Study to Determine the Potential DDIs When the Daclatasvir/Asunaprevir/BMS-791325 Three Drug Antiviral Combination Tablet (FDC) is Coadministered With a Cocktail of Cytochrome P450 (CYP) Probe Substrates and Transporter Probe Substrates (Digoxin and Pravastatin) in Healthy Subjects

Phase 1

Completed

• Conditions: Hepatitis C
• Interventions: Drug: Cocktail; Drug: DCV 3DAA FDC; Drug: BMS-791325

• Registration Number: NCT02045966
• Lead Sponsor: Bristol-Myers Squibb

Brief Summary

The primary purpose of this study is to assess the effect of the Daclatasvir/Asunaprevir/BMS-791325 fixed dose combination (FDC) tablet on the pharmacokinetics of the cocktail CYP and transporter probe substrates and to assess the effect of the DCV 3DAA FDC \[DCV 3DAA FDC = fixed dose combination formulation of 3 direct-acting antivirals (3DAA) (DCV 30 mg, ASV 200 mg, and BMS-791325 75 mg)\] + BMS-791325 75-mg single-agent tablet on the Pharmacokinetic (PK) of the cocktail CYP and transporter probe substrates.

Detailed Description

IND number: 79,599 and 101,943

Primary purpose: Other: study is being conducted to investigate the potential drug-drug interactions (DDIs) when the Daclatasvir/Asunaprevir/BMS-791325 FDC formulation is coadministered with a cocktail of cytochrome P450 (CYP) probe substrates (Caffeine, Metoprolol, Montelukast, Flurbiprofen, Omeprazole, and Midazolam) and transporter probe substrates (Digoxin and Pravastatin) in healthy subjects. It is also intended to characterize the PK of Daclatasvir (DCV), Asunaprevir (ASV), BMS-791325, and its major metabolite, BMS-794712, at steady state.

Study Timeline

• Study First Submitted: 2014-01-23
• Study First Submitted QC: 2014-01-23
• Study First Posted: 2014-01-27
• Study Start: 2014-02
• Primary Completion: 2014-04
• Study Completion: 2014-04
• Status Verified: 2014-06
• Last Update Submitted: 2014-06-16
• Last Update Posted: 2014-06-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 16

Inclusion Criteria

• Healthy subjects as determined by no clinically significant deviation from normal in medical history, physical examinations, vital sign measurements, 12-lead ECG measurements, and clinical laboratory test results
• Body mass index (BMI) of 18.0 to 32.0 kg/m2, inclusive. BMI = weight (kg)/[height (m)]2
• Men and women, ages 18 to 45 years, inclusive
• Women must not be of childbearing potential, must not be breastfeeding

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Exclusion Criteria

• Any significant acute or chronic medical illness
• History of important arrhythmias including, but not limited to, ventricular fibrillation, ventricular tachycardia, complete atrioventricular (A-V) block, Wolff-Parkinson-White syndrome
• History of cardiac arrhythmias or palpitations associated with presyncope or syncope, or history of unexplained syncope
• History of heart disease
• History of prolonged QT interval or torsades de pointes (TdP)
• History of hypokalemia
• Family history of sudden cardiac death at a young age, TdP, or Long QT syndrome
• History of asthma, bronchospasm, or sleep apnea
• History of rhabdomyolysis
• History of a bleeding disorder
• History of Raynaud's disease
• History of peptic ulcer disease or significant gastrointestinal bleed
• History of biliary disorders, including Gilbert's disease or Dubin-Johnson disease
• Current or recent (within 3 months of study drug administration) gastrointestinal disease
• Any major surgery within 4 weeks of study drug administration
• Any gastrointestinal surgery (including cholecystectomy) that could impact upon the absorption of study drug

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm 1: Cocktail + DCV 3DAA FDC + BMS-791325	DCV 3DAA FDC	Treatment A: Cocktail of CYP and transporter probe substrates orally as a single dose on Day 1 Treatment B: DCV 3DAA FDC tablet administered orally BID on Days 6 to 15 Treatment C: DCV 3DAA FDC tablet administered orally BID on Days 16 to 20, plus the cocktail of CYP and transporter probe substrates administered orally as a single dose on Day 16 only Treatment D: DCV 3DAA FDC tablet plus BMS-791325 75-mg single-agent tablet administered orally BID on Days 21 to 30 Treatment E: DCV 3DAA FDC tablet plus BMS-791325 75-mg single-agent tablet administered orally BID on Days 31 to 35, plus the cocktail of CYP and transporter probe substrates administered orally as a single dose on Day 31 only
Arm 1: Cocktail + DCV 3DAA FDC + BMS-791325	BMS-791325	Treatment A: Cocktail of CYP and transporter probe substrates orally as a single dose on Day 1 Treatment B: DCV 3DAA FDC tablet administered orally BID on Days 6 to 15 Treatment C: DCV 3DAA FDC tablet administered orally BID on Days 16 to 20, plus the cocktail of CYP and transporter probe substrates administered orally as a single dose on Day 16 only Treatment D: DCV 3DAA FDC tablet plus BMS-791325 75-mg single-agent tablet administered orally BID on Days 21 to 30 Treatment E: DCV 3DAA FDC tablet plus BMS-791325 75-mg single-agent tablet administered orally BID on Days 31 to 35, plus the cocktail of CYP and transporter probe substrates administered orally as a single dose on Day 31 only
Arm 1: Cocktail + DCV 3DAA FDC + BMS-791325	Cocktail	Treatment A: Cocktail of CYP and transporter probe substrates orally as a single dose on Day 1 Treatment B: DCV 3DAA FDC tablet administered orally BID on Days 6 to 15 Treatment C: DCV 3DAA FDC tablet administered orally BID on Days 16 to 20, plus the cocktail of CYP and transporter probe substrates administered orally as a single dose on Day 16 only Treatment D: DCV 3DAA FDC tablet plus BMS-791325 75-mg single-agent tablet administered orally BID on Days 21 to 30 Treatment E: DCV 3DAA FDC tablet plus BMS-791325 75-mg single-agent tablet administered orally BID on Days 31 to 35, plus the cocktail of CYP and transporter probe substrates administered orally as a single dose on Day 31 only

Primary Outcome Measures

Name	Time	Method
Area under the concentration-time curve from time zero extrapolated to infinite time [AUC(INF)] for each cocktail CYP and transporter probe substrate	51 time points up to day 36

Secondary Outcome Measures

Name	Time	Method
Area under the concentration-time curve in one dosing interval [AUC(TAU)] for Daclatasvir, Asunaprevir, BMS-791325, and the metabolite, BMS- 794712 at steady state	24 time points up to day 31
Maximum observed concentration (Cmax) for each cocktail CYP and transporter probe substrate	51 time points up to day 36
AUC(0-T) for the measured metabolites of the cocktail CYP and transporter probe substrates	51 time points up to day 36
Apparent total body clearance (CLT/F) for each cocktail CYP and transporter probe substrate	51 time points up to day 36
Ratio of metabolite AUC(TAU) to parent AUC(TAU), corrected for molecular weight [MR_AUC(TAU)] for BMS-791325 and the metabolite, BMS-794712	24 time points up to day 31
Trough observed plasma concentration (Ctrough) for Daclatasvir, Asunaprevir, BMS-791325, and the metabolite, BMS-794712	24 time points up to day 31
Safety measured by the occurrence of AEs and SAEs, abnormalities in vital sign measurements exceeding pre-defined thresholds, findings on ECG measurements and physical examinations, and marked abnormalities in clinical laboratory test results	Up to day 36	AEs = Adverse events; SAEs = Serious Adverse events; ECG = Electrocardiogram
Area under the concentration-time curve from time zero to the time of the last quantifiable concentration [AUC(0-T)] for each cocktail CYP and transporter probe substrate	51 time points up to day 36
Cmax for the measured metabolites of the cocktail CYP and transporter probe substrates	51 time points up to day 36
AUC(INF) for the measured metabolites of the cocktail CYP and transporter probe substrates	51 time points up to day 36
Ratio of metabolite Cmax to parent Cmax, corrected for molecular weight (MR_Cmax) for each cocktail CYP and transporter probe substrate and their metabolites	51 time points up to day 36
Ratio of metabolite AUC(INF) to parent AUC(INF), corrected for molecular weight [MR_AUC(INF)] for each cocktail CYP and transporter probe substrate and their metabolites	51 time points up to day 36
Half life (T-HALF) for each cocktail CYP and transporter probe substrate and their metabolites	51 time points up to day 36
Concentration at 12 hours (C12) for Daclatasvir, Asunaprevir, BMS-791325, and the metabolite, BMS- 794712 at steady state	24 time points up to day 31
MR_Cmax for BMS-791325 and the metabolite, BMS-794712	24 time points up to day 31
Time of maximum observed concentration (Tmax) for each cocktail CYP and transporter probe substrate and their metabolites	51 time points up to day 36
Ratio of metabolite AUC(0-T) to parent AUC(0-T), corrected for molecular weight [MR_AUC(0-T)] for each cocktail CYP and transporter probe substrate and their metabolites	51 time points up to day 36
Cmax for Daclatasvir, Asunaprevir, BMS-791325, and the metabolite, BMS- 794712 at steady state	24 time points up to day 31
Tmax for Daclatasvir, Asunaprevir, BMS-791325, and the metabolite, BMS- 794712 at steady state	24 time points up to day 31