Multiple-Dose Administration of a Free-Fatty Acid ...€¦ · ResULts OveRview The study enrolled...
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Table 1 Summary of the Pharmacokinetic Parameters of Warfarin in Plasma Pharmacokinetic Parameter Warfarin Alone (n=25) Warfarin + Epanova (n=25) (R)-warfarin AUC 0-t (ng hr/mL) 101000 (19.0) 105000 (20.5) 000 (2 ) 9000 (22 8) AUC 0-∞ (ng hr/mL) 115000 (21.1) 119000 (22.8) C max (ng/mL) 2240 (22.7) 2050 (21.7) t max (hr) 0.999 (0.499, 5.00) 1.00 (0.494, 5.00) t ½ (hr) 55.0 (19.6) 55.1 (17.7) (S)-warfarin AUC 0-t (ng hr/mL) 62800 (28.7) 64800 (31.1) AUC 0-∞ (ng hr/mL) 66100 (32.1) 68300 (34.7) C max (ng/mL) 2300 (23.4) 2080 (23.5) t max (hr) 0.999 (0.499, 2.01) 0.999 (0.494, 5.00) t ½ (hr) 42.1 (20.1) 42.6 (23.0) AUC 0-t , AUC 0-∞ , and C max are presented as Geometric Mean (Geometric CV%). t max is presented as Median (Minimum, Maximum). t ½ is presented as Arithmetic Mean (Arithmetic CV%). ½ • • • • ™ Table 2 Summary of the Pharmacodynamic Parameters of Warfarin Pharmacodynamic Parameter Warfarin Alone (n=26) Warfarin + Epanova ™ (n=25) INR AUC 0-168 247 (20.2) 225 (14.6) INR max 2.14 (31.5) 1.77 (23.2) INR AUC 0-168 and INR max 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 AUC 0-t (ng hr/mL) 104659.28 • 101257.14 103.36 100.81 - 105.97 AUC 0-∞ (ng hr/mL) 119006.62 114785.21 103.68 100.61 - 106.84 C max (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 AUC 0-t (ng hr/mL) 64810.54 62845.55 103.13 100.32 - 106.01 AUC 0-∞ (ng hr/mL) 68346.95 66141.98 103.33 100.27 - 106.49 C max (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 AUC 0-168 224.91 244.87 91.85 89.85 - 93.90 INR max 1.77 2.11 84.02 80.96 - 87.19 • • • - BACKGROUND • In patients with severe hypertriglyceridemia (TG ≥ 500 mg/dL), the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III recognized that statins are not powerful triglyceride (TG)-lowering drugs, and therefore recommended the use of specific therapies such as n-3 (omega) fatty acids as an adjunct to diet to lower TG levels. 1 • Once absorbed, the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) lower serum TGs by reducing hepatic secretion of TG-rich lipoproteins. 1 • Epanova™ is a complex mixture of omega-3 free-fatty acids, primarily EPA and DHA, being developed as an adjunct to diet to reduce triglyceride levels in adult patients with severe hypertriglyceridemia, and as an adjunct to statin therapy in patients with persistent hypertriglyceridemia at high risk for cardiovascular disease. • Warfarin, an anticoagulant administered as a racemic mixture of (R)- and (S)-enantiomers, is prescribed for patients with thrombotic and embolic disorders, and to reduce the risk of thrombosis in high-risk patients. Warfarin acts by inhibiting vitamin K-dependent coagulation factors. Its efficacy can be monitored by measurement of prothrombin time (PT) converted to the standardized parameter of the International Normalized Ratio (INR). Fluctuations in the state of anticoagulation in a patient taking warfarin can have clinical consequences, such as bleeding associated with excessive anticoagulation or thrombosis secondary to subtherapeutic anticoagulation. • In clinical practice, Epanova™ may be co-administered with warfarin. Since warfarin has a narrow therapeutic index and omega-3 fatty acids may affect the absorption of warfarin and lipid-soluble vitamins such as vitamin K to potentiate the risk of bleeding, the effects of Epanova™ on the pharmacokinetics (PK) and pharmacodynamics (PD) of warfarin were investigated. OBJECTIVE To determine the effect of multiple-dose Epanova™ on the PK and PD of a single 25 mg dose of warfarin. METHODS Study Design • Open-label, 2-treatment, fixed-sequence study in 26 healthy male and female participants (18 – 55 yrs of age). • The duration of the study was approximately 29.5 days (excluding screening). • Participants were screened for study participation within 28 days of dosing. Multiple-Dose Administration of a Free-Fatty Acid Formulation of EpA/DhA has No Effect on the pharmacokinetics or pharmacodynamics of Single-Dose Warfarin Michael Davidson 1,2 , Ted Marenco 3 , Elliot Offman 3 , Anne hohnstein 4 , Judith Johnson 1 , Douglas Kling 1 1 Omthera pharmaceuticals, Inc., princeton, NJ, USA. 2 University of Chicago, Chicago, IL, USA. 3 Celerion, Montreal, QC, Canada. 4 Celerion, Lincoln, NE, USA. CONCLUSIONS • Once-daily 4 g doses of Epanova™ for 21 days had no effect on the PK nor PD of a single 25 mg dose of warfarin, in that the systemic exposure to plasma (R)- and (S)-warfarin, and the PT INR, were comparable following warfarin alone and warfarin co-administered with Epanova™. • There were no serious adverse events in this study and no participant was discontinued due to an adverse event. • A Therapeutic Lifestyle Changes (TLC, a heart-healthy diet low in saturated fat, trans fat, and cholesterol, created by the National Institutes of Health to help reduce the risk of cardiovascular disease) diet was followed throughout the entire study. • Beginning on Day -1, the participants were served a daily breakfast containing < 10% fat. Participants were required to fast for a minimum of 10 hours overnight prior to breakfast and continue to fast for at least 4 hours thereafter. Participants were also served lunch and dinner daily. • On Day 1 following an overnight fast, participants were administered a single 25 mg dose of warfarin with 240 mL of water at Hour 0. • Blood samples were collected over 168 hours following warfarin dosing on Day 1 to calculate PK and PD parameters of warfarin. • On Days 8 to 28, participants were administered a 4 g (4 x 1 g capsules) dose of Epanova™ alone, and co-administered with a single 25 mg dose of warfarin on Day 22. All doses of Epanova™ were administered approximately 30 minutes following the start of a low-fat breakfast, with the exception of the Day 22 dose which was co-administered with warfarin following an overnight fast. The breakfast was to be completed prior to Hour 0 dosing of each study day. • Blood samples were collected over 168 hours following warfarin and Epanova™ co-administration on Day 22 to calculate PK and PD parameters of warfarin. Pharmacokinetic Blood Sampling • Blood samples were collected on Days 1 and 22 for the determination of plasma (R)- and (S)-warfarin concentrations at: predose, and 0.5, 1, 2, 3, 4, 5, 6, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose. • Blood samples were collected on Days 1 and 22 for the determination of the PT INR at: predose, and 0.5, 1, 2, 4, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose. Bioanalytical Assay Plasma samples were assayed for (R)- and (S)-warfarin using HPLC/MS-MS with an LLOQ of 12.5 ng/mL. Pharmacokinetic Analysis The following PK parameters were calculated for plasma (R)- and (S)-warfarin following warfarin alone (Day 1), and warfarin co- administered with Epanova™ (Day 22): AUC 0-t : Area under the plasma concentration versus time curve from time 0 to the time of the last measurable concentration; AUC 0-∞ : Area under the plasma concentration versus time curve from time 0 to infinity; C max : Maximum measured plasma concentration; t max : Time at which C max occurred; t ½ : Apparent terminal elimination half-life. Figure 1 Mean Plasma (R)-warfarin Concentrations Versus Time Concentration (ng/mL) 1500 2000 2500 Warfarin Alone Warfarin + Epanova ™ Time (Hours) 0 24 48 72 96 120 144 168 Plasma (R)-warfarin C 0 500 1000 Figure 2 Mean Plasma (S)-warfarin Concentrations Versus Time n Concentration (ng/mL) 1000 1500 2000 2500 Warfarin Alone Warfarin + Epanova ™ Time (Hours) 0 24 48 72 96 120 144 168 Plasma (S)-warfarin 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 REFERENCES 1. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report. Circulation. 2002; 106:3143-421. Pharmacodynamic Analysis The following PD parameters were calculated for the INR on Days 1 and 22: INR AUC 0-168 : Area under the INR versus time curve from time 0 to 168 hours postdose; INR max : Maximum measured INR value. Statistical Analysis • Analysis of variance was performed on the ln-transformed AUC 0-t , AUC 0-∞ , and C max of plasma (R)- and (S)-warfarin, as well as the ln-transformed INR AUC 0-168 and INR max . • No drug interaction was to be claimed if the 90% confidence intervals (CIs) for the geometric mean ratios (GMRs) of the back- transformed AUC 0-t , AUC 0-∞ , and Cmax of plasma (R)- and (S)-warfarin, and the back-transformed INR AUC 0-168 and INR max , for warfarin co-administered with Epanova™ versus warfarin alone, fell within 80.00% - 125.00%. RESULTS OVERVIEW The study enrolled 26 healthy adult male and female participants, and 25 participants (20 males and 5 females) completed the study. Figures 1 and 2 – Mean plasma (R)-warfarin (Figure 1) and (S)-warfarin (Figure 2) concentrations were similar following a single oral dose of 25 mg warfarin (Day 1), and following a single oral dose of 25 mg warfarin co-administered with multiple-dose Epanova™ (Day 22). Figure 3 – Mean INR were similar following a single oral dose of 25 mg warfarin (Day 1), and following a single oral dose of 25 mg warfarin co-administered with multiple-dose Epanova™ (Day 22). Tables 1 and 2 - The geometric mean overall (AUC 0-t and AUC 0-∞ ) and peak (C max ) exposures to (R)- and (S)-warfarin, as well as the median t max and mean t ½ , were comparable following warfarin alone and warfarin co-administered with Epanova™ (Table 1). Similarly, the geometric mean INR AUC 0-168 and INR max were comparable following warfarin alone and warfarin co-administered with Epanova™ (Table 2). Tables 3 and 4 - The 90% CIs for the GMRs (warfarin + Epanova™ / warfarin alone) of the ln-transformed AUC 0-t , AUC 0-∞ , and C max for (R)-and (S)-warfarin in plasma were within 80.00% – 125.00% (Table 3). Similarly, the 90% CIs for the GMRs (warfarin + Epanova™ / warfarin alone) of the ln-transformed INR AUC 0-168 and INR max were within 80.00% – 125.00% (Table 4). T2284
Transcript of Multiple-Dose Administration of a Free-Fatty Acid ...€¦ · ResULts OveRview The study enrolled...
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
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Warfarin + Epanova™
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Figure 2 Mean Plasma (S)-warfarin Concentrations Versus Time
n C
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Figure 3 Mean INR Versus Time
INR
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Warfarin + Epanova™
Time (Hours)0 24 48 72 96 120 144 168
0.0
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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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