2.8E-06 1.4E-05 (38-40)

Lamotrigine antiepileptic 1994 256.1 55.0 9.5E-07 3.0E-06 (41-43)

Linezolid antibacterial 2000 337.4 31.0 6.3E-06 4.3E-05 (44)

Lopinavir antiretroviral 2000 628.8 98.0 3.1E-07 3.8E-07 (45)

Loratadine antihistamine 1993 382.9 97.0 3.7E-10 2.3E-09 (25; 46; 47)

Metronidazole antibacterial 1981 171.2 11.0 3.1E-05 2.1E-04 (22; 25; 48)

Mexiletine antiarrhythmic (class IB) 1998 215.7 70.0 4.7E-07 1.1E-06 (22; 49)

Mibefradil antihypertensive (calcium antagonist) Approved 1997

Withdrawn 1998* 568.6 99.6 1.9E-07 1.1E-05 (50)

Mitoxantrone antineoplastic 1996 517.4 78.0 2.8E-08 6.8E-08 (51; 52)

Nebivolol antihypertensive (beta-blocker) 2007 441.9 98.0 6.7E-11 8.6E-10 (53-56)

Nelfinavir antiretroviral 1997 567.8 98.0 1.1E-07 1.7E-07 (57)

Nifedipine antihypertensive (calcium channel block) 1989 346.3 97.0 2.3E-09 1.0E-08 (22; 58; 59)

Nitrendipine antihypertensive (calcium channel block) - 360.4 99.0 1.8E-10 1.2E-09 (22; 60-63)

Olanzapine antipsychotic 1996 312.4 93.0 1.3E-09 4.4E-09 (17; 64; 65)

Paroxetine antidepressant 1992 374.8 93.0 1.2E-09 1.2E-08 (66; 67)

Phenytoin antiepileptic 1956 252.3 84.4 4.0E-06 1.1E-05 (3; 68; 69)

Piperacillin antibacterial 1993 517.6 30.0 1.8E-07 4.0E-07 (25; 70)

Propranolol antihypertensive (beta-blocker) 2003 295.8 86.6 1.2E-08 7.3E-08 (16; 71)

Quetiapine antipsychotic 1997 883.1 83.0 9.5E-08 2.1E-07 (72-74)

Raltegravir antiretroviral 2007 482.5 83.0 1.4E-08 4.0E-08 (75)

Ribavirin antiviral 1998 482.5 83.0 1.4E-08 4.0E-08 (25; 76)

Ritonavir antiretroviral 1996 721.0 98.0 4.5E-07 7.4E-07 (77; 78)

Sildenafil phosphodiesterase inhibitor 1998 666.7 88.5 2.2E-08 2.0E-07 (16; 79; 80)

Silodosin alpha-blocker 2008 495.5 97.0 1.4E-09 5.7E-09 (81-83)

Sitagliptin peptidase inhibitor 2006 523.3 38.0 2.1E-07 1.1E-06 (84-86)

Tadalafil phosphodiesterase inhibitor 2003 389.4 94.0 1.5E-08 5.0E-08 (87; 88)

Telbivudine antiviral 2006 242.2 3.3 8.0E-07 2.2E-05 (89; 90)

Vardenafil phosphodiesterase inhibitor 2003 579.1 95.0 6.9E-07 1.8E-06 (91-93)

Verapamil antihypertensive (calcium channel block) 1998 491.1 90.0 2.5E-08 8.1E-08 (6; 94)

Voriconazole antifungal 2004 349.3 58.0 3.0E-06 4.6E-06 (95)

*Mebefradil was withdrawn for potentially fatal interactions with more than 25 other compounds. The danger apparently arises from the reduction of activity of liver enzymes (96), which may increase plasma concentrations of concomitantly administered drugs to dangerous levels.

Supplemental Table 2: Clinical parameters of QT-prolonging drugs, including mode of action, United States Food and Drug Administration (FDA) approval status, molecular weight (MW), human plasma protein binding (PPB) percentage, and unbound effective therapeutic plasma concentration (ETPCfree). Where necessary, ETPCfree was calculated from reported maximum plasma concentrations using MW and PPB. Where multiple reports of PPB were available, the minimum value was used in calculations.

Compound Indication FDA Approval

Status MW PPB ETPCfree

Range [M] References

Alfuzosin prostatic hyperplasia 2003 425.9 82 5.7E-09 5.9E-09 (97; 98)

Amiodarone antiarrhythmic (class III) 1985 681.0 96 1.0E-10 3.7E-06 (99-103)

Amitriptyline antidepressant (tricyclic) 1976 277.4 91.4 4.6E-09 7.9E-07 (16; 99; 104-

107)

Arsenic Trioxide oncology 2000 125.9 5.5 1.5E-07 5.2E-07 (108; 109)

Astemizole antihistamine (2nd generation) Approved 1988 Withdrawn 1999 458.6 96.7 5.3E-11 7.8E-09 (99; 110; 111)

Bepridil antiarrhythmic (class I and IV) Approved 1990 Withdrawn 2004 384.5 95.4 1.0E-08 3.3E-06 (16; 99; 112)

Chlorpromazine antipsychotic 1954 355.3 91 3.0E-09 9.8E-07 (99; 113-116)

Cibenzoline antiarrhythmic (class Ia, 3, 4) - 262.4 50 1.1E-07 1.6E-06 (99; 117-120)

Cisapride gastrointestinal

Approved 1993

Withdrawn 2000 465.9 97.5 2.0E-09 1.3E-07 (99; 121-124)

Clemastine antihistamine (1st generation) 1977 344.0 98 3.4E-11 4.7E-09 (99; 125-127)

Dasatinib oncology 2006 488.0 96 1.4E-09 9.2E-09 (128; 129)

Desipramine antidepressant (tricyclic) 1964 266.3 80 1.1E-08 6.0E-07 (99; 116; 130;

131)

Diphenhydramine antihistamine (1st generation) 1946 291.8 74 2.2E-08 2.2E-07 (99; 132-134)

Disopyramide antiarrhythmic (class Ia) 1977 339.5 51 2.5E-07 1.2E-05 (99; 135; 136)

Dofetilide antiarrhythmic (class III) 1999 441.6 60 4.0E-10 9.1E-09 (99; 137; 138)

Donepezil Alzheimer's (cholinesterase inhibitor) 1996 379.5 60 3.4E-09 6.4E-08 (139; 140)

Droperidol antiemetic and antipsychotic Approved 1970 Withdrawn 2001 379.4 75 6.6E-08 1.6E-07 (99; 141-143)

Erythromycin antibiotic 1981 733.9 64.5 1.0E-07 3.4E-05 (99; 144-149)

Flecainide antiarryhthmic (class Ic) 1985 414.4 61 3.0E-07 1.9E-06 (99; 116; 150)

Grepafloxacin antibiotic Approved 1997 Withdrawn 1999 359.4 50 6.3E-07 4.4E-06 (99; 151-153)

Halofantrine antimalarial 1992 536.9 83 2.7E-07 1.0E-06 (99; 154-157)

Haloperidol antiemetic and antipsychotic 1967 375.9 92 1.2E-09 4.5E-08 (99; 158; 159)

Ibutilide antiarryhthmic (class III) 1996 384.6 40 4.7E-10 2.3E-07 (99; 160-164)

Imipramine antidepressant (tricyclic) 1959 949.2 82 5.5E-09 3.2E-07 (16; 116; 165-

167)

Lapatinib oncology (tyrosine kinase inhibitor) 2007 943.5 99 1.1E-08 3.9E-08 (168-173)

Maraviroc antiretroviral 2007 513.7 76 4.7E-08 5.1E-07 (174-177)

Moxifloxacin antibiotic 1999 437.9 70 2.0E-07 4.8E-06 (152; 178-180)

Nilotinib oncology (tyrosine kinase inhibitor) 2007 584.0 98 2.1E-08 1.2E-07 (169; 181-185)

Paliperidone antipsychotic 2006 426.5 74 2.4E-09 6.9E-08 (159; 186-188)

Pentamidine antiprotozoal 1984 592.7 60 8.0E-09 1.0E-06 (99; 189; 190)

Pimozide antipsychotic 1984 461.6 99 8.7E-11 4.3E-10 (99; 159; 191-

194)

Procainamide antiarrhythmic (class Ia) 1950 235.3 14 7.3E-06 6.4E-05 (99; 116; 195-

198)

Quinidine antiarrhythmic (class Ia) 1950 324.4 87 2.9E-07 2.2E-05 (99; 116; 199;

200)

Ranolazine antianginal 2006 427.5 61 6.2E-07 5.2E-06 (201-204)

Risperidone antipsychotic 1993 410.5 88 2.9E-10 1.8E-08 (99; 159)

Sematilide antiarrhythmic (class III) - 312.2 4 2.0E-06 8.3E-06 (99; 205; 206)

Sertindole antipsychotic - 440.9 99 2.0E-11 3.2E-07 (99; 159)

Sotalol (d,l-) antiarrhythmic (class II, III), beta blocker 1992 308.8 0.0 1.3E-06 1.5E-05 (99; 207-210)

Sparfloxacin antibiotic Approved 1996 Withdrawn 2001 392.4 45 2.0E-07 3.4E-06

(99; 151; 152; 211)

Sunitinib oncology (tyrosine kinase inhibitor) 2006 532.6 95 1.9E-09 1.9E-08 (169; 212-215)

Terfenadine antihistamine (2nd generation) Approved 1985 Withdrawn 1998 471.7 97 9.8E-11 9.5E-09 (99; 216-218)

Thioridazine antipsychotic 1962 370.6 45 2.1E-08 1.8E-06 (99; 219-221)

Tolterodine antimuscarinic (urology) 1998 475.6 96.3 8.6E-11 2.2E-09 (222-224)

Ziprasidone antipsychotic 2001 467.4 99.9 2.6E-11 6.8E-10 (225-227)

Supplemental Table 3: Table of patient unbound drug levels linked to electrophysiological effect by clinical trial. Unbound concentrations are calculated using MW and PPB values in Supplemental Table 2.

Unbound plasma concentrations (PC) are the range of the smallest Cmax (peak concentration) linked to QTc prolongation greater than 10 ms in controlled clinical study cohorts, and the lowest levels linked with increased arrhythmia incidence. Reports are classified according to whether the defined proarrhythmic effect is reported together with PC, or if the effect is reported without documentation of PC.

Compound Clinical QTc Prolongation >10ms

Concentration Range [M] Arrhythmia (min) [M] References With PC

Effect Without PC Report

Long QT Arrhythmia

Alfuzosin (228)

Amiodarone

(229-231) (229; 232-234)

Amitriptyline

(99; 230; 235-237) (236; 238)

Arsenic Trioxide 5.2E-07 5.2E-07

(109) (239; 240) (239-242)

Astemizole

9.9E-10 (234) (99) (243; 244)

Bepridil 7.2E-08 7.2E-08

(245) (99; 246; 247) (233)

Chlorpromazine

(230; 248)

Cibenzoline 1.0E-06 1.2E-06

(99; 118) (249) (233)

Cisapride 6.3E-09 8.3E-09

(124) (230; 250) (250)

Clemastine

(251)

Dasatinib

(252; 253)

Desipramine 5.4E-08 1.3E-07

(254) (99; 230; 255) (238)

Diphenhydramine

(234; 256) (99)

Disopyramide

(99; 230; 249) (233)

Dofetilide 1.0E-09 9.1E-09

(99; 138)

Donepezil

(257) (257; 258)

Droperidol 9.4E-08 9.4E-08

(259) (99; 260-263) (262)

Erythromycin

(99; 230; 264-266) (233; 267)

Flecainide 5.9E-07 7.2E-07

(268; 269) (230; 270-274) (233; 274)

Grepafloxacin

(275) (276)

Halofantrine 2.0E-07 6.8E-07

(99; 277) (155; 278; 279) (280)

Haloperidol 1.6E-09 3.8E-09

(226; 281) (230; 260; 282) (233; 260; 283)

Ibutilide 1.6E-08 1.6E-08 1.6E-08 (160) (164; 284) (233)

Imipramine

(230) (238)

Lapatinib 2.5E-08 2.5E-08

(172) (202; 285)

Maraviroc

(175)

Moxifloxacin 2.1E-06 4.1E-06

(202; 286-288) (178; 215; 230;

289; 290)

Nilotinib 5.7E-08 5.7E-08

(182) (230; 291; 292)

Paliperidone 6.9E-08 6.9E-08

(186) (293) (186)

Pentamidine

(294-296) (294)

Pimozide 9.5E-11 9.5E-11

(194) (230; 260)

Procainamide 1.8E-05 1.8E-05

(99) (230) (233)

Quinidine 6.4E-08 2.3E-06

(99; 199; 200; 297; 298) (200; 230; 299) (233)

Ranolazine 3.5E-06 9.1E-06

(202; 300) (301)

Risperidone

(230; 260; 302) (283; 303)

Sematilide 2.0E-06 6.1E-06 2.5E-06 (99; 205; 304) (305) (205)

Sertindole

(260; 306; 307)

Sotalol (d,l-) 1.3E-06 1.4E-05

(210; 308; 309) (209; 230) (160; 209; 233)

Sparfloxacin 6.2E-07 3.0E-06

(99; 310) (211; 311; 312)

Sunitinib 1.2E-08 1.9E-08

(215) (212) (212)

Terfenadine 2.0E-10 1.3E-09 3.0E-09 (99; 217; 313; 314) (230) (233; 244; 251)

Thioridazine 1.5E-07 1.1E-06

(219; 221; 315; 316) (230; 260) (233; 283)

Tolterodine

(230; 317)

Ziprasidone 3.6E-10 6.8E-10

(226; 315; 318; 319) (220; 230; 260) (319)

Supplemental Table 4: Table of drug electrophysiological effects observed in in vivo and ex vivo animal studies. Studies included were performed on non-rodent, large animal species such as monkey, rabbit, guinea pig, cat and dog. Peak unbound plasma concentration associated with in vivo QTc prolongation of greater than 10 ms (range of study minimums), or increased arrhythmia incidence (minimum of studies), by whole-animal, close-chested methods such as telemetery or Holter monitor. Unbound concentrations are calculated using MW and PPB values in Supplemental Table 2. Ex vivo preparations include open-

chest and Langendorff studies of the heart, wedge preparations, isolated primary ventricular cardiomyocytes, and Purkinje fibers.

Compound In Vivo QTc

Prolong. >10ms [M] Arrhythmia In Vivo [M]

In Vivo References

Ex Vivo QTc/APD Prolong. >10ms [M]

Arrhythmia Ex Vivo [M]

Ex Vivo References

Alfuzosin

3.0E-08 1.0E-05

(228; 320)

Amiodarone 3.0E-10 2.9E-09 2.9E-09 (99; 321) 1.0E-07 5.9E-05

(99; 322)

Amitriptyline 3.8E-07 3.8E-07 2.1E-06 (323; 324) 1.0E-06 1.0E-05

(99)

Arsenic Trioxide

1.0E-05 3.5E-04 1.0E-05 (239; 325)

Astemizole 7.2E-10 1.0E-05 7.2E-10 (99; 110; 234;

326; 327) 3.0E-10 9.5E-07

(99; 322; 328)

Bepridil 2.6E-08 6.7E-08

(110; 327) 1.0E-07 2.6E-05

(99; 322; 329)

Chlorpromazine

1.0E-05 1.3E-05

(99; 330)

Cibenzoline

Cisapride 2.0E-10 1.3E-07 2.3E-08 (99; 110; 124;

327; 331) 6.0E-09 3.0E-06 1.0E-07 (99; 217; 320; 322;

332)

Clemastine

1.0E-07 1.0E-05 1.0E-07 (99; 322; 330; 333)

Dasatinib

3.0E-05 3.0E-05

(129)

Desipramine Diphenhydramine

2.0E-06 1.0E-05

(99; 234; 330)

Disopyramide

5.0E-06 4.0E-05

(99)

Dofetilide 3.0E-08 3.0E-08

(99) 1.0E-09 1.0E-06 3.0E-09 (99; 320; 322; 332;

334; 335)

Donepezil Droperidol 1.2E-07 1.2E-07

(336) 1.0E-08 1.0E-06 3.0E-08 (99; 336-340)

Erythromycin

1.4E-05 3.0E-04 1.0E-04 (99; 152; 267; 322;

334; 341; 342)

Flecainide 2.7E-06 2.7E-06

(343) 2.4E-06 2.4E-05

(99)

Grepafloxacin

1.4E-05 2.6E-05

(99; 151)

Halofantrine 8.0E-08 8.0E-08

(344) 2.0E-06 2.0E-06

(280)

Haloperidol 2.8E-09 3.5E-08

(110; 327) 2.6E-08 1.0E-07 3.0E-07 (322; 345)

Ibutilide 1.6E-09 1.6E-09

(346) 1.0E-08 1.0E-06

(99; 347)

Imipramine Lapatinib

5.0E-06 5.0E-06

(170; 348)

Maraviroc 4.3E-07 1.2E-06

(174) 3.0E-06 3.0E-06

(174)

Moxifloxacin

3.0E-06 3.0E-05 9.0E-05 (151; 152; 332)

Nilotinib

1.0E-06 1.0E-06

(349)

Paliperidone

1.0E-07 1.0E-06 1.0E-06 (350; 351)

Pentamidine

1.0E-05 3.0E-04

(352-354)

Pimozide 2.2E-10 2.2E-10

(110) 7.5E-08 1.0E-07 3.0E-07 (322; 355)

Procainamide

1.0E-04 1.0E-04

(99)

Quinidine 3.0E-07 2.6E-06 1.4E-07 (99; 110; 326;

327) 2.4E-07 1.0E-06 1.0E-05 (99; 322; 356)

Ranolazine

5.0E-05 1.0E-04

(357)

Risperidone 6.0E-08 6.0E-08

(345) 1.0E-07 1.0E-06 3.0E-07 (121; 329; 332; 345;

358-360)

Sematilide 3.1E-06 1.1E-05 3.1E-06 (99; 321) 1.0E-07 1.0E-05

(99; 347)

Sertindole 1.0E-09 2.0E-07

(99; 260) 3.0E-07 1.0E-06 1.0E-06 (99; 334; 345)

Sotalol (d,l-) 1.3E-06 2.3E-05

(99; 336) 5.0E-07 1.0E-04 1.0E-04

(99; 121; 320; 322; 345; 347; 356; 361-

363)

Sparfloxacin 6.3E-06 9.8E-05

(99; 364) 6.6E-06 1.0E-04 3.0E-05 (99; 151; 152; 322; 332; 334; 364; 365)

Sunitinib 2.7E-08 3.1E-08

(215) 1.0E-06 1.0E-06

(215)

Terfenadine 1.5E-10 3.0E-07

(99; 110; 234; 327) 1.0E-08 1.0E-06 1.0E-08

(99; 217; 322; 328; 330; 356; 366-368)

Thioridazine 2.4E-07 9.1E-07

(110; 327) 3.0E-07 1.0E-05

(99; 322; 340; 367)

Tolterodine

3.2E-08 3.2E-08

(369)

Ziprasidone

1.0E-07 1.0E-06 6.0E-06 (370; 371)

Supplemental Table 5: Calcium transient prolongation by clinically QT-prolonging drugs in the 90 compound training set, measured by kinetic image cytometry of human iPSC-derived cardiomyocytes. Molar concentrations corresponding to >140% effect size on CTD75, EC20 and EC50 when a fit was possible, cessation of calcium transients are recorded, along with the maximum effect size observed, and other response and protocol notes.

Compound CTD75

>140% [M] CTD75

EC20 [M] CTD75

EC50 [M] CT Stopped

[M] Notes

Alfuzosin 5.0E-06 4.8E-06 6.8E-06 5.0E-04 Prolonged CTD75 to 286% of control

Amiodarone 1.0E-05 9.2E-07 1.6E-06 1.0E-04 Prolonged CTD75 to 141% of control

Amitriptyline

8.69E-10 8.69E-10 1.0E-05 Prolonged CTD75 to 115% of control

Arsenic Trioxide

1.75E-01 2.45E+01 With 48 hour exposure, CTD75 prolonged to 126% of control.

Cytotoxicity noted at 100 µM

Astemizole 1.0E-09 4.0E-10 1.1E-09 1.0E-07 Prolonged CTD75 to 345% of control

Bepridil 1.0E-06 7.2E-08 1.5E-07 1.0E-05 Prolonged CTD75 to 178% of control

Chlorpromazine

1.0E-05 Prolonged CTD75 to 124% of control

Cibenzoline 1.0E-05 7.5E-07 1.7E-06 Prolonged CTD75 to 141% of control

Cisapride 1.0E-07 1.0E-07 1.6E-07 Prolonged CTD75 to 337% of control

Clemastine 1.0E-07 2.6E-08 9.8E-08 1.0E-05 Prolonged CTD75 to 445% of control

Dasatinib 1.0E-06 5.1E-07 5.8E-07 With 4 hour exposure, CTD75 prolonged to 162% of control

Desipramine


Diphenhydramine 1.0E-05 8.5E-07 1.5E-06 Prolonged CTD75 to 175% of control

Disopyramide 1.0E-05 1.0E-05 1.6E-05 Prolonged CTD75 to 343% of control

Dofetilide 1.0E-08 2.5E-10 3.0E-09 Prolonged CTD75 to 452% of control

Donepezil 1.0E-05


Droperidol 5.0E-08 1.2E-07 1.7E-07 1.0E-06 Prolonged CTD75 to 472% of control

Erythromycin 5.0E-04

Prolonged CTD75 to 219% of control DMSO 0.5% in all doses and controls

Flecainide 1.0E-05


Grepafloxacin

Prolonged CTD75 to 112% of control

Halofantrine 1.0E-06


Haloperidol 5.0E-08 1.5E-07 5.7E-07 Prolonged CTD75 to 384% of control

Ibutilide 1.0E-09 Prolonged CTD75 to 322% of control

Imipramine


Lapatinib

6.81E-06 8.53E-06 Prolonged CTD75 to 133% of control.

Cytotoxicity noted.

Maraviroc 1.0E-04


Moxifloxacin 1.0E-04


Nilotinib

1.0E-04 With 48 hour exposure, CTD75 prolonged to 105% of control.

Cytotoxicity noted.

Paliperidone 1.0E-06


Pentamidine 1.0E-05

1.0E-04 With 48 hour exposure, CTD75 prolonged to 476% of control

Cytotoxicity noted at 10 µM

Pimozide 1.0E-09 8.8E-11 1.5E-10 1.0E-07 Prolonged CTD75 to 227% of control

Procainamide 1.0E-04 5.8E-05 9.9E-05 Prolonged CTD75 to 183% of control

Quinidine 5.0E-06 9.9E-07 2.9E-06 5.0E-04 Prolonged CTD75 to 329% of control DMSO 0.5% in all doses and controls

Ranolazine 2.0E-05 1.8E-06 5.4E-06 1.0E-04 Prolonged CTD75 to 156% of control

Risperidone 5.0E-07 5.8E-07 8.3E-07 Prolonged CTD75 to 427% of control

Sematilide 1.0E-05 7.7E-06 4.1E-05 Prolonged CTD75 to 292% of control

Sertindole 1.0E-07 9.1E-08 1.7E-07 1.0E-05 Prolonged CTD75 to 357% of control

Sotalol (d,l-) 3.1E-05 3.5E-05 5.5E-05 Prolonged CTD75 to 569% of control

Sparfloxacin 1.0E-04 Prolonged CTD75 to 365% of control

Sunitinib 1.0E-05


Terfenadine


Thioridazine 2.5E-06 6.1E-07 1.4E-06 1.0E-05 Prolonged CTD75 to 166% of control

Tolterodine 1.0E-07 1.0E-04 Prolonged CTD75 to 425% of control

Ziprasidone 1.0E-06 1.2E-07 1.6E-07 Prolonged CTD75 to 360% of control

Supplemental Table 6: Assessment of CTD75 prolongation by QT prolonging and non-prolonging compounds in the blinded 35 compound test set. The test set includes 16 compounds carried over from the 90 compound training set, 2 tested twice with separate concentration titrations, and 17 new compounds (effect referenced). Test concentrations causing CTD75 prolongation beyond 140% of control calcium transient duration or causing cessation of spontaneous calcium transient activity are tabulated.

QT Prolonging Compounds QT Non-Prolonging Compounds

Compound Name CTD75 Prolongation CT Stopped Compound Name CTD75 Prolongation CT Stopped

Arsenic trioxide Not Detected

Aspirin Not Detected

Azithromycin (230; 372) Not Detected

Forskolin Not Detected Barium chloride (373) Not Detected

Levcromakalim Not Detected 10uM

Bay K8644 (374) 25nM 100uM Mexiletine (Set 1) Not Detected 100uM

Bepridil (Set 1) Not Detected 10uM Mexiletine (Set 2) Not Detected 50uM

Bepridil (Set 2) 1.11uM 10uM Nicorandil Not Detected Chlorpromazine Not Detected 5uM Nimodipine Not Detected 10uM

Dimenhydrinate (375) 10uM 100uM Nisoldipine Not Detected 1uM

Dofetilide 1nM

Nitrendipine Not Detected 1uM

E4031 (376) 10nM

NS1463 Not Detected 100uM

Flecainide 1uM 100uM Pinacidil Not Detected Ibutilide 1nM

Primidone Not Detected

Mesoridazine (219) 10uM

Serotonin Not Detected

Procainamide Not Detected

Verapamil Not Detected 10uM

Propoxyphene (377) 10uM 100uM Quinidine 10uM 100uM Ranolazine 100uM

Spafloxacin 100uM Sunitinib 11.1uM Terfenadine Not Detected 10uM

Veratridine (378) 10uM 100uM

Supplemental References

1. Stangier J, Su C, Fraunhofer A, Tetzloff W. 2000. Pharmacokinetics of acetaminophen and ibuprofen when coadministered with telmisartan in healthy volunteers. Journal of clinical pharmacology 40:1338-46

2. Ameer B, Greenblatt DJ, Divoll M, Abernethy DR, Shargel L. 1981. High-performance liquid chromatographic determination of acetaminophen in plasma: single-dose pharmacokinetic studies. Journal of chromatography 226:224-30

3. Herrera AM, Scott DO, Lunte CE. 1990. Microdialysis sampling for determination of plasma protein binding of drugs. Pharmaceutical research 7:1077-81

4. Dhariwal KR, Hartzell WO, Levine M. 1991. Ascorbic acid and dehydroascorbic acid measurements in human plasma and serum. The American journal of clinical nutrition 54:712-6

5. 2013. Ascorbic Acid. In Drug Facts and Comparisons, ed. EK Kastrup, et.al.:35-7. St. Louis, Missouri: Wolters Kluwer Health. Number of 35-7 pp.

6. Kratochwil NA, Huber W, Muller F, Kansy M, Gerber PR. 2002. Predicting plasma protein binding of drugs: a new approach. Biochemical pharmacology 64:1355-74

7. 2013. Aspirin (Acetylsalicylic Acid; ASA). In Drug Facts and Comparisons, ed. EK Kastrup, et.al.:1480-2. St. Louis, Missouri: Wolters Kluwer Health. Number of 1480-2 pp.

8. 2013. Caffeine. In Drug Facts and Comparisons, ed. EK Kastrup, et.al.:1345-50. St. Louis, Missouri: Wolters Kluwer Health. Number of 1345-50 pp.

9. Stoeckel K, McNamara PJ, Brandt R, Plozza-Nottebrock H, Ziegler WH. 1981. Effects of concentration-dependent plasma protein binding on ceftriaxone kinetics. Clinical pharmacology and therapeutics 29:650-7

10. Schror K. 2002. The pharmacology of cilostazol. Diabetes, obesity & metabolism 4 Suppl 2:S14-9 11. Chapman TM GK. 2003. Cilostazol: a review of its use in intermittent claudication. American

journal of cardiovascular drugs : drugs, devices, and other interventions 3:117-38 12. Mallikaarjun S, Forbes WP, Bramer SL. 1999. Effect of renal impairment on the pharmacokinetics

of cilostazol and its metabolites. Clin Pharmacokinet 37 Suppl 2:33-40 13. Zlotos G, Bucker A, Kinzig-Schippers M, Sorgel F, Holzgrabe U. 1998. Plasma protein binding of

gyrase inhibitors. Journal of pharmaceutical sciences 87:215-20 14. FDA. 2004. Pharmacology Review(s) (CIPRO Ciprofloxacin Hydrochlorine Tablets). In Application

Numbers 19-537/S-049, 20-780/S-013, 19-847/S-027, 19-857/S-031, ed. CfDEa Research 15. FDA. 2004. Medical Review(s) (CIPRO Ciprofloxacin Hydrochlorine Tablets). In Application

Numbers 19-537/S-049, 20-780/S-013, 19-847/S-027, 19-857/S-031, ed. CfDEa Research 16. Waters NJ, Jones R, Williams G, Sohal B. 2008. Validation of a rapid equilibrium dialysis approach

for the measurement of plasma protein binding. Journal of pharmaceutical sciences 97:4586-95 17. Wang CY, Zhang ZJ, Li WB, Zhai YM, Cai ZJ, et al. 2004. The differential effects of steady-state

fluvoxamine on the pharmacokinetics of olanzapine and clozapine in healthy volunteers. Journal of clinical pharmacology 44:785-92

18. Dahl ML, Llerena A, Bondesson U, Lindstrom L, Bertilsson L. 1994. Disposition of clozapine in man: lack of association with debrisoquine and S-mephenytoin hydroxylation polymorphisms. British journal of clinical pharmacology 37:71-4

19. Glue P, Gale C, Menkes DB, Hung N. 2012. Evaluation of bioequivalence between clozapine suspension and tablet formulations : a multiple-dose, fed and fasted study. Clinical drug investigation 32:723-7

20. Parker VD, Richards LS, Nichols AI, Behrle JA, Fruncillo RJ. 2005. The absolute bioavailability of an oral sustained-release formulation of desvenlafaxine succinate in healthy subjects. Clinical Pharmacology & Therapeutics 77:P47-P

21. 2013. Desvenlafaxine. In Drug Facts and Comparisons, ed. EK Kastrup, et.al.:1667-72. St. Louis, Missouri: Wolters Kluwer Health. Number of 1667-72 pp.

22. Yamazaki K, Kanaoka M. 2004. Computational prediction of the plasma protein-binding percent of diverse pharmaceutical compounds. Journal of pharmaceutical sciences 93:1480-94

23. Christensen H, Asberg A, Holmboe AB, Berg KJ. 2002. Coadministration of grapefruit juice increases systemic exposure of diltiazem in healthy volunteers. European journal of clinical pharmacology 58:515-20

24. Zelis RF, Kinney EL. 1982. The pharmacokinetics of diltiazem in healthy American men. The American journal of cardiology 49:529-32

25. Zhang F, Xue J, Shao J, Jia L. 2012. Compilation of 222 drugs' plasma protein binding data and guidance for study designs. Drug Discov Today 17:475-85

26. Gajula R, Maddela R, Ravi V, Inamadugu J, Pilli N. 2013. A rapid and sensitive liquid chromatography–tandem mass spectrometric assay for duloxetine in human plasma: Its pharmacokinetic application. Journal of Pharmaceutical Analysis 3:36-44

27. FDA. 2012. Clinical Review (Cymbalta® Duloxetine Hydrochloride). In sNDA 21427-S41 28. FDA. 2008. Clinical Pharmacology and Biopharmaceutics Review(s) (Promacta). In Application

Number: NDA 22-291, ed. CfDEa Research 29. Schwartz JI, Yeh KC, Berger ML, Tomasko L, Hoover ME, et al. 1995. Novel oral medication

delivery system for famotidine. Journal of clinical pharmacology 35:362-7 30. Ikawa K, Shimatani T, Hayato S, Morikawa N, Tazuma S. 2007. Pharmacokinetic and

pharmacodynamic properties of lafutidine after postprandial oral administration in healthy subjects: comparison with famotidine. Biological & pharmaceutical bulletin 30:1003-6

31. Merck. 2011. PEPCID® (FAMOTIDINE) TABLETS (Label). ed. US FDA: Merck Sharp & Dohme Corp. 32. Lin JH, Chremos AN, Kanovsky SM, Schwartz S, Yeh KC, Kann J. 1987. Effects of antacids and food

on absorption of famotidine. British journal of clinical pharmacology 24:551-3 33. Pfizer. 2011. DIFLUCAN® (Label) (Fluconazole Tablets) (Fluconazole Injection - for intravenous

infusion only) (Fluconazole for Oral Suspension) ed. US FDA: Roerig, Pfizer Inc. 34. Gupta S, Banfield C, Kantesaria B, Flannery B, Herron J. 2004.

Pharmacokinetics/pharmacodynamics of desloratadine and fluoxetine in healthy volunteers. Journal of clinical pharmacology 44:1252-9

35. Moraes MO, Lerner FE, Corso G, Bezerra FA, Moraes ME, De Nucci G. 1999. Fluoxetine bioequivalence study: quantification of fluoxetine and norfluoxetine by liquid chromatography coupled to mass spectrometry. Journal of clinical pharmacology 39:1053-61

36. Aronoff GR, Bergstrom RF, Pottratz ST, Sloan RS, Wolen RL, Lemberger L. 1984. Fluoxetine kinetics and protein binding in normal and impaired renal function. Clinical pharmacology and therapeutics 36:138-44

37. FDA. 2000. MEMLV021-AE1 (Luvox). In NDA 20-243/S-021, ed. CfDEa Research 38. Johnson MA, Verpooten GA, Daniel MJ, Plumb R, Moss J, et al. 1998. Single dose

pharmacokinetics of lamivudine in subjects with impaired renal function and the effect of haemodialysis. British journal of clinical pharmacology 46:21-7

39. Bruno R, Regazzi MB, Ciappina V, Villani P, Sacchi P, et al. 2001. Comparison of the plasma pharmacokinetics of lamivudine during twice and once daily administration in patients with HIV. Clin Pharmacokinet 40:695-700

40. Yuen GJ, Morris DM, Mydlow PK, Haidar S, Hall ST, Hussey EK. 1995. Pharmacokinetics, absolute bioavailability, and absorption characteristics of lamivudine. Journal of clinical pharmacology 35:1174-80

41. Birnbaum AK, Kriel RL, Im Y, Remmel RP. 2001. Relative bioavailability of lamotrigine chewable dispersible tablets administered rectally. Pharmacotherapy 21:158-62

42. FDA. 2003. Approved Labeling (LAMICTAL lamotrigine tablets). In Application Number: 20-764/S-011, 20-241/S-017, ed. CfDEa Research: GlaxoSmithKline

43. FDA. 2003. Clinical Pharmacology and Biopharmaceutics Review(s). In Application Number: 20-764/S-011, 20-241/S-017, ed. CfDEa Research: GlaxoSmithKline

44. Pfizer. 2014. ZYVOX® (linezolid) Injection, Tablets and Oral Suspension (Label). ed. US FDA: Pfizer 45. 2013. Lopinavir/Ritonavir. In Drug Facts and Comparisons, ed. EK Kastrup, et.al.:2714-6. St.

Louis, Missouri: Wolters Kluwer Health. Number of 2714-6 pp. 46. Radwanski E, Hilbert J, Symchowicz S, Zampaglione N. 1987. Loratadine: multiple-dose

pharmacokinetics. Journal of clinical pharmacology 27:530-3 47. Hilbert J, Radwanski E, Weglein R, Luc V, Perentesis G, et al. 1987. Pharmacokinetics and dose

proportionality of loratadine. Journal of clinical pharmacology 27:694-8 48. 2013. Metronidazole. In Drug Facts and Comparisons, ed. EK Kastrup, et.al.:2457-62. St. Louis,

Missouri: Wolters Kluwer Health. Number of 2457-62 pp. 49. Häselbart V, Doevendans J, Wolf M. 1981. Kinetics and bioavailability of mexiletine in healthy

subjects. Clinical pharmacology and therapeutics 29 50. Welker HA, Wiltshire H, Bullingham R. 1998. Clinical pharmacokinetics of mibefradil. Clin

Pharmacokinet 35:405-23 51. Nicoletto MO, Padrini R, Galeotti F, Ferrazzi E, Cartei G, et al. 2000. Pharmacokinetics of

intraperitoneal hyperthermic perfusion with mitoxantrone in ovarian cancer. Cancer chemotherapy and pharmacology 45:457-62

52. Chassany O, Urien S, Claudepierre P, Bastian G, Tillement JP. 1996. Comparative serum protein binding of anthracycline derivatives. Cancer chemotherapy and pharmacology 38:571-3

53. Kamali F, Howes A, Thomas S, Ford G, Snoeck E. 1997. A pharmacokinetic and pharmacodynamic interaction study between nebivolol and the H2-receptor antagonists cimetidine and ranitidine. British journal of clinical pharmacology 43:201-4

54. Baldwin CM, Keam SJ. 2009. Nebivolol: in the treatment of hypertension in the US. American journal of cardiovascular drugs : drugs, devices, and other interventions 9:253-60

55. Briciu C, Neag M, Muntean D, Vlase L, Bocsan C, et al. 2014. A pharmacokinetic drug interaction study between nebivolol and paroxetine in healthy volunteers. Journal of Clinical Pharmacy and Therapeutics 39:535

56. Janssen. 2011. BYSTOLIC® (nebivolol) tablets. ed. US FDA 57. Agouron. 2012. VIRACEPT® (nelfinavir mesylate) Tablets (Label). ed. US FDA 58. Robertson DR, Waller DG, Renwick AG, George CF. 1988. Age-related changes in the

pharmacokinetics and pharmacodynamics of nifedipine. British journal of clinical pharmacology 25:297-305

59. Kleinbloesem CH, van Brummelen P, van de Linde JA, Voogd PJ, Breimer DD. 1984. Nifedipine: kinetics and dynamics in healthy subjects. Clinical pharmacology and therapeutics 35:742-9

60. Krol GJL, J. T.; Mazzu, A. L.; Burkholder, D. E.; Birkett, J. P.; Taylor, R. J.; Bon, C. 1987. Bioequivalence of Different Nitrendipine Tablet Dosage Formulations. J Cardiovasc Pharm 9:S129

61. Fujimura A, Ohashi K, Sugimoto K, Kumagai Y, Ebihara A. 1989. Chronopharmacological study of nitrendipine in healthy subjects. Journal of clinical pharmacology 29:909-15

62. Soons PA, Breimer DD. 1991. Stereoselective pharmacokinetics of oral and intravenous nitrendipine in healthy male subjects. British journal of clinical pharmacology 32:11-6

63. Kirch W, Hutt HJ, Heidemann H, Ramsch K, Janisch HD, Ohnhaus EE. 1984. Drug interactions with nitrendipine. J Cardiovasc Pharmacol 6 Suppl 7:S982-5

64. Callaghan JT, Bergstrom RF, Ptak LR, Beasley CM. 1999. Olanzapine. Pharmacokinetic and pharmacodynamic profile. Clin Pharmacokinet 37:177-93

65. Kassahun K, Mattiuz E, Nyhart E, Jr., Obermeyer B, Gillespie T, et al. 1997. Disposition and biotransformation of the antipsychotic agent olanzapine in humans. Drug metabolism and disposition: the biological fate of chemicals 25:81-93

66. Yasui-Furukori N, Saito M, Inoue Y, Niioka T, Sato Y, et al. 2007. Terbinafine increases the plasma concentration of paroxetine after a single oral administration of paroxetine in healthy subjects. European journal of clinical pharmacology 63:51-6

67. GlaxoSmithKline. 2012. PAXIL® (paroxetine hydrochloride) Tablets and Oral Suspension (Label). ed. US FDA: GlaxoSmithKline

68. Pfizer. 2014. Dilantin-125® (Phenytoin Oral Suspension, USP) (Label). ed. US FDA 69. FDA. 2001. Approval Package (Dilantin-125). In Application Number: NDA 10-151/S-022, 029,

030, 032, 033 & 034, ed. CfDEa Research: Pfizer 70. Pfizer. 2013. ZOSYN® (piperacillin/tazobactam) (Label). ed. US FDA 71. Akrimax. 2013. INNOPRAN XL (propranolol hydrochloride) (Label). ed. US FDA 72. FDA. 2009. Clinical Pharmacology and Biopharmaceutics Review (Seroquel®). In NDA 20639 SE5-

045/046 ed. CfDEa Research: Astra-Zeneca 73. Figueroa C, Brecher M, Hamer-Maansson JE, Winter H. 2009. Pharmacokinetic profiles of

extended release quetiapine fumarate compared with quetiapine immediate release. Progress in neuro-psychopharmacology & biological psychiatry 33:199-204

74. AstraZeneca. 2011. SEROQUEL® (quetiapine fumarate) Tablets ed. US FDA 75. Merck. 2007. ISENTRESS® (raltegravir) (Label). ed. US FDA 76. Merck. 2013. REBETOL® (ribavirin USP) Capsules, Oral Solution (Label). ed. US FDA 77. Gatti G DBA, Casazza R, De Pascalis C, Bassetti M, Cruciani M, Vella S, Bassetti D. 1999. The

relationship between ritonavir plasma levels and side-effects: implications for therapeutic drug monitoring. AIDS 13:2083-9

78. Abbott. 2012. NORVIR (ritonavir) (Label). ed. US FDA 79. Nichols DJ, Muirhead GJ, Harness JA. 2002. Pharmacokinetics of sildenafil after single oral doses

in healthy male subjects: absolute bioavailability, food effects and dose proportionality. British journal of clinical pharmacology 53 Suppl 1:5S-12S

80. Pfizer. 1998. VIAGRA® (sildenafil citrate) (Label). ed. US FDA 81. Yoshida M, Homma Y, Kawabe K. 2007. Silodosin, a novel selective alpha 1A-adrenoceptor

selective antagonist for the treatment of benign prostatic hyperplasia. Expert opinion on investigational drugs 16:1955-65

82. Zhou Y, Sun P, Liu Y, Zhao X, Meng L, Cui Y. 2011. Safety and pharmacokinetic studies of silodosin, a new α1A-adrenoceptor selective antagonist, in healthy Chinese male subjects. Biological & pharmaceutical bulletin 34:1240-5

83. Watson. 2013. RAPAFLO® (silodosin) (Label). ed. US FDA 84. Bergman A, Ebel D, Liu F, Stone J, Wang A, et al. 2007. Absolute bioavailability of sitagliptin, an

oral dipeptidyl peptidase-4 inhibitor, in healthy volunteers. Biopharmaceutics & drug disposition 28:315-22

85. Krishna R, Bergman A, Larson P, Cote J, Lasseter K, et al. 2007. Effect of a single cyclosporine dose on the single-dose pharmacokinetics of sitagliptin (MK-0431), a dipeptidyl peptidase-4 inhibitor, in healthy male subjects. Journal of clinical pharmacology 47:165-74

86. Merck. 2008. JANUVIA™ (sitagliptin) Tablets (Label). ed. US FDA 87. Lilly. 2014. CIALIS (tadalafil) tablets (Label). ed. US FDA 88. Lilly. 2014. ADCIRCA (tadalafil) tablets for oral administration (Label). ed. US FDA 89. Zhou XJ, Lim SG, Lloyd DM, Chao GC, Brown NA, Lai CL. 2006. Pharmacokinetics of telbivudine

following oral administration of escalating single and multiple doses in patients with chronic hepatitis B virus infection: pharmacodynamic implications. Antimicrobial agents and chemotherapy 50:874-9

90. Novartis. 2013. Tyzeka® (telbivudine) (Label). ed. US FDA 91. Klotz T, Sachse R, Heidrich A, Jockenhovel F, Rohde G, et al. 2001. Vardenafil increases penile

rigidity and tumescence in erectile dysfunction patients: a RigiScan and pharmacokinetic study. World journal of urology 19:32-9

92. Bayer. 2014. STAXYN (vardenafil hydrochloride) (Label). ed. US FDA 93. Bayer. 2014. LEVITRA (vardenafil hydrochloride) (Label). ed. US FDA 94. Pfizer. 2009. CALAN - verapamil hydrochloride tablet, film coated (Label). ed. US FDA 95. FDA. 2004. Approval Package (VFEND® voriconazole). In Application Number: NDA 21-266/S009,

NDA 21-267/S009, NDA 21-630/S003, ed. CfDEa Research: Pfizer 96. SoRelle R. 1998. Withdrawal of Posicor from market. Circulation 98:831-2 97. Sanofi-Aventis. 2012. UROXATRAL® (alfuzosin HCl) extended-release tablets (Label). ed. US FDA 98. Mistri HN, Jangid AG, Pudage A, Rathod DM, Shrivastav PS. 2008. Highly sensitive and rapid LC–

ESI-MS/MS method for the simultaneous quantification of uroselective α1-blocker, alfuzosin and an antimuscarinic agent, solifenacin in human plasma. Journal of Chromatography B 876:236-44

99. Redfern WS, Carlsson L, Davis AS, Lynch WG, MacKenzie I, et al. 2003. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc Res 58:32-45

100. Veronese M, McLean S, Hendriks R. 1988. Plasma protein binding of amiodarone in a patient population: measurement by erythrocyte partitioning and a novel glass-binding method. British journal of clinical pharmacology 26:721-31

101. Ramusovic S, Laer S, Meibohm B, Lagler FB, Paul T. 2013. Pharmacokinetics of intravenous amiodarone in children. Archives of disease in childhood 98:989-93

102. Sanofi. 2014. Cordarone® (amiodarone HCl) TABLETS (Label). ed. US FDA 103. FDA. 1998. Approved Draft Labeling (Amiodarone Hydrochloride Tablets). In Application Number

74-739, ed. CfDEa Research 104. Montgomery SA, McAuley R, Rani SJ, Montgomery DB, Braithwaite R, Dawling S. 1979.

Amitriptyline plasma concentration and clinical response. Br Med J 1:230-1 105. Pike E, Skuterud B. 1982. Plasma binding variations of amitriptyline and nortriptyline. Clinical

pharmacology and therapeutics 32:228-34 106. Morrison D, Roy S, Rayner C, Amer A, Howard D, et al. 2007. A randomized, crossover study to

evaluate the pharmacokinetics of amantadine and oseltamivir administered alone and in combination. PLoS One 2:e1305

107. Aoki FY, Stiver HG, Sitar DS, Boudreault A, Ogilvie RI. 1985. Prophylactic amantadine dose and plasma concentration-effect relationships in healthy adults. Clinical pharmacology and therapeutics 37:128-36

108. FDA. 2000. Clinical Pharmacology and Biopharmaceutics Review(s) (Arsenic Trioxide Injection). In Application Number 21-248, ed. CfDEa Research

109. Siu CW, Au WY, Yung C, Kumana CR, Lau CP, et al. 2006. Effects of oral arsenic trioxide therapy on QT intervals in patients with acute promyelocytic leukemia: implications for long-term cardiac safety. Blood 108:103-6

110. Ando K, Hombo T, Kanno A, Ikeda H, Imaizumi M, et al. 2005. QT PRODACT: In Vivo QT Assay With a Conscious Monkey for Assessment of the Potential for Drug-Induced QT Interval Prolongation. Journal of Pharmacological Sciences 99:487-500

111. Lefebvre RA, Van Peer A, Woestenborghs R. 1997. Influence of itraconazole on the pharmacokinetics and electrocardiographic effects of astemizole. British journal of clinical pharmacology 43:319-22

112. Pritchard JF, McKown LA, Dvorchik BH, O'Neill PJ. 1985. Plasma protein binding of bepridil. Journal of clinical pharmacology 25:347-53

113. FDA. 1999. Approval Letter (Chlorpromazine Hydrochloride Oral Concentrate, USP). In Application Number 40224, ed. CfDEa Research

114. Curry SH. 1970. Plasma protein binding of chlorpromazine. The Journal of pharmacy and pharmacology 22:193-7

115. Curry SH. 1971. Chlorpromazine: concentrations in plasma, excretion in urine and duration of effect. Proceedings of the Royal Society of Medicine 64:285-9

116. Lombardo F, Obach RS, Shalaeva MY, F G. 2002. Prediction of volume of distribution values in humans for neutral and basic drugs using physicochemical measurements and plasma protein binding data. J Med Chem 45:2867-76

117. Brazzell RK, Aogaichi K, Heger JJ, Jr., Somberg JC, Carliner NH, Morganroth J. 1984. Cibenzoline plasma concentration and antiarrhythmic effect. Clinical pharmacology and therapeutics 35:307-16

118. Touboul P, Atallah G, Kirkorian G, de Zuloaga C, Dufour A, et al. 1986. Electrophysiologic effects of cibenzoline in humans related to dose and plasma concentration. American heart journal 112:333-9

119. Kostis JB, Krieger S, Moreyra A, Cosgrove N. 1984. Cibenzoline for treatment of ventricular arrhythmias: a double-blind placebo-controlled study. J Am Coll Cardiol 4:372-7

120. Mehanna AS. 2012. Cardiac agents: cardiac glycosides, antianginal, and antiarrhythmic drugs. In Foye's Principles of Medicinal Chemistry, ed. TL Lemke, DA Williams:725: Lippincott Williams & Wilkins. Number of 725 pp.

121. Limberis JT, McDermott JS, Salmen HJ, Su Z, Mikhail A, et al. 2007. The effects of plasma proteins on delayed repolarization in vitro with cisapride, risperidone, and D, L-sotalol. Journal of pharmacological and toxicological methods 56:11-7

122. Kivisto KT, Lilja JJ, Backman JT, Neuvonen PJ. 1999. Repeated consumption of grapefruit juice considerably increases plasma concentrations of cisapride. Clinical pharmacology and therapeutics 66:448-53

123. Smout AJ, Bogaard JW, Grade AC, ten Thije OJ, Akkermans LM, Wittebol P. 1985. Effects of cisapride, a new gastrointestinal prokinetic substance, on interdigestive and postprandial motor activity of the distal oesophagus in man. Gut 26:246-51

124. Johnson&Johnson. 2011. Briefing Document for FDA Gastrointestinal Drugs Advisory Committee Meeting Regarding Serotonin (5-hydroxytryptamine) Receptor 4 Agonists. ed. FDA: Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

125. FDA. 2001. Clinical Pharmacology and Biopharmaceutics Review(s) (Tavist). In Application Number NDA 21-082, ed. CfDEa Research

126. Hansson H, Bergvall K, Bondesson U, Hedeland M, Torneke K. 2004. Clinical pharmacology of clemastine in healthy dogs. Veterinary dermatology 15:152-8

127. Schran HF, Petryk L, Chang CT, O'Connor R, Gelbert MB. 1996. The pharmacokinetics and bioavailability of clemastine and phenylpropanolamine in single-component and combination formulations. Journal of clinical pharmacology 36:911-22

128. Takahashi N, Miura M, Scott SA, Niioka T, Sawada K. 2012. Pharmacokinetics of dasatinib for Philadelphia-positive acute lymphocytic leukemia with acquired T315I mutation. Journal of hematology & oncology 5:23

129. FDA. 2006. Pharmacology Review(s) (Sprycel). In Application Number 21-986 & 22-072, ed. CfDEa Research

130. Patroneva A, Connolly SM, Fatato P, Pedersen R, Jiang Q, et al. 2008. An assessment of drug-drug interactions: the effect of desvenlafaxine and duloxetine on the pharmacokinetics of the CYP2D6 probe desipramine in healthy subjects. Drug metabolism and disposition: the biological fate of chemicals 36:2484-91

131. Verbeeck RK, Cardinal JA, Hill AG, Midha KK. 1983. Binding of phenothiazine neuroleptics to plasma proteins. Biochemical pharmacology 32:2565-70

132. Zhou H, Adedoyin A, Wilkinson G. 1990. Differences in plasma binding of drugs between Caucasians and Chinese subjects. Clinical pharmacology and therapeutics 48:10-7

133. Blyden GT, Greenblatt DJ, Scavone JM, Shader RI. 1986. Pharmacokinetics of diphenhydramine and a demethylated metabolite following intravenous and oral administration. Journal of clinical pharmacology 26:529-33

134. BD-Simplist. 2013. Diphenhydramine Hydrochloride Injection, USP (Label). ed. US FDA 135. Lima JJ, Boudoulas H, Blanford M. 1981. Concentration-dependence of disopyramide binding to

plasma protein and its influence on kinetics and dynamics. The Journal of pharmacology and experimental therapeutics 219:741-7

136. Meffin PJ, Robert EW, Winkle RA, Harapat S, Peters FA, Harrison DC. 1979. Role of concentration-dependent plasma protein binding in disopyramide disposition. J Pharmacokinet Biopharm 7:29-46

137. Mounsey JP, DiMarco JP. 2000. Dofetilide. Circulation 102:2665-70 138. FDA. 1999. Clinical Pharmacology and Biopharmaceutics Review(s) (Tykosyn). In Application

Number NDA 20931, ed. CfDEa Research 139. Rogers SL, Friedhoff LT. 1998. Pharmacokinetic and pharmacodynamic profile of donepezil HCl

following single oral doses. British journal of clinical pharmacology 46 Suppl 1:1-6 140. Tiseo PJ, Rogers SL, Friedhoff LT. 1998. Pharmacokinetic and pharmacodynamic profile of

donepezil HCl following evening administration. British journal of clinical pharmacology 46 Suppl 1:13-8

141. Higashi Y, Kitahara M, Fujii Y. 2006. Simultaneous analysis of haloperidol, its three metabolites and two other butyrophenone-type neuroleptics by high performance liquid chromatography with dual ultraviolet detection. Biomedical chromatography : BMC 20:166-72

142. Grunwald Z, Torjman M, Schieren H, Bartkowski RR. 1993. The pharmacokinetics of droperidol in anesthetized children. Anesthesia and analgesia 76:1238-42

143. Fischler M, Bonnet F, Trang H, Jacob L, Levron JC, et al. 1986. The pharmacokinetics of droperidol in anesthetized patients. Anesthesiology 64:486-9

144. Prandota J, Tillement JP, d'Athis P, Campos H, Barre J. 1980. Binding of erythromycin base to human plasma proteins. The Journal of international medical research 8 Suppl 2:1-8

145. Parsons RL, David J, Paddock GM, Stamp ST. 1978. Plasma concentration/time curve of erythromycin after a 12-hour intravenous infusion of erythromycin lactobionate in man. Postgraduate medical journal 54:68-71

146. Digenis GA, Sandefer EP, Parr AF, Beihn R, McClain C, et al. 1990. Gastrointestinal behavior of orally administered radiolabeled erythromycin pellets in man as determined by gamma scintigraphy. Journal of clinical pharmacology 30:621-31

147. Josefsson K, Bergan T, Magni L. 1982. Dose-related pharmacokinetics after oral administration of a new formulation of erythromycin base. British journal of clinical pharmacology 13:685-91

148. Austin KL, Mather LE, Philpot CR, McDonald PJ. 1980. Intersubject and dose-related variability after intravenous administration of erythromycin. British journal of clinical pharmacology 10:273-9

149. Abbott. 2010. Pce (erythromycin) Tablet (Label). ed. US FDA 150. Doki K, Homma M, Kuga K, Aonuma K, Sakai S, et al. 2007. Gender-associated differences in

pharmacokinetics and anti-arrhythmic effects of flecainide in Japanese patients with supraventricular tachyarrhythmia. European journal of clinical pharmacology 63:951-7

151. Patmore L, Fraser S, Mair D, Templeton A. 2000. Effects of sparfloxacin, grepafloxacin, moxifloxacin, and ciprofloxacin on cardiac action potential duration. European journal of pharmacology 406:449-52

152. Lu HR, Vlaminckx E, Van de Water A, Rohrbacher J, Hermans A, Gallacher DJ. 2006. In-vitro experimental models for the risk assessment of antibiotic-induced QT prolongation. European journal of pharmacology 553:229-39

153. Efthymiopoulos C, Bramer SL, Maroli A. 1997. Pharmacokinetics of grepafloxacin after oral administration of single and repeat doses in healthy young males. Clin Pharmacokinet 33 Suppl 1:1-8

154. Bassi PU, Onyeji CO, Ukponmwan OE. 2004. Effects of tetracycline on the pharmacokinetics of halofantrine in healthy volunteers. British journal of clinical pharmacology 58:52-5

155. SmithKline. 2002. Prescribing Information (Halfan). ed. US FDA 156. Cenni B, Meyer J, Brandt R, Betschart B. 1995. The antimalarial drug halofantrine is bound

mainly to low and high density lipoproteins in human serum. British journal of clinical pharmacology 39:519–26

157. Borsini F, Crumb W, Pace S, Ubben D, Wible B, et al. 2012. In vitro cardiovascular effects of dihydroartemisin-piperaquine combination compared with other antimalarials. Antimicrobial agents and chemotherapy 56:3261-70

158. Fryer RM. 2012. Mathematical Derivation of Therapeutic Index Based on hERG IC50 Taking Into Account Fraction Unbound in Plasma and Clinical Cmax. Therapeutic Innovation & Regulatory Science 46:519-20

159. Patteet L, Morrens M, Maudens KE, Niemegeers P, Sabbe B, Neels H. 2012. Therapeutic drug monitoring of common antipsychotics. Therapeutic drug monitoring 34:629-51

160. Kowey PR, VanderLugt JT, Luderer JR. 1996. Safety and risk/benefit analysis of ibutilide for acute conversion of atrial fibrillation/flutter. The American journal of cardiology 78:46-52

161. Tian L, Li Y, Huang Y, Kuang F, Li F, Hua L. 2005. Sensitive method for the determination of ibutilide in human plasma by liquid chromatography-tandem mass spectrometry. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 816:81-5

162. Tisdale JE, Overholser BR, Sowinski KM, Wroblewski HA, Amankwa K, et al. 2008. Pharmacokinetics of ibutilide in patients with heart failure due to left ventricular systolic dysfunction. Pharmacotherapy 28:1461-70

163. Murray KT. 1998. Ibutilide. Circulation 97:493-7 164. Li Y, Tian L, Huang Y, Hua L. 2007. Pharmacokinetic and pharmacodynamic properties of a single

intravenous dose of ibutilide fumarate: a phase I, randomized, open-label, increasing-dose study in healthy Chinese men. Clinical therapeutics 29:1957-66

165. Rogóz Z, Skuza G, Daniel WA, Wójcikowski J, Dudek D, A W. 2007. Amantadine as an additive treatment in patients suffering from drug-resistant unipolar depression. Pharmacol Rep 59:778-84

166. Ciraulo DA, Barnhill JG, Jaffe JH. 1988. Clinical pharmacokinetics of imipramine and desipramine in alcoholics and normal volunteers. Clinical pharmacology and therapeutics 43:509-18

167. Patheon. 2012. Tofranil-PM™ (imipramine pamoate) capsules (Label). ed. US FDA

168. Storniolo AM, Pegram MD, Overmoyer B, Silverman P, Peacock NW, et al. 2008. Phase I dose escalation and pharmacokinetic study of lapatinib in combination with trastuzumab in patients with advanced ErbB2-positive breast cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 26:3317-23

169. van Erp NP, Gelderblom H, Guchelaar HJ. 2009. Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer treatment reviews 35:692-706

170. FDA. 2007. Pharmacology Review(s) (Tykerb). In Application Number 22-059, ed. CfDEa Research 171. GlaxoSmithKline. 2013. TYKERB (lapatinib) tablets (Label). ed. US FDA 172. Koch KM, Reddy NJ, Cohen RB, Lewis NL, Whitehead B, et al. 2009. Effects of food on the

relative bioavailability of lapatinib in cancer patients. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27:1191-6

173. Devriese LA, Koch KM, Mergui-Roelvink M, Matthys GM, Ma WW, et al. 2014. Effects of low-fat and high-fat meals on steady-state pharmacokinetics of lapatinib in patients with advanced solid tumours. Investigational new drugs 32:481-8

174. FDA. 2007. Pharmacology Review (Selzentry). In Application Number 22-128, ed. CfDEa Research 175. Pfizer. 2014. SELZENTRY (maraviroc) tablets (Label). ed. US FDA 176. Abel S, Back DJ, Vourvahis M. 2009. Maraviroc: pharmacokinetics and drug interactions.

Antiviral therapy 14:607-18 177. Carter NJ, Keating GM. 2007. Maraviroc. Drugs 67:2277-90 178. Bayer. 2011. AVELOX (moxifloxacin hydrochloride) Tablet, film-coated, Injection, solution for IV

use (Label). ed. US FDA 179. Balfour JA, Wiseman LR. 1999. Moxifloxacin. Drugs 57:363-74 180. Stass H, Dalhoff A, Kubitza D, Schuhly U. 1998. Pharmacokinetics, safety, and tolerability of

ascending single doses of moxifloxacin, a new 8-methoxy quinolone, administered to healthy subjects. Antimicrobial agents and chemotherapy 42:2060-5

181. FDA. 2007. Pharmacology Review (Tasigna). In Application Number 22-068, ed. CfDEa Research 182. FDA. 2007. Clinical Pharmacology and Biopharmaceutics Review(s) (Tasigna). In Application

Number 22-068, ed. CfDEa Research 183. Novartis. 2014. TASIGNA® (nilotinib) Capsules (Label). ed. US FDA 184. Plosker GL, DM R. 2008. Nilotinib. Drugs 68:449-59 185. Garnock-Jones KP. 2011. Nilotinib: in the first-line treatment of newly diagnosed Philadelphia

chromosome-positive chronic myeloid leukaemia in chronic phase. Drugs 71:1579-90 186. Janssen. 2011. INVEGA® (paliperidone) Extended-Release Tablets (Label). ed. US FDA 187. Vermeir M, Naessens I, Remmerie B, Mannens G, Hendrickx J, et al. 2008. Absorption,

metabolism, and excretion of paliperidone, a new monoaminergic antagonist, in humans. Drug metabolism and disposition: the biological fate of chemicals 36:769-79

188. Hough D, Lindenmayer JP, Gopal S, Melkote R, Lim P, et al. 2009. Safety and tolerability of deltoid and gluteal injections of paliperidone palmitate in schizophrenia. Progress in neuro-psychopharmacology & biological psychiatry 33:1022-31

189. Poola NR, Kalis M, Plakogiannis FM, Taft DR. 2003. Characterization of pentamidine excretion in the isolated perfused rat kidney. The Journal of antimicrobial chemotherapy 52:397-404

190. APP. 2010. NebuPent (pentamidine isethionate) (Label). ed. FDA 191. Sallee FR, Pollock BG, Stiller RL, Stull S, Everett G, Perel JM. 1987. Pharmacokinetics of pimozide

in adults and children with Tourette's syndrome. Journal of clinical pharmacology 27:776-81 192. Gao H, Yao L, Mathieu HW, Zhang Y, Maurer TS, et al. 2008. In silico modeling of nonspecific

binding to human liver microsomes. Drug metabolism and disposition: the biological fate of chemicals 36:2130-5

193. McCreadie RG, Mackie M, Wiles DH, Jorgensen A, Hansen V, Menzies C. 1984. Within-individual variation in steady state plasma levels of different neuroleptics and prolactin. The British Journal of Psychiatry 144:625-9

194. Desta Z, Kerbusch T, Flockhart DA. 1999. Effect of clarithromycin on the pharmacokinetics and pharmacodynamics of pimozide in healthy poor and extensive metabolizers of cytochrome P450 2D6 (CYP2D6). Clinical pharmacology and therapeutics 65:10-20

195. Koch-Weser J, Klein SW. 1971. Procainamide dosage schedules, plasma concentrations, and clinical effects. JAMA 215:1454-60

196. J K-W. 1971. Pharmacokinetic of procainamide in man. Ann N Y Acad Sci 179:370-82 197. Karlsson E. 1975. Procainamide and phenytoin. Comparative study of their antiarrhythmic

effects at apparent therapeutic plasma levels. British Heart journal 37:731-40 198. Myerburg RJ, Kessler KM, Kiem I, Pefkaros KC, Conde CA, et al. 1981. Relationship between

plasma levels of procainamide, suppression of premature ventricular complexes and prevention of recurrent ventricular tachycardia. Circulation 64:280-90

199. Benton RE, Sale M, Flockhart DA, Woosley RL. 2000. Greater quinidine-induced QTc interval prolongation in women. Clinical pharmacology and therapeutics 67:413-8

200. Olatunde A, Price Evans DA. 1982. Blood quinidine levels and cardiac effects in white British and Nigerian subjects. British journal of clinical pharmacology 14:513-8

201. CVTherapeutics. 2008. Ranexa (ranolazine) extended-release tablets (Label). ed. US FDA 202. Garnett CE, Beasley N, Bhattaram VA, Jadhav PR, Madabushi R, et al. 2008. Concentration-QT

relationships play a key role in the evaluation of proarrhythmic risk during regulatory review. Journal of clinical pharmacology 48:13-8

203. Tan QY, Li HD, Zhu RH, Zhang QZ, Zhang J, Peng WX. 2013. Tolerability and pharmacokinetics of ranolazine following single and multiple sustained-release doses in Chinese healthy adult volunteers: a randomized, open-label, Latin square design, phase I study. American journal of cardiovascular drugs : drugs, devices, and other interventions 13:17-25

204. M J. 2006. Clinical pharmacokinetics of ranolazine. Clin Pharmacokinet 45:469-91 205. Wong W, Pavlou HN, Birgersdotter UM, Hilleman DE, Mohiuddin SM, Roden DM. 1992.

Pharmacology of the class III antiarrhythmic agent sematilide in patients with arrhythmias. The American journal of cardiology 69:206-12

206. Hinderling PH, Dilea C, Koziol T, Millington G. 1993. Comparative kinetics of sematilide in four species. Drug metabolism and disposition: the biological fate of chemicals 21:662-9

207. Anttila M, Arstila M, Pfeffer M, Tikkanen R, Vallinkoski V, Sundquist H. 1976. Human pharmacokinetics of sotalol. Acta pharmacologica et toxicologica 39:118-28

208. Poirier JM, Jaillon P, Lecocq B, Lecocq V, Ferry A, Cheymol G. 1990. The pharmacokinetics of d-sotalol and d,l-sotalol in healthy volunteers. European journal of clinical pharmacology 38:579-82

209. Bayer. 2011. BETAPACE AF® (sotalol HCl) (Label). ed. US FDA 210. Neuvonen PJ, Elonen E, Tanskanen A, Tuomilehto J. 1982. Sotalol prolongation of the QTc

interval in hypertensive patients. Clinical pharmacology and therapeutics 32:25-32 211. Bertek. 2003. Zagam (sparfloxacin) (Label). ed. US FDA 212. Pfizer. 2011. SUTENT® (sunitinib malate) capsules, oral (Label). ed. FDA 213. Houk BE, Bello CL, Kang D, Amantea M. 2009. A population pharmacokinetic meta-analysis of

sunitinib malate (SU11248) and its primary metabolite (SU12662) in healthy volunteers and oncology patients. Clinical cancer research : an official journal of the American Association for Cancer Research 15:2497-506

214. Kim A, Balis FM, Widemann BC. 2009. Sorafenib and sunitinib. The oncologist 14:800-5

215. Bello CL, Mulay M, Huang X, Patyna S, Dinolfo M, et al. 2009. Electrocardiographic characterization of the QTc interval in patients with advanced solid tumors: pharmacokinetic- pharmacodynamic evaluation of sunitinib. Clinical cancer research : an official journal of the American Association for Cancer Research 15:7045-52

216. Lalonde RL, Lessard D, Gaudreault J. 1996. Population pharmacokinetics of terfenadine. Pharmaceutical research 13:832-8

217. Webster R, Allan G, Anto-Awuakye K, Harrison A, Kidd T, et al. 2001. Pharmacokinetic/pharmacodynamic assessment of the effects of E4031, cisapride, terfenadine and terodiline on monophasic action potential duration in dog. Xenobiotica; the fate of foreign compounds in biological systems 31:633-50

218. Awni WM, Cavanaugh JH, Leese P, Kasier J, Cao G, et al. 1997. The pharmacokinetic and pharmacodynamic interaction between zileuton and terfenadine. European journal of clinical pharmacology 52:49-54

219. Salih IS, Thanacoody RH, McKay GA, Thomas SH. 2007. Comparison of the effects of thioridazine and mesoridazine on the QT interval in healthy adults after single oral doses. Clinical pharmacology and therapeutics 82:548-54

220. Kongsamut S, Kang J, Chen XL, Roehr J, Rampe D. 2002. A comparison of the receptor binding and HERG channel affinities for a series of antipsychotic drugs. European journal of pharmacology 450:37-41

221. Thanacoody RH, Daly AK, Reilly JG, Ferrier IN, Thomas SH. 2007. Factors affecting drug concentrations and QT interval during thioridazine therapy. Clinical pharmacology and therapeutics 82:555-65

222. FDA. 2004. Approval Package (Detrol 1 and 2 mg). In Application Number 20-771/S-011, ed. CfDEa Research

223. Malhotra BK, Glue P, Sweeney K, Anziano R, Mancuso J, Wicker P. 2007. Thorough QT study with recommended and supratherapeutic doses of tolterodine. Clinical pharmacology and therapeutics 81:377-85

224. FDA. 1998. Clinical Pharmacology and Biopharmaceutics Review(s) (Detrol). In Application Number NDA 20-771, ed. CfDEa Research

225. Pfizer. 2008. Geodon (ziprasidone HCl) Capsules. (Label). ed. US FDA 226. Miceli JJ, Tensfeldt TG, Shiovitz T, Anziano RJ, O'Gorman C, Harrigan RH. 2010. Effects of high-

dose ziprasidone and haloperidol on the QTc interval after intramuscular administration: a randomized, single-blind, parallel-group study in patients with schizophrenia or schizoaffective disorder. Clinical therapeutics 32:472-91

227. FDA. 2001. Clinical Pharmacology and Biopharmaceutics Review (Ziprasidone). In Application Number 20-825, ed. CfDEa Research

228. Lacerda AE, Kuryshev YA, Chen Y, Renganathan M, Eng H, et al. 2008. Alfuzosin delays cardiac repolarization by a novel mechanism. The Journal of pharmacology and experimental therapeutics 324:427-33

229. Baxter. 2011. NEXTERONE (amiodarone HCl) Injection (Label). ed. U FDA 230. Iribarren C, Round AD, Peng JA, Lu M, Zaroff JG, et al. 2013. Validation of a population-based

method to assess drug-induced alterations in the QT interval: a self-controlled crossover study. Pharmacoepidemiology and drug safety 22:1222-32

231. Singh BN, Wadhani N. 2004. Antiarrhythmic and proarrhythmic properties of QT-prolonging antianginal drugs. J Cardiovasc Pharmacol Ther 9 Suppl 1:S85-97

232. Hohnloser SH, Klingenheben T, Singh BN. 1994. Amiodarone-associated proarrhythmic effects. A review with special reference to torsade de pointes tachycardia. Annals of internal medicine 121:529-35

233. Darpö B. 2001. Spectrum of drugs prolonging QT interval and the incidence of torsades de pointes. Eur Heart J Suppl 3:K70-K80

234. Woosley RL. 1996. Cardiac actions of antihistamines. Annual review of pharmacology and toxicology 36:233-52

235. Castro V, Clements C, Murphy S, Gainer V, Fava M, et al. 2013. QT interval and antidepressant use: a cross sectional study of electronic health records. BMJ 346:F288

236. Kerr GW, McGuffie AC, Wilkie S. 2001. Tricyclic antidepressant overdose: a review. Emergency medicine journal : EMJ 18:236-41

237. da Cunha RJ, Barrucand L, Verçosa N. 2009. A study on electrocardiographic changes secondary to the use of tricyclic antidepressants in patients with chronic pain. Rev Bras Anestesiol 59:46-55

238. Ray WA, Meredith S, Thapa PB, Hall K, Murray KT. 2004. Cyclic antidepressants and the risk of sudden cardiac death. Clinical pharmacology and therapeutics 75:234-41

239. Yamazaki K, Terada H, Satoh H, Naito K, Takeshita A, et al. 2006. Arrhythmogenic effects of arsenic trioxide in patients with acute promyelocytic leukemia and an electrophysiological study in isolated guinea pig papillary muscles. Circulation journal : official journal of the Japanese Circulation Society 70:1407-14

240. Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, et al. 2001. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 19:3852-60

241. Fox E, Razzouk BI, Widemann BC, Xiao S, O'Brien M, et al. 2008. Phase 1 trial and pharmacokinetic study of arsenic trioxide in children and adolescents with refractory or relapsed acute leukemia, including acute promyelocytic leukemia or lymphoma. Blood 111:566-73

242. Barbey JT, Pezzullo JC, Soignet SL. 2003. Effect of arsenic trioxide on QT interval in patients with advanced malignancies. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 21:3609-15

243. Huang SM, Lesko LJ. 2004. Drug-drug, drug-dietary supplement, and drug-citrus fruit and other food interactions: what have we learned? Journal of clinical pharmacology 44:559-69

244. Lindquist M, Edwards IR. 1997. Risks of non-sedating antihistamines. The Lancet 349:1322 245. Lecocq B, Lecocq V, Prost P, Fleurot O, Boisson P, Jaillon P. 1990. Effects of bepridil and CERM

4205 (ORG 30701) on the relation between cardiac cycle length and QT duration in healthy volunteers. The American journal of cardiology 66:636-41

246. Schmitt C, Brachmann J, Holzel C, Waldecker B, Schols W, et al. 1990. Electrophysiologic effects of bepridil in patients with refractory ventricular tachycardia assessed by programmed electrical stimulation. Clinical cardiology 13:864-8

247. Hill JA, Pepine CJ. 1984. Effects of bepridil on the resting electrocardiogram. International journal of cardiology 6:319-23

248. Huston JR, Bell GE. 1966. The effect of thioridazine hydrochloride and chlorpromazine on the electrocardiogram. JAMA 198:134-8

249. Murakawa Y, Yamashita T, Ajiki K, Sezaki K, Omata M. 1998. Ostensible day-night difference of QT prolongation during long-term treatment with antiarrhythmic drugs: Reappraisal of the law of "regression to the mean". J Cardiovasc Pharm 32:62-5

250. FDA. 2011. FDA Gastrointestinal Diseases Advisory Committee Briefing Document: Evaluation of cardiac safety and serotonin receptor (5HT4) agonists. ed. CfDEa Research

251. Pratt CM, Hertz RP, Ellis BE, Crowell SP, Louv W, Moye L. 1994. Risk of developing life-threatening ventricular arrhythmia associated with tefenadine in comparison with over-the-counter antihistamines, ibuprofen and clemastine. The American journal of cardiology 73:346-52

252. Johnson FM, Agrawal S, Burris H, Rosen L, Dhillon N, et al. 2010. Phase 1 pharmacokinetic and drug-interaction study of dasatinib in patients with advanced solid tumors. Cancer 116:1582-91

253. Bristol-MyersSquibb. 2011. SPRYCEL® (dasatinib) Tablet for Oral Use (Label). ed. US FDA: Bristol-MyersSquibb

254. Veith RC, Bloom V, Bielski R, Friedel RO. 1982. ECG effects of comparable plasma concentrations of desipramine and amitriptyline. Journal of clinical psychopharmacology 2:394-8

255. Johnson A, Giuffre RM, O'Malley K. 1996. ECG changes in pediatric patients on tricyclic antidepressants, desipramine, and imipramine. Canadian journal of psychiatry. Revue canadienne de psychiatrie 41:102-6

256. Zareba W, Moss AJ, Rosero SZ, Hajj-Ali R, Konecki J, Andrews M. 1997. Electrocardiographic findings in patients with diphenhydramine overdose. The American journal of cardiology 80:1168-73

257. Tariot P, Salloway S, Yardley J, Mackell J, Moline M. 2012. Long-term safety and tolerability of donepezil 23 mg in patients with moderate to severe Alzheimer's disease. BMC Res Notes 8:283

258. Howes L. 2014. Cardiovascular effects of drugs used to treat Alzheimer's disease. Drug Saf 37:391-5

259. Charbit B, Alvarez JC, Dasque E, Abe E, Demolis JL, Funck-Brentano C. 2008. Droperidol and ondansetron-induced QT interval prolongation: a clinical drug interaction study. Anesthesiology 109:206-12

260. Goodnick PJ, Jerry J, Parra F. 2002. Psychotropic drugs and the ECG: focus on the QTc interval. Expert opinion on pharmacotherapy 3:479-98

261. Stuth EA, Stucke AG, Cava JR, Hoffman GM, Berens RJ. 2004. Droperidol for perioperative sedation causes a transient prolongation of the QTc time in children under volatile anesthesia. Paediatric anaesthesia 14:831-7

262. Sneyd JR. 2009. Droperidol: past, present and future. Anaesthesia 64:1161-4 263. Kao LW, Kirk MA, Evers SJ, Rosenfeld SH. 2003. Droperidol, QT prolongation, and sudden death:

what is the evidence? Annals of emergency medicine 41:546-58 264. Tschida SJ, Guay DR, Straka RJ, Hoey LL, Johanning R, Vance-Bryan K. 1996. QTc-interval

prolongation associated with slow intravenous erythromycin lactobionate infusions in critically ill patients: a prospective evaluation and review of the literature. Pharmacotherapy 16:663-74

265. Oberg K, Bauman J. 1995. QT interval prolongation and torsades de pointes due to erythromycin lactobionate. Pharmacotherapy 15:687-92

266. Vuppalanchi R, Juluri R, Ghabril M, Kim S, Thong N, et al. 2011. Drug-induced QT prolongation in cirrhotic patients with transjugular intrahepatic portosystemic shunt. Journal of clinical gastroenterology 45:638-42

267. Drici MD, Knollmann BC, Wang WX, Woosley RL. 1998. Cardiac actions of erythromycin: influence of female sex. JAMA 280:1774-6

268. Anderson JL, Lutz JR, Allison SB. 1983. Electrophysiologic and antiarrhythmic effects of oral flecainide in patients with inducible ventricular tachycardia. J Am Coll Cardiol 2:105-14

269. Duff HJ, Roden DM, Maffucci RJ, Vesper BS, Conard GJ, et al. 1981. Suppression of resistant ventricular arrhythmias by twice daily dosing with flecainide. The American journal of cardiology 48:1133-40

270. Nathan AW, Hellestrand KJ, Bexton RS, Banim SO, Spurrell RA, Camm AJ. 1984. Proarrhythmic effects of the new antiarrhythmic agent flecainide acetate. American heart journal 107:222-8

271. Lim KS, Jang IJ, Kim BH, Kim J, Jeon JY, et al. 2010. Changes in the QTc interval after administration of flecainide acetate, with and without coadministered paroxetine, in relation to cytochrome P450 2D6 genotype: data from an open-label, two-period, single-sequence crossover study in healthy Korean male subjects. Clinical therapeutics 32:659-66

272. Nathan AW, Hellestrand KJ, Bexton RS, Spurrell RA, Camm AJ. 1985. The proarrhythmic effects of flecainide. Drugs 29 Suppl 4:45-53

273. Estes NA, 3rd, Garan H, Ruskin JN. 1984. Electrophysiologic properties of flecainide acetate. The American journal of cardiology 53:26B-9B

274. Aliot E, Capucci A, Crijns H, Goette A, Tamargo J. 2011. Twenty-five years in the making: flecainide is safe and effective for the management of atrial fibrillation. Europace 13:161-73

275. Lipsky BA, Baker CA. 1999. Fluoroquinolone toxicity profiles: a review focusing on newer agents. Clin Infect Dis 28:352-64

276. Stahlmann R, Schwabe R. 1997. Safety profile of grepafloxacin compared with other fluoroquinolones. The Journal of antimicrobial chemotherapy 40 Suppl A:83-92

277. Bindschedler M, Lefevre G, Degen P, Sioufi A. 2002. Comparison of the cardiac effects of the antimalarials co-artemether and halofantrine in healthy participants. The American journal of tropical medicine and hygiene 66:293-8

278. Nosten F, ter Kuile FO, Luxemburger C, Woodrow C, Kyle DE, et al. 1993. Cardiac effects of antimalarial treatment with halofantrine. Lancet 341:1054-6

279. Monlun E, Le Metayer P, Szwandt S, Neau D, Longy-Boursier M, et al. 1995. Cardiac complications of halofantrine: a prospective study of 20 patients. Transactions of the Royal Society of Tropical Medicine and Hygiene 89:430-3

280. Wesche DL, Schuster BG, Wang WX, Woosley RL. 2000. Mechanism of cardiotoxicity of halofantrine. Clinical pharmacology and therapeutics 67:521-9

281. Desai M, Tanus-Santos JE, Li L, Gorski JC, Arefayene M, et al. 2003. Pharmacokinetics and QT interval pharmacodynamics of oral haloperidol in poor and extensive metabolizers of CYP2D6. The pharmacogenomics journal 3:105-13

282. Blom M, Bardai A, van Munster B, Nieuwland M, de Jong H, et al. 2011. Differential changes in QTc duration during in-hospital haloperidol use. PLoS ONE 6:e23728

283. Hennessy S, Bilker W, Knauss J, Margolis D, Kimmel S, et al. 2002. Cardiac arrest and ventricular arrhythmia in patients taking antipsychotic drugs: cohort study using administrative data. BMJ 325:1070

284. Indik J, Pearson E, Fried K, Woosley RL. 2006. Bazett and Fridericia QT correction formulas interfere with measurement of drug-induced changes in QT interval. Heart rhythm : the official journal of the Heart Rhythm Society 3:1003-7

285. Dogan E, Yorgun H, Petekkaya I, Ozer N, Altundag K, Ozisik Y. 2012. Evaluation of cardiac safety of lapatinib therapy for ErbB2-positive metastatic breast cancer: a single center experience. Medical oncology 29:3232-9

286. Shah R. 2013. Drug-induced QT interval prolongation: does ethnicity of the thorough QT study population matter? British journal of clinical pharmacology 75:347-58

287. Noel GJ, Natarajan J, Chien S, Hunt TL, Goodman DB, Abels R. 2003. Effects of three fluoroquinolones on QT interval in healthy adults after single doses. Clinical pharmacology and therapeutics 73:292-303

288. Florian JA, Tornoe CW, Brundage R, Parekh A, Garnett CE. 2011. Population pharmacokinetic and concentration--QTc models for moxifloxacin: pooled analysis of 20 thorough QT studies. Journal of clinical pharmacology 51:1152-62

289. Hough DW, Natarajan J, Vandebosch A, Rossenu S, Kramer M, Eerdekens M. 2011. Evaluation of the effect of paliperidone extended release and quetiapine on corrected QT intervals: a randomized, double-blind, placebo-controlled study. International clinical psychopharmacology 26:25-34

290. Davis JD, Hackman F, Layton G, Higgins T, Sudworth D, Weissgerber G. 2008. Effect of single doses of maraviroc on the QT/QTc interval in healthy subjects. British journal of clinical pharmacology 65 Suppl 1:68-75

291. Kantarjian H, Giles F, Wunderle L, Bhalla K, O'Brien S, et al. 2006. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 354:2542-51

292. Kim TD, le Coutre P, Schwarz M, Grille P, Levitin M, et al. 2012. Clinical cardiac safety profile of nilotinib. Haematologica 97:883-9

293. Janicak PG, Winans EA. 2007. Paliperidone ER: a review of the clinical trial data. Neuropsychiatr Dis Treat 3:869-97

294. Eisenhauer MD, Eliasson AH, Taylor AJ, Coyne PE, Jr., Wortham DC. 1994. Incidence of cardiac arrhythmias during intravenous pentamidine therapy in HIV-infected patients. Chest 105:389-95

295. Stein K, Fenton C, Lehany A, Okin P, Kligfield P. 1991. Incidence of QT interval prolongation during pentamidine therapy of Pneumocystis carinii pneumoni. The American journal of cardiology 68:1091-4

296. Girgis I, Gualberti J, Langan L, Malek S, Mustaciuolo V, et al. 1997. A prospective study of the effect of I.V. pentamidine therapy on ventricular arrhythmias and QTc prolongation in HIV-infected patients. Chest 112:646-53

297. Min DI, Ku YM, Geraets DR, Lee H. 1996. Effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of quinidine in healthy volunteers. Journal of clinical pharmacology 36:469-76

298. Shin J-G, Kang W-k, Shon J-H, Arefayene M, Yoon Y-R, et al. 2007. Possible interethnic differences in quinidine-induced QT prolongation between healthy Caucasian and Korean subjects. British journal of clinical pharmacology 63:206-15

299. FDA. 2010. Clinical Pharmacology and Biopharmaceutics Review(s). In Application Number 021879Orig1s000, ed. CfDEa Research

300. Jerling M. 2006. Clinical pharmacokinetics of ranolazine. Clin Pharmacokinet 45:469-91 301. FDA. 2006. Medical Review(s) (ranolazine). In Application Number NDA 21-526, ed. CfDEa

Research 302. Watanabe J, Suzuki Y, Fukui N, Ono S, Sugai T, et al. 2012. Increased risk of antipsychotic-related

QT prolongation during nighttime: a 24-hour holter electrocardiogram recording study. Journal of clinical psychopharmacology 32:18-22

303. Janssen. 2009. RISPERDAL® (Label). ed. FDA 304. Stambler B, Gottlieb S, Singh B, Ramanathan K, Ogilby J, Ellenbogen K. 1995. Hemodynamic

effects of intravenous sematilide in patients with congestive heart failure: a class III antiarrhythmic agent without cardiodepressant effects. J Am Coll Cardiol 26:1679-84

305. Sager PT, Nademanee K, Antimisiaris M, Pacifico A, Pruitt C, et al. 1993. Antiarrhythmic effects of selective prolongation of refractoriness. Electrophysiologic actions of sematilide HCl in humans. Circulation 88:1072-82

306. Atmaca M, Yavuzkir M, Mermi O, Topuz M, Kanmaz E, Tezcan E. 2008. Effect of sertindole on QTc interval in patients with schizophrenia. Neurosci Lett 442:1-3

307. Karamatskos E, Lambert M, Mulert C, Naber D. 2012. Drug safety and efficacy evaluation of sertindole for schizophrenia. Expert Opin Drug Saf 11:1047-62

308. Wang T, Bergstrand RH, Thompson KA, Siddoway LA, Duff HJ, et al. 1986. Concentration-dependent pharmacologic properties of sotalol. The American journal of cardiology 57:1160-5

309. Senges J, Lengfelder W, Jauernig R, Czygan E, Brachmann J, et al. 1984. Electrophysiologic testing in assessment of therapy with sotalol for sustained ventricular tachycardia. Circulation 69:577-84

310. Demolis JL, Charransol A, Funck-Brentano C, Jaillon P. 1996. Effects of a single oral dose of sparfloxacin on ventricular repolarization in healthy volunteers. British journal of clinical pharmacology 41:499-503

311. Lipsky BA, Dorr MB, Magner DJ, Talbot GH. 1999. Safety profile of sparfloxacin, a new fluoroquinolone antibiotic. Clinical therapeutics 21:148-59

312. Jaillon P, Morganroth J, Brumpt I, Talbot G. 1996. Overview of electrocardiographic and cardiovascular safety data for sparfloxacin. Sparfloxacin Safety Group. The Journal of antimicrobial chemotherapy 37 Suppl A:161-7

313. Martin D, Zussman B, Everitt D, Benincosa L, Etheredge R, Jorkasky D. 1997. Paroxetine does not affect the cardiac safety and pharmacokinetics of terfenadine in healthy adult men. Journal of clinical psychopharmacology 17:451-9

314. Honig PK, Wortham DC, Zamani K, Conner DP, Mullin JC, Cantilena LR. 1993. Terfenadine-ketoconazole interaction. Pharmacokinetic and electrocardiographic consequences. JAMA 269:1513-8

315. Harrigan EP, Miceli JJ, Anziano R, Watsky E, Reeves KR, et al. 2004. A randomized evaluation of the effects of six antipsychotic agents on QTc, in the absence and presence of metabolic inhibition. Journal of clinical psychopharmacology 24:62-9

316. Hartigan-Go K, Bateman DN, Nyberg G, Martensson E, Thomas SH. 1996. Concentration-related pharmacodynamic effects of thioridazine and its metabolites in humans. Clinical pharmacology and therapeutics 60:543-53

317. Pfizer. 2012. Detrol® (tolterodine) tolterodine tartrate tablets (Label). ed. US FDA 318. Potkin SG, Preskorn S, Hochfeld M, Meng X. 2013. A thorough QTc study of 3 doses of

iloperidone including metabolic inhibition via CYP2D6 and/or CYP3A4 and a comparison to quetiapine and ziprasidone. Journal of clinical psychopharmacology 33:3-10

319. FDA. 2001. Medical Review (Ziprasidone). In Application Number 20-825, ed. CfDEa Research 320. Hardy ME, Pollard CE, Small BG, Bridgland-Taylor M, Woods AJ, et al. 2009. Validation of a

voltage-sensitive dye (di-4-ANEPPS)-based method for assessing drug-induced delayed repolarisation in beagle dog left ventricular midmyocardial myocytes. Journal of pharmacological and toxicological methods 60:94-106

321. Yoshida H, Sugiyama A, Satoh Y, Ishida Y, Yoneyama M, et al. 2002. Comparison of the in vivo electrophysiological and proarrhythmic effects of amiodarone with those of a selective class III drug, sematilide, using a canine chronic atrioventricular block model. Circulation journal : official journal of the Japanese Circulation Society 66:758-62

322. Aubert M, Osterwalder R, Wagner B, Parrilla I, Cavero I, et al. 2006. Evaluation of the rabbit Purkinje fibre assay as an in vitro tool for assessing the risk of drug-induced torsades de pointes in humans. Drug Saf 29:237-54

323. Nattel S, Keable H, Sasyniuk BI. 1984. Experimental amitriptyline intoxication: electrophysiologic manifestations and management. J Cardiovasc Pharmacol 6:83-9

324. Ansel GM, Coyne K, Arnold S, Nelson SD. 1993. Mechanisms of ventricular arrhythmia during amitriptyline toxicity. J Cardiovasc Pharmacol 22:798-803

325. Lu HR, Vlaminckx E, Cools F, Gallacher DJ. 2012. Direct effects of arsenic trioxide on action potentials in isolated cardiac tissues: importance of the choice of species, type of cardiac tissue and perfusion time. Journal of pharmacological and toxicological methods 66:135-44

326. Yamamoto K, Tamura T, Imai R, Yamamoto M. 2001. Acute canine model for drug-induced Torsades de Pointes in drug safety evaluation-influences of anesthesia and validation with quinidine and astemizole. Toxicol Sci 60:165-76

327. Toyoshima S, Kanno A, Kitayama T, Sekiya K, Nakai K, et al. 2005. QT PRODACT: In Vivo QT Assay in the Conscious Dog for Assessing the Potential for QT Interval Prolongation by Human Pharmaceuticals. Journal of Pharmacological Sciences 99:459-71

328. Salata JJ, Jurkiewicz NK, Wallace AA, Stupienski RF, 3rd, Guinosso PJ, Jr., Lynch JJ, Jr. 1995. Cardiac electrophysiological actions of the histamine H1-receptor antagonists astemizole and terfenadine compared with chlorpheniramine and pyrilamine. Circulation research 76:110-9

329. Said T, Wilson L, Jeyaraj D, Fossa A, DS R. 2012. Transmural dispersion of repolarization as a preclinical marker of drug-induced proarrhythmia. J Cardiovasc Pharmacol 60:165-71

330. Wang WX, Ebert SN, Liu XK, Chen YW, Drici MD, Woosley RL. 1998. "Conventional" antihistamines slow cardiac repolarization in isolated perfused (Langendorff) feline hearts. J Cardiovasc Pharmacol 32:123-8

331. Fossa AA, DePasquale MJ, Raunig DL, Avery MJ, Leishman DJ. 2002. The relationship of clinical QT prolongation to outcome in the conscious dog using a beat-to-beat QT-RR interval assessment. The Journal of pharmacology and experimental therapeutics 302:828-33

332. Chen X, Cordes JS, Bradley JA, Sun Z, Zhou J. 2006. Use of arterially perfused rabbit ventricular wedge in predicting arrhythmogenic potentials of drugs. Journal of pharmacological and toxicological methods 54:261-72

333. Ki I, Inui A, Ito T. 1996. Effects of histamine H1 receptor antagonists on action potentials in guinea-pig isolated papillary muscles. Archives internationales de pharmacodynamie et de therapie 331:59-73

334. Lu HR, Vlaminckx E, Teisman A, Gallacher DJ. 2005. Choice of cardiac tissue plays an important role in the evaluation of drug-induced prolongation of the QT interval in vitro in rabbit. Journal of pharmacological and toxicological methods 52:90-105

335. Gwilt M, Arrowsmith J, Blackburn K, Burges R, Cross P, et al. 1991. UK-68,798: a novel, potent and highly selective class III antiarrhythmic agent which blocks potassium channels in cardiac cells. The Journal of pharmacology and experimental therapeutics 256:318-24

336. Vormberge T, Hoffmann M, Himmel H. 2006. Safety pharmacology assessment of drug-induced QT-prolongation in dogs with reduced repolarization reserve. Journal of pharmacological and toxicological methods 54:130-40

337. Drolet B, Zhang S, Deschênes D, Rail J, Nadeau S, et al. 1999. Droperidol lengthens cardiac repolarization due to block of the rapid component of the delayed rectifier potassium current. J Cardiovasc Electrophysiol 10:1597-604

338. AP S, J K, H E, P F. 2010. The subtype-specific effects of droperidol on action potential duration in cellular and computational models of long QT syndrome. Anesthesia and analgesia 111:638-46

339. Adamantidis MM, Kerram P, Caron JF, Dupuis BA. 1993. Droperidol exerts dual effects on repolarization and induces early afterdepolarizations and triggered activity in rabbit Purkinje fibers. The Journal of pharmacology and experimental therapeutics 266:884-93

340. Adamantidis MM, Kerram P, Dupuis BA. 1994. In vitro electrophysiological detection of iatrogenic arrhythmogenicity. Fundam Clin Pharmacol 8:391-407

341. Antzelevitch C, Sun Z-Q, Zhang Z-Q, Yan G-X. 1996. Cellular and Ionic Mechanisms Underlying Erythromycin-Induced Long QT Intervals and Torsade de Pointes. Journal of the American College of Cardiology 28:1836-48

342. Rubart M, Pressler ML, Pride HP, Zipes DP. 1993. Electrophysiological mechanisms in a canine model of erythromycin- associated long QT syndrome. Circulation 88:1832-44

343. Chezalviel F, Weissenburger J, Ertzbischoff O, Poirier JM, Harle X, et al. 1990. Comparison of the cardiac electrophysiological effects of flecainide and hydroquinidine in anesthetized dog: concentration-response relationship. J Cardiovasc Pharmacol 15:50-6

344. Batey AJ, Lightbown ID, Lambert JP, Edwards G, Coker SJ. 1997. Comparison of the acute cardiotoxicity of the antimalarial drug halofantrine in vitro and in vivo in anaesthetized guinea-pigs. British journal of pharmacology 122:563-9

345. Drici MD, Wang WX, Liu XK, Woosley RL, Flockhart DA. 1998. Prolongation of QT interval in isolated feline hearts by antipsychotic drugs. Journal of clinical psychopharmacology 18:477-81

346. Humphrey SJ, Smith MP, Hsu CY, Walters RR. 2001. Cardiovascular effects of the R- and S-enantiomers of ibutilide in conscious beagle dogs. Methods and findings in experimental and clinical pharmacology 23:449-55

347. Naccarelli GV, Lee KS, Gibson JK, VanderLugt J. 1996. Electrophysiology and pharmacology of ibutilide. The American journal of cardiology 78:12-6

348. Lee HA, Kim EJ, Hyun SA, Park SG, Kim KS. 2010. Electrophysiological effects of the anti-cancer drug lapatinib on cardiac repolarization. Basic & clinical pharmacology & toxicology 107:614-8

349. Lu Z, Wu CY, Jiang YP, Ballou LM, Clausen C, et al. 2012. Suppression of phosphoinositide 3-kinase signaling and alteration of multiple ion currents in drug-induced long QT syndrome. Science translational medicine 4:131ra50

350. Vigneault P, Kaddar N, Bourgault S, Caillier B, Pilote S, et al. 2011. Prolongation of cardiac ventricular repolarization under paliperidone: how and how much? J Cardiovasc Pharmacol 57:690-5

351. EMA. 2007. Invega, INN-paliperidone. In Article 8(3) application, ed. EEM Agency 352. Kuryshev YA, Ficker E, Wang L, Hawryluk P, Dennis AT, et al. 2005. Pentamidine-induced long QT

syndrome and block of hERG trafficking. The Journal of pharmacology and experimental therapeutics 312:316-23

353. Cordes JS, Sun Z, Lloyd DB, Bradley JA, Opsahl AC, et al. 2005. Pentamidine reduces hERG expression to prolong the QT interval. British journal of pharmacology 145:15-23

354. Katchman AN, Koerner J, Tosaka T, Woosley RL, Ebert SN. 2006. Comparative evaluation of HERG currents and QT intervals following challenge with suspected torsadogenic and nontorsadogenic drugs. The Journal of pharmacology and experimental therapeutics 316:1098-106

355. Drolet B, Rousseau G, Daleau P, Cardinal R, Simard C, Turgeon J. 2001. Pimozide (Orap) prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current in native cardiac myocytes. J Cardiovasc Pharmacol Ther 6:255-60

356. Peng S, Lacerda AE, Kirsch GE, Brown AM, Bruening-Wright A. 2010. The action potential and comparative pharmacology of stem cell-derived human cardiomyocytes. Journal of pharmacological and toxicological methods 61:277-86

357. Antzelevitch C, Belardinelli L, Wu L, Fraser H, Zygmunt AC, et al. 2004. Electrophysiologic Properties and Antiarrhythmic Actions of a Novel Antianginal Agent. Journal of Cardiovascular Pharmacology and Therapeutics 9:S65-S83

358. Magyar J, Banyasz T, Bagi Z, Pacher P, Szentandrassy N, et al. 2002. Electrophysiological effects of risperidone in mammalian cardiac cells. Naunyn-Schmiedeberg's archives of pharmacology 366:350-6

359. Drolet B, Yang T, Daleau P, Roden DM, Turgeon J. 2003. Risperidone prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current. J Cardiovasc Pharmacol 41:934-7

360. Christ T, Wettwer E, Ravens U. 2005. Risperidone-induced action potential prolongation is attenuated by increased repolarization reserve due to concomitant block of I(Ca,L). Naunyn-Schmiedeberg's archives of pharmacology 371:393-400

361. Milberg P, Pott C, Frommeyer G, Fink M, Ruhe M, et al. 2012. Acute inhibition of the Na(+)/Ca(2+) exchanger reduces proarrhythmia in an experimental model of chronic heart failure. Heart rhythm : the official journal of the Heart Rhythm Society 9:570-8

362. Frommeyer G, Milberg P, Uphaus T, Kaiser D, Kaese S, et al. 2013. Antiarrhythmic effect of ranolazine in combination with class III drugs in an experimental whole-heart model of atrial fibrillation. Cardiovasc Ther 31:e63-71

363. Cerignoli F, Charlot D, Whittaker R, Ingermanson R, Gehalot P, et al. 2012. High throughput measurement of Ca(2)(+) dynamics for drug risk assessment in human stem cell-derived cardiomyocytes by kinetic image cytometry. Journal of pharmacological and toxicological methods 66:246-56

364. Satoh Y, Sugiyama A, Chiba K, Tamura K, Hashimoto K. 2000. QT-prolonging effects of sparfloxacin, a fluoroquinolone antibiotic, assessed in the in vivo canine model with monophasic action potential monitoring. J Cardiovasc Pharmacol 36:510-5

365. Adamantidis MM, Dumotier BM, Caron JF, Bordet R. 1998. Sparfloxacin but not levofloxacin or ofloxacin prolongs cardiac repolarization in rabbit Purkinje fibers. Fundam Clin Pharm 12:70-6

366. Hondeghem LM, Dujardin K, Hoffmann P, Dumotier B, De Clerck F. 2011. Drug-induced QTC prolongation dangerously underestimates proarrhythmic potential: lessons from terfenadine. J Cardiovasc Pharmacol 57:589-97

367. Kagstrom J, Sjogren EL, Ericson AC. 2007. Evaluation of the guinea pig monophasic action potential (MAP) assay in predicting drug-induced delay of ventricular repolarisation using 12 clinically documented drugs. Journal of pharmacological and toxicological methods 56:186-93

368. Nozaki Y, Honda Y, Tsujimoto S, Watanabe H, Kunimatsu T, Funabashi H. 2014. Availability of human induced pluripotent stem cell-derived cardiomyocytes in assessment of drug potential for QT prolongation. Toxicology and applied pharmacology 278:72-7

369. Kang J, Chen XL, Wang H, Ji J, Reynolds W, et al. 2004. Cardiac ion channel effects of tolterodine. The Journal of pharmacology and experimental therapeutics 308:935-40

370. Ducroq J, Printemps R, Le Grand M. 2005. Additive effects of ziprasidone and D,L-sotalol on the action potential in rabbit Purkinje fibres and on the hERG potassium current. Journal of pharmacological and toxicological methods 52:115-22

371. Wu L, Shryock JC, Song Y, Belardinelli L. 2006. An increase in late sodium current potentiates the proarrhythmic activities of low-risk QT-prolonging drugs in female rabbit hearts. The Journal of pharmacology and experimental therapeutics 316:718-26

372. Hancox JC, Hasnain M, Vieweg WV, Crouse EL, Baranchuk A. 2013. Azithromycin, cardiovascular risks, QTc interval prolongation, torsade de pointes, and regulatory issues: A narrative review based on the study of case reports. Ther Adv Infect Dis 1:155-65

373. Tsuboi M, Antzelevitch C. 2006. Cellular basis for electrocardiographic and arrhythmic manifestations of Andersen-Tawil syndrome (LQT7). Heart rhythm : the official journal of the Heart Rhythm Society 3:328-35

374. Tsai CT, Wu CK, Chiang FT, Tseng CD, Lee JK, et al. 2011. In-vitro recording of adult zebrafish heart electrocardiogram - a platform for pharmacological testing. Clin Chim Acta 412:1963-7

375. McKechnie K, Froese A. 2010. Ventricular tachycardia after ondansetron administration in a child with undiagnosed long QT syndrome. Can J Anaesth 57:453-7

376. Kim JG, Sung DJ, Kim HJ, Park SW, Won KJ, et al. 2016. Impaired Inactivation of L-Type Ca2+ Current as a Potential Mechanism for Variable Arrhythmogenic Liability of HERG K+ Channel Blocking Drugs. PLoS One 11:e0149198

377. Raffa RB, Burmeister JJ, Yuvasheva E, Pergolizzi JV, Jr. 2012. QTc interval prolongation by d-propoxyphene: what about other analgesics? Expert opinion on pharmacotherapy 13:1397-409

378. Nand V, Doggrell SA, Barnett CW. 1997. Effects of veratridine on the action potentials and contractility of right and left ventricles from normo- and hypertensive rats. Clin Exp Pharmacol Physiol 24:570-6

supplement supplemental table 1supplement supplemental table 1: clinical parameters of...

Documents