Hepatitis C
Conditions
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.
Interventions
DRUGCocktail
Cocktail = Caffeine 200 mg, Metoprolol 50 mg, Montelukast 10 mg, Flurbiprofen 50 mg, Omeprazole 40 mg, Midazolam 5 mg, Digoxin 0.25 mg, and Pravastatin 40 mg
DRUGDCV 3DAA FDC
DCV 30 mg + ASV 200 mg + BMS-791325 75 mg
DRUGBMS-791325
Sponsors
Bristol-Myers Squibb
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com 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 * 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Maximum observed concentration (Cmax) for each cocktail CYP and transporter probe substrate | 51 time points 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(0-T) 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 | — |
| Time of maximum observed concentration (Tmax) 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 | — |
| 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(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 | — |
| Tmax for Daclatasvir, Asunaprevir, BMS-791325, and the metabolite, BMS- 794712 at steady state | 24 time points up to day 31 | — |
| Apparent total body clearance (CLT/F) for each cocktail CYP and transporter probe substrate | 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 | — |
| 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 | — |
| 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 | — |
| MR_Cmax for BMS-791325 and the metabolite, BMS-794712 | 24 time points up to day 31 | — |
| 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 |
| 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 | — |
Outcome results
None listed