confirmation of the drug-drug interaction potential between...

IWCPAT 2017, Chicago

Confirmation of the Drug-drug Interaction Potential

Between Cobicistat-boosted Antiretroviral Regimens

and Hormonal Contraceptives

Sophia R. Majeed, Steve K. West, Shuping Jiang, Jessica Andrews, Savita O. Sinha,

Kah Hiing J. Ling, Moupali Das, Huyen Cao, Brian P. Kearney, Joseph M. Custodio

Gilead Sciences, Inc., Foster City, CA

Oral # 5

Disclosures

I am an employee of Gilead Sciences, Inc.

2

Background

DHHS guidelines recommend offering effective and appropriate contraceptive methods to

all HIV-infected women1

Drug-drug interactions (DDIs) between ARVs and hormonal (“oral”) contraceptives (OCs)

are well documented2-7

– OCs are extensively metabolized by CYP enzymes (including CYP3A, CYP2C9/19), UGT and

SULT

1. Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States.

http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. Accessed 6/5/17; 2. STRIBILD [package insert]. Foster City, CA: Gilead Sciences Inc; 2012;

3. German P et al. IWCPHT 2011, Abstract O_17; 4. KALETRA (lopinavir/ritonavir) [package insert]. North Chicago, IL: AbbVie Inc; 2000; 5. Younis IR, et

al. J Clin Pharm. 2016;56(5):541-547; 6. REYATAZ [package insert]. Princeton, NJ: Briston-Myers Squibb Co; 2003; 7. PREZISTA [package insert].

Titusville, NJ: Janssen; 2016.

http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf

Background

Effect of COBI on OC (norgestimate/ethinyl estradiol [EE]) evaluated previously with

EVG/COBI/FTC/TDF in healthy subjects and confirmed in HIV-infected women1,2

1. STRIBILD [package insert]. Foster City, CA: Gilead Sciences Inc; 2. German P et al. IWCPHT 2011, Abstract O_17; 3. Squires K, et al. Asia Pacific AIDS

& Co-Infections Conference 2016, poster P68; 4. Olsson B, Landgren BM. Clin Ther 2001;23 (11):1876-88.

*Compared to historical data of levonorgestrel/EE administered alone4.

Consistent with CYP3A inhibition by COBI

PK Parameter

EVG/COBI/FTC/TDF +

norgestimate/EE1

n=13

EVG/COBI/FTC/TDF +

levonorgestrel/EE3

n=20

Norelgestromin AUC𝜏 130% ↑

Cmax 110% ↑

Norgestrel AUC𝜏 110% ↑*

Cmax 60% ↑*

EE AUC𝜏 25% ↓ 20% ↑*

Cmax ↔ 10% ↑*

Background

For RTV-boosted protease inhibitors, DDIs between ATV and DRV and

OCs have been evaluated1,2

DDI with COBI-boosted ATV or DRV and OCs was not available

– Phase I DDI study conducted as a regulatory request to confirm the magnitude

and direction of a potential interaction with OCs

1. PREZISTA [package insert]. Titusville, NJ: Janssen; 2016; 2. REYATAZ [package insert]. Princeton, NJ: Briston-Myers Squibb Co; 2003.

Aim

Yaz® (DRSP/EE) is a combination oral contraceptive containing

progestational and estrogenic compounds

– Drospirenone (DRSP): 3 mg

– Ethinyl Estradiol (EE): 20 µg

Primary: to evaluate the effect of the PK enhancer COBI, plus ATV ( ATV +

COBI) or DRV (DRV + COBI) on the pharmacokinetics (PK) of DRSP/EE

Secondary: safety and tolerability of administration of ATV + COBI or DRV

+ COBI when given alone or in combination with DRSP/EE

Study Design and Methods

PK analysis:

– Plasma concentrations OCs (DRSP and EE) and ATV, DRV and COBI determined using validated LC/MS-MS assays

– Primary PK parameters (mean [%CV]) include AUC∞/last (h∙ng/mL) and Cmax (ng/mL)

– Geometric least squares mean ratio (GMR; [Test Treatment vs Reference Treatment]) and 90% confidence intervals (CI)

estimated using ANOVA; compared against lack of PK alteration bounds of 70–143%

Safety assessed throughout the study

AUC∞/last, area under plasma concentration-time curve from time 0 to ∞/last measurable concentration; Cmax, maximal concentration; CV, coefficient of

variation; LC/MS-MS, liquid chromatography tandem-mass spectrometry;

Hea

lth

y W

om

en

Phase I open-label, two cohort, fixed sequence study in healthy women

Day

Cohort 1,n=18

Cohort 2,n=18

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Intensive plasma PK over 96 h

DRV + COBI

800 + 150 mg

ATV + COBI

300 + 150 mg

Washout

Washout

Intensive plasma PK over 96 h

DRSP/

EE

DRSP/

EE

DRSP/

EE

DRSP/

EE

Results: Demographics

*All discontinuations were due to Grade 1 maculopapular rash.

DRV + COBI

n=18

ATV + COBI

n=18

Completed/enrolled, n 15/18* 14/18*

Median age, y (range) 28 (18–43) 30 (22–44)

Median body mass index, kg/m2 (range) 26 (20–30) 26 (23–30)

Mean creatinine clearance, mL/min (range) 129 (95–186) 122 (96–171)

Race, %

Black 50 39

White 50 56

Asian 0 6

Ethnicity, %

Hispanic/Latino 39 50

8

Results: Safety

All treatments were generally well tolerated

7 subjects discontinued due to Grade 1 maculopapular rash, a known AE of boosted PIs

AEs were consistent with the known safety profiles of the approved products1,2,3

1. Yaz USPI 2. EVOTAZ [package insert]. Princeton, NJ: Bristol-Myers Squibb Co; 2015. 3. PREZCOBIX [package insert]. Titusville, NJ: Janssen

Pharmaceuticals Inc; 2015. 9

Cohort 1 Cohort 2

AE by Preferred Term

DRSP/EE

n=18

DRV + COBI

n=18

DRV + COBI

+ DRSP/EE

n=15

DRSP/EE

n=18

ATV + COBI

n=18

ATV + COBI

+ DRSP/EE

n=14

Any TEAEs 4 7 0 2 16 1

Ocular icterus 0 0 0 0 5 0

Infrequent bowel movements 2 0 0 0 1 0

Nausea 0 2 0 1 0 0

Diarrhea 0 0 0 0 2 0

Hyperbilirubinemia 0 0 0 0 15 0

Headache 0 2 0 2 3 0

Presyncope 2 0 0 0 0 1

Oropharyngeal pain 0 2 0 0 0 0

Rash maculo-popular 0 3 0 0 5 0

Acne 0 0 0 0 2 0

0 2 4 4 8 7 2 9 6

1

1 0

1 0 0

0 1 2 2 4 3 6 4 8

1

1 0

1 0 0M

ea

n D

RS

P C

on

ce

ntr

ation,

ng/m

L (

±S

D)

Time, h Time, h

PK Parameter

Mean (%CV)

ATV + COBI

+ DRSP/EE [Test]

n=14

DRSP/EE

[Reference]

n=18

GMR%

(90% CI)

[Test/Reference]

PK Parameter

Mean (%CV)

ATV + COBI

+ DRSP/EE [Test]

n=14

DRSP/EE

[Reference]

n=18

GMR%

(90% CI)

[Test/Reference]

AUC∞, h∙ng/mL 1118 (38) 466 (21) 230 (200, 264) AUC∞, h∙pg/mL 296 (21) 396 (27) 78 (73, 85)

Cmax, ng/mL 33 (23) 29 (20) 112 (105, 119) Cmax, pg/mL 27 (22) 34 (24) 82 (76, 89)

Results: Effect of ATV + COBI on DRSP/EE PK

ATV + COBI increased DRSP exposure

– Attributed to inhibition of CYP3A by COBI

– Similar increase in DRSP exposures observed with CYP3A inhibitor ketoconazole1

ATV + COBI did not impact EE PK (within no-effect boundary)

1. Wiesinger, et al. Br J Clin Pharmacol. 2015;80(6):1399-410.10

DRSP EE

Me

an

EE

Co

nce

ntr

ation,

pg/m

L (

±S

D)

ATV + COBI

DRSP/EE

0 2 4 4 8 7 2 9 6

1

1 0

1 0 0

0 1 2 2 4 3 6 4 8

1

1 0

1 0 0

Results: Effect of DRV + COBI on DRSP/EE PK

DRV + COBI increased DRSP exposure; attributed to inhibition of CYP3A by COBI

DRV + COBI reduced EE exposure; decreases in EE exposures observed with DRV/ritonavir (RTV)1

– May be attributed to induction (eg, P-gp, CYP2C9)

1. PREZISTA [package insert]. Titusville, NJ: Janssen Pharmaceuticals Inc; 2006.11

DRV + COBI

DRSP/EE

PK Parameter

Mean (%CV)

DRV + COBI

+ DRSP/EE [Test]

n=15

DRSP/EE

[Reference]

n=18

GMR%

(90% CI)

[Test/Reference]

PK Parameter

Mean (%CV)

DRV + COBI

+ DRSP/EE [Test]

n=15

DRSP/EE

[Reference]

n=18

GMR%

(90% CI)

[Test/Reference]

AUC∞, h∙ng/mL 895 (24) 567 (24) 158 (147, 171) AUC∞, h∙pg/mL 308 (28) 439 (32) 70 (63, 77)

Cmax, ng/mL 36 (21) 31 (20) 115 (105, 126) Cmax, pg/mL 29 (35) 33 (36) 86 (77, 95)

Me

an

DR

SP

Con

ce

ntr

ation,

ng/m

L (

±S

D)

Time, h Time, h

DRSP EE

Me

an

EE

Co

nce

ntr

ation,

pg/m

L (

±S

D)

Conclusions

All treatments were generally well tolerated; no new safety findings

1. YAZ [package insert]. Wayne, NJ: Bayer Healthcare Pharmaceuticals Inc; 2001;

2.YASMIN [package insert]. NJ: Bayer Healthcare Pharmaceuticals Inc; 2001.12

DRSP exposure increased with ATV+COBI and

DRV+COBI

EE exposure was unchanged with ATV+COBI and

modestly decreased with DRV+COBI EE

DRSP

Yaz prescribing information recommends clinical monitoring when used

with strong CYP3A inhibitors due to potential for hyperkalemia1,2

– This recommendation remains when Yaz is administered with COBI-containing

products

Acknowledgments

We extend our thanks to the study participants and study teams. These studies were funded by Gilead

Sciences, Inc.

13

Backup

14

0 2 4 4 8 7 2 9 6

1

1 0

1 0 0

Results: Effect of ATV+COBI on DRSP PK





PK Parameter

Mean (%CV)

ATV + COBI

+ DRSP/EE [Test]

n=14

DRSP/EE

[Reference]

n=18

GMR%

(90% CI)

[Test/Reference]

AUC∞, h∙ng/mL 1118 (38) 466 (21) 230 (200, 264)

Cmax, ng/mL 33 (23) 29 (20) 112 (105, 119)

Me

an

DR

SP

Co

nce

ntr

ation

, n

g/m

L (

±S

D)

Time, h

ATV + COBI

DRSP

Results: Effect of DRV+COBI on EE PK



PK Parameter

Mean (%CV)

ATV + COBI

+ DRSP/EE [Test]

n=14

DRSP/EE

[Reference]

n=18

GMR%

(90% CI)

[Test/Reference]

AUC∞, h∙pg/mL 296 (21) 396 (27) 78 (73, 85)

Cmax, pg/mL 27 (22) 34 (24) 82 (76, 89)

Me

an

EE

Co

nce

ntr

atio

n, pg

/mL (

±S

D)

Time, h

ATV + COBI

DRSP

0 1 2 2 4 3 6 4 8

1

1 0

1 0 0

0 2 4 4 8 7 2 9 6

1

1 0

1 0 0

Results: Effect of DRV+COBI on DRSP PK



PK Parameter

Mean (%CV)

DRV + COBI

+ DRSP/EE [Test]

n=15

DRSP/EE

[Reference]

n=18

GMR%

(90% CI)

[Test/Reference]

AUC∞, h∙ng/mL 895 (24) 567 (24) 158 (147, 171)

Cmax, ng/mL 36 (21) 31 (20) 115 (105, 126)

Me

an

DR

SP

Co

nce

ntr

ation

, n

g/m

L (

±S

D)

Time, h

DRV + COBI

DRSP

0 1 2 2 4 3 6 4 8

1

1 0

1 0 0

Results: Effect of DRV+COBI on EE PK




PK Parameter

Mean (%CV)

DRV + COBI

+ DRSP/EE [Test]

n=15

DRSP/EE

[Reference]

n=18

GMR%

(90% CI)

[Test/Reference]

AUC∞, h∙pg/mL 308 (28) 439 (32) 70 (63, 77)

Cmax, pg/mL 29 (35) 33 (36) 86 (77, 95)

Me

an

EE

Co

nce

ntr

atio

n, pg

/mL (

±S

D)

Time, h

DRV + COBI

EE

Study Design and MethodsStudy 2

A PK substudy was done in the WAVES open label extension phase to evaluate the effect of

EVG/COBI/FTC/TDF on the PK of commonly used OCs1,2

Plasma concentrations determined using validated LC/MS/MS assays

Primary PK parameters (mean [%CV]) include AUC𝜏/last (h∙ng/mL) and Cmax (ng/mL)

Norgestrel (NG) and EE exposures compared to historical data

1. STRIBILD [package insert]. Foster City, CA: Gilead Sciences Inc; 2012. 2. Squires K, et al. Asia Pacific AIDS & Co-Infections Conference 2016, poster

P68.19

Intensive Plasma PK over 96 h

*levonorgestrel/EE; n=20, norgestimate/EE; n=1, drospirenone/EE; n=4

EVG/COBI/FTC/TDF (150/150/200/300 mg) po qd

Day 1 4 5 6 732

OC

Regimen*

HIV-infected, treatment-

naive women

N=25

0 2 4 4 8 7 2 9 6

1

1 0

1 0 0

0 2 4 4 8 7 2 9 6

1

1 0

1 0 0

Results: Effect of DRV+COBI and ATV+COBI on

DRSP PK






DRSP

DRV+COBI

ARV+COBI

PK Parameter

Mean (%CV)

DRV + COBI

+ DRSP/EE [Test]

n=15

DRSP/EE

[Reference]

n=18

GMR%

(90% CI)

[Test/Reference]

ATV + COBI

+ DRSP/EE [Test]

n=14

DRSP/EE

[Reference]

n=18

GMR%

(90% CI)

[Test/Reference]

AUC∞, h∙ng/mL 895 (24) 567 (24) 158 (147, 171) 1118 (38) 466 (21) 230 (200, 264)

Cmax, ng/mL 36 (21) 31 (20) 115 (105, 126) 33 (23) 29 (20) 112 (105, 119)

Me

an

DR

SP

Con

ce

ntr

ation,

ng/m

L (

±S

D)

Time, h Time, h

0 1 2 2 4 3 6 4 8

1

1 0

1 0 0

0 1 2 2 4 3 6 4 8

1

1 0

1 0 0

PK Parameter

Mean (%CV)

DRV + COBI

+ DRSP/EE [Test]

n=15

DRSP/EE

[Reference]

n=18

GMR%

(90% CI)

[Test/Reference]

ATV + COBI

+ DRSP/EE [Test]

n=14

DRSP/EE

[Reference]

n=18

GMR%

(90% CI)

[Test/Reference]

AUC∞, h∙pg/mL 308 (28) 439 (32) 70 (63, 77) 296 (21) 396 (27) 78 (73, 85)

Cmax, pg/mL 29 (35) 33 (36) 86 (77, 95) 27 (22) 34 (24) 82 (76, 89)

Results: Effect of DRV+COBI and ATV+COBI on

EE PK





EE

DRV+COBI

ARV+COBI

Me

an

EE

Co

nce

ntr

ation

,

pg/m

L (

±S

D)

Time, h Time, h

D R S P E E

0

1 0 0

2 0 0

3 0 0

D R S P E E

0

1 0 0

2 0 0

3 0 0

Results: Effect of DRV + COBI and ATV + COBI on DRSP/EE

PK



– May be attributed to induction of non-CYP3A pathways (ie, P-gp, CYP2C9)






DRV + COBI

DRSP/EE

GM

R%

(9

0%

CI)

AUClast

Cmax

ATV + COBI

DRSP/EE

143

70

143

70

AUC∞

confirmation of the drug-drug interaction potential between...

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