Table 1 Summary of the Pharmacokinetic Parameters of Warfarin in PlasmaPharmacokinetic Parameter
Warfarin Alone (n=25)
Warfarin + Epanova (n=25)
(R)-warfarin AUC0-t (ng hr/mL) 101000 (19.0) 105000 (20.5)
000 (2 ) 9000 (22 8)AUC0-∞ (ng hr/mL) 115000 (21.1) 119000 (22.8) Cmax (ng/mL) 2240 (22.7) 2050 (21.7)tmax (hr) 0.999 (0.499, 5.00) 1.00 (0.494, 5.00) t½ (hr) 55.0 (19.6) 55.1 (17.7) (S)-warfarin AUC0-t (ng hr/mL) 62800 (28.7) 64800 (31.1) AUC0-∞ (ng hr/mL) 66100 (32.1) 68300 (34.7) Cmax (ng/mL) 2300 (23.4) 2080 (23.5) tmax (hr) 0.999 (0.499, 2.01) 0.999 (0.494, 5.00) t½ (hr) 42.1 (20.1) 42.6 (23.0) AUC0-t, AUC0-∞, and Cmax are presented as Geometric Mean (Geometric CV%). tmax is presented as Median (Minimum, Maximum). t½ is presented as Arithmetic Mean (Arithmetic CV%). ½ p ( )
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Table 2 Summary of the Pharmacodynamic Parameters of WarfarinPharmacodynamic Parameter
Warfarin Alone (n=26)
Warfarin + Epanova™ (n=25)
INR AUC0-168 247 (20.2) 225 (14.6) INRmax 2.14 (31.5) 1.77 (23.2) INR AUC0-168 and INRmax are presented as Geometric Mean (Geometric CV%).
Table 3 Summary of the Statistical Comparisons of the Pharmacokinetic Parameters of Plasma Warfarin
Pharmacokinetic Parameter
Geometric Least-Squares Means Geometric Mean Ratio 90% Confidence Interval Warfarin + Epanova™ Warfarin Alone
(R)-warfarin AUC0-t (ng hr/mL) 104659.28 • 101257.14 103.36 100.81 - 105.97 AUC0-∞ (ng hr/mL) 119006.62 114785.21 103.68 100.61 - 106.84 Cmax (ng/mL) 2052.48 2240.29 91.62 87.44 - 96.00 (S)-warfarin
Table 4 Summary of the Statistical Comparisons of the Pharmacodynamic Parameters of Warfarin
(S) warfarin AUC0-t (ng hr/mL) 64810.54 62845.55 103.13 100.32 - 106.01 AUC0-∞ (ng hr/mL) 68346.95 66141.98 103.33 100.27 - 106.49 Cmax (ng/mL) 2081.49 2302.04 90.42 85.28 - 95.86
Pharmacodynamic Parameter
Geometric Least-Squares Means Geometric Mean Ratio 90% Confidence Interval Warfarin + Epanova™ Warfarin Alone
INR AUC0-168 224.91 244.87 91.85 89.85 - 93.90 INRmax 1.77 2.11 84.02 80.96 - 87.19
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BACKGROUND• Inpatientswithseverehypertriglyceridemia(TG≥500mg/dL),
theNationalCholesterolEducationProgram(NCEP)AdultTreatmentPanel(ATP)IIIrecognizedthatstatinsarenotpowerfultriglyceride(TG)-loweringdrugs,andthereforerecommendedtheuseofspecifictherapiessuchasn-3(omega)fattyacidsasanadjuncttodiettolowerTGlevels.1
• Onceabsorbed,theomega-3fattyacidseicosapentaenoicacid(EPA)anddocosahexaenoicacid(DHA)lowerserumTGsbyreducinghepaticsecretionofTG-richlipoproteins.1
• Epanova™isacomplexmixtureofomega-3free-fattyacids,primarilyEPAandDHA,beingdevelopedasanadjuncttodiettoreducetriglyceridelevelsinadultpatientswithseverehypertriglyceridemia,andasanadjuncttostatintherapyinpatientswithpersistenthypertriglyceridemiaathighriskforcardiovasculardisease.
• Warfarin,ananticoagulantadministeredasaracemicmixtureof(R)-and(S)-enantiomers,isprescribedforpatientswiththromboticandembolicdisorders,andtoreducetheriskofthrombosisinhigh-riskpatients.WarfarinactsbyinhibitingvitaminK-dependentcoagulationfactors.Itsefficacycanbemonitoredbymeasurementofprothrombintime(PT)convertedtothestandardizedparameteroftheInternationalNormalizedRatio(INR).Fluctuationsinthestateofanticoagulationinapatienttakingwarfarincanhaveclinicalconsequences,suchasbleedingassociatedwithexcessiveanticoagulationorthrombosissecondarytosubtherapeuticanticoagulation.
• Inclinicalpractice,Epanova™maybeco-administeredwithwarfarin.Sincewarfarinhasanarrowtherapeuticindexandomega-3fattyacidsmayaffecttheabsorptionofwarfarinandlipid-solublevitaminssuchasvitaminKtopotentiatetheriskofbleeding,theeffectsofEpanova™onthepharmacokinetics(PK)andpharmacodynamics(PD)ofwarfarinwereinvestigated.
OBjeCtiveTodeterminetheeffectofmultiple-doseEpanova™onthePKandPDofasingle25mgdoseofwarfarin.
MethODsstudy Design• Open-label,2-treatment,fixed-sequencestudyin26healthymale
andfemaleparticipants(18–55yrsofage).• Thedurationofthestudywasapproximately29.5days(excluding
screening).• Participantswerescreenedforstudyparticipationwithin28days
ofdosing.
Multiple-Dose Administration of a Free-Fatty Acid Formulation of EpA/DhA has No Effect on the pharmacokinetics or pharmacodynamics of Single-Dose WarfarinMichael Davidson1,2, Ted Marenco3, Elliot Offman3, Anne hohnstein4, Judith Johnson1, Douglas Kling1
1Omthera pharmaceuticals, Inc., princeton, NJ, USA. 2University of Chicago, Chicago, IL, USA. 3Celerion, Montreal, QC, Canada. 4Celerion, Lincoln, NE, USA.
CONCLUsiONs • Once-daily4gdosesofEpanova™for21dayshadnoeffectonthePKnorPD
ofasingle25mgdoseofwarfarin,inthatthesystemicexposuretoplasma(R)-and(S)-warfarin,andthePTINR,werecomparablefollowingwarfarinaloneandwarfarinco-administeredwithEpanova™.
• Therewerenoseriousadverseeventsinthisstudyandnoparticipantwasdiscontinuedduetoanadverseevent.
• ATherapeuticLifestyleChanges(TLC,aheart-healthydietlowinsaturatedfat,transfat,andcholesterol,createdbytheNationalInstitutesofHealthtohelpreducetheriskofcardiovasculardisease)dietwasfollowedthroughouttheentirestudy.
• BeginningonDay-1,theparticipantswereservedadailybreakfastcontaining<10%fat.Participantswererequiredtofastforaminimumof10hoursovernightpriortobreakfastandcontinuetofastforatleast4hoursthereafter.Participantswerealsoservedlunchanddinnerdaily.
• OnDay1followinganovernightfast,participantswereadministeredasingle25mgdoseofwarfarinwith240mLofwateratHour0.
• Bloodsampleswerecollectedover168hoursfollowingwarfarindosingonDay1tocalculatePKandPDparametersofwarfarin.
• OnDays8to28,participantswereadministereda4g(4x1gcapsules)doseofEpanova™alone,andco-administeredwithasingle25mgdoseofwarfarinonDay22.AlldosesofEpanova™wereadministeredapproximately30minutesfollowingthestartofalow-fatbreakfast,withtheexceptionoftheDay22dosewhichwasco-administeredwithwarfarinfollowinganovernightfast.ThebreakfastwastobecompletedpriortoHour0dosingofeachstudyday.
• Bloodsampleswerecollectedover168hoursfollowingwarfarinandEpanova™co-administrationonDay22tocalculatePKandPDparametersofwarfarin.
Pharmacokinetic Blood sampling• BloodsampleswerecollectedonDays1and22forthe
determinationofplasma(R)-and(S)-warfarinconcentrationsat:predose,and0.5,1,2,3,4,5,6,12,24,48,72,96,120,144,and168hourspostdose.
• BloodsampleswerecollectedonDays1and22forthedeterminationofthePTINRat:predose,and0.5,1,2,4,12,24,48,72,96,120,144,and168hourspostdose.
Bioanalytical AssayPlasmasampleswereassayedfor(R)-and(S)-warfarinusingHPLC/MS-MSwithanLLOQof12.5ng/mL.
Pharmacokinetic AnalysisThefollowingPKparameterswerecalculatedforplasma(R)-and(S)-warfarinfollowingwarfarinalone(Day1),andwarfarinco-administeredwithEpanova™(Day22):
AUC0-t :Areaundertheplasmaconcentrationversustimecurvefromtime0tothetimeofthelastmeasurableconcentration;
AUC0-∞ :Areaundertheplasmaconcentrationversustimecurvefromtime0toinfinity;
Cmax :Maximummeasuredplasmaconcentration;tmax : TimeatwhichCmaxoccurred;t½ :Apparentterminaleliminationhalf-life.
Figure 1 Mean Plasma (R)-warfarin Concentrations Versus Time
Con
cent
ratio
n (n
g/m
L)
1500
2000
2500
Warfarin Alone
Warfarin + Epanova™
Time (Hours)0 24 48 72 96 120 144 168
Plas
ma
(R)-w
arfa
rin C
0
500
1000
Figure 2 Mean Plasma (S)-warfarin Concentrations Versus Time
n C
once
ntra
tion
(ng/
mL)
1000
1500
2000
2500
Warfarin Alone
Warfarin + Epanova™
Time (Hours)0 24 48 72 96 120 144 168
Plas
ma
(S)-w
arfa
rin
0
500
1000
Figure 3 Mean INR Versus Time
INR
1.5
2.0
2.5
Warfarin Alone
Warfarin + Epanova™
Time (Hours)0 24 48 72 96 120 144 168
0.0
0.5
1.0
RefeReNCes1. NationalCholesterolEducationProgram(NCEP)ExpertPanelonDetection,Evaluation,and
TreatmentofHighBloodCholesterolinAdults(AdultTreatmentPanelIII).ThirdReportoftheNationalCholesterolEducationProgram(NCEP)ExpertPanelonDetection,Evaluation,andTreatmentofHighBloodCholesterolinAdults(AdultTreatmentPanelIII)FinalReport.Circulation.2002;106:3143-421.
Pharmacodynamic AnalysisThefollowingPDparameterswerecalculatedfortheINRonDays1and22:
INRAUC0-168 :AreaundertheINRversustimecurvefromtime0to168hourspostdose;
INRmax :MaximummeasuredINRvalue.
statistical Analysis• Analysisofvariancewasperformedontheln-transformedAUC0-t,AUC0-∞,andCmaxofplasma(R)-and(S)-warfarin,aswellastheln-transformedINRAUC0-168andINRmax.
• Nodruginteractionwastobeclaimedifthe90%confidenceintervals(CIs)forthegeometricmeanratios(GMRs)oftheback-transformedAUC0-t,AUC0-∞,andCmaxofplasma(R)-and(S)-warfarin,andtheback-transformedINRAUC0-168andINRmax,forwarfarinco-administeredwithEpanova™versuswarfarinalone,fellwithin80.00%-125.00%.
ResULts OveRviewThestudyenrolled26healthyadultmaleandfemaleparticipants,and25participants(20malesand5females)completedthestudy.
figures 1 and 2 –Meanplasma(R)-warfarin(Figure1)and(S)-warfarin(Figure2)concentrationsweresimilarfollowingasingleoraldoseof25mgwarfarin(Day1),andfollowingasingleoraldoseof25mgwarfarinco-administeredwithmultiple-doseEpanova™(Day22).
figure 3 –MeanINRweresimilarfollowingasingleoraldoseof25mgwarfarin(Day1),andfollowingasingleoraldoseof25mgwarfarinco-administeredwithmultiple-doseEpanova™(Day22).
tables 1 and 2 -Thegeometricmeanoverall(AUC0-tandAUC0-∞)andpeak(Cmax)exposuresto(R)-and(S)-warfarin,aswellasthemediantmaxandmeant½,werecomparablefollowingwarfarinaloneandwarfarinco-administeredwithEpanova™(Table1).Similarly,thegeometricmeanINRAUC0-168andINRmaxwerecomparablefollowingwarfarinaloneandwarfarinco-administeredwithEpanova™(Table2).
tables 3 and 4 -The90%CIsfortheGMRs(warfarin+Epanova™/warfarinalone)oftheln-transformedAUC0-t,AUC0-∞,andCmaxfor(R)-and(S)-warfarininplasmawerewithin80.00%–125.00%(Table3).Similarly,the90%CIsfortheGMRs(warfarin+Epanova™/warfarinalone)oftheln-transformedINRAUC0-168andINRmaxwerewithin80.00%–125.00%(Table4).
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