Clinical trial NCT02045966: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hepatitis C
Lead sponsor: Bristol-Myers Squibb
Sponsor class: INDUSTRY
First posted: 2014-01-27
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP

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.

Eligibility 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

Primary outcomes:
measure: Area under the concentration-time curve from time zero extrapolated to infinite time [AUC(INF)] for each cocktail CYP and transporter probe substrate
timeFrame: 51 time points up to day 36
Secondary outcomes:
measure: Maximum observed concentration (Cmax) for each cocktail CYP and transporter probe substrate
timeFrame: 51 time points up to day 36
measure: 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
timeFrame: 51 time points up to day 36
measure: Cmax for the measured metabolites of the cocktail CYP and transporter probe substrates
timeFrame: 51 time points up to day 36
measure: AUC(0-T) for the measured metabolites of the cocktail CYP and transporter probe substrates
timeFrame: 51 time points up to day 36
measure: AUC(INF) for the measured metabolites of the cocktail CYP and transporter probe substrates
timeFrame: 51 time points up to day 36
measure: Time of maximum observed concentration (Tmax) for each cocktail CYP and transporter probe substrate and their metabolites
timeFrame: 51 time points up to day 36
measure: Half life (T-HALF) for each cocktail CYP and transporter probe substrate and their metabolites
timeFrame: 51 time points up to day 36
measure: Ratio of metabolite Cmax to parent Cmax, corrected for molecular weight (MR_Cmax) for each cocktail CYP and transporter probe substrate and their metabolites
timeFrame: 51 time points up to day 36
measure: 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
timeFrame: 51 time points up to day 36
measure: 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
timeFrame: 51 time points up to day 36
measure: Apparent total body clearance (CLT/F) for each cocktail CYP and transporter probe substrate
timeFrame: 51 time points up to day 36
measure: Cmax for Daclatasvir, Asunaprevir, BMS-791325, and the metabolite, BMS- 794712 at steady state
timeFrame: 24 time points up to day 31
measure: Tmax for Daclatasvir, Asunaprevir, BMS-791325, and the metabolite, BMS- 794712 at steady state
timeFrame: 24 time points up to day 31
measure: Concentration at 12 hours (C12) for Daclatasvir, Asunaprevir, BMS-791325, and the metabolite, BMS- 794712 at steady state
timeFrame: 24 time points up to day 31
measure: 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
timeFrame: 24 time points up to day 31
measure: MR_Cmax for BMS-791325 and the metabolite, BMS-794712
timeFrame: 24 time points up to day 31
measure: Ratio of metabolite AUC(TAU) to parent AUC(TAU), corrected for molecular weight [MR_AUC(TAU)] for BMS-791325 and the metabolite, BMS-794712
timeFrame: 24 time points up to day 31
measure: Trough observed plasma concentration (Ctrough) for Daclatasvir, Asunaprevir, BMS-791325, and the metabolite, BMS-794712
timeFrame: 24 time points up to day 31
measure: 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
timeFrame: Up to day 36
Other outcomes:
Locations:
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References: