Effect of a Fixed Dose Combination Formulation of Daclatasvir/Asunaprevir/BMS-791325 on the Pharmacokinetics of a Cocktail of CYP Probe Substrates (Caffeine, Metoprolol, Montelukast, Flurbiprofen, Omeprazole, and Midazolam) and Transporter Probe Substrates (Digoxin and Pravastatin) in Healthy Subjects
Overview
- Phase
- Phase 1
- Intervention
- Cocktail
- Conditions
- Hepatitis C
- Sponsor
- Bristol-Myers Squibb
- Enrollment
- 16
- Primary Endpoint
- Area under the concentration-time curve from time zero extrapolated to infinite time [AUC(INF)] for each cocktail CYP and transporter probe substrate
- Status
- Completed
- Last Updated
- 11 years ago
Overview
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.
Investigators
Eligibility Criteria
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
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
Arms & Interventions
Arm 1: Cocktail + DCV 3DAA FDC + 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
Intervention: Cocktail
Arm 1: Cocktail + DCV 3DAA FDC + 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
Intervention: DCV 3DAA FDC
Arm 1: Cocktail + DCV 3DAA FDC + 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
Intervention: BMS-791325
Outcomes
Primary Outcomes
Area under the concentration-time curve from time zero extrapolated to infinite time [AUC(INF)] for each cocktail CYP and transporter probe substrate
Time Frame: 51 time points up to day 36
Secondary Outcomes
- 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)
- 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)
- 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)