Study to Evaluate Effect of Belatacept on Pharmacokinetics of Inje Cocktail in Healthy Volunteers
- Conditions
- Transplant Rejection
- Interventions
- Biological: Belatacept
- Registration Number
- NCT01766050
- Lead Sponsor
- Bristol-Myers Squibb
- Brief Summary
The purpose of this study is to determine the effects of belatacept on the pharmacokinetics of caffeine, losartan, omeprazole, dextromethorphan and midazolam
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 45
- BMI 18 to 30 kg/m2
- Men and women ages 18 to 45
- Active tuberculosis
- Any recent infection requiring antibiotic treatment within 4 weeks of dosing
- Positive urine screen for drugs of abuse
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Arm: Inje Cocktail + Belatacept Belatacept Inje Cocktail consisting of (200 mg Caffeine, 50 mg losartan tablet, 40 mg Omeprazole capsule, 30 mg Dextromethorphan capsule and 5 mg Midazolam oral syrup) administered on Days 1, 4, 7 and 11 Belatacept 10 mg/kg Intravenous (IV) solution, administered on Day 4 Arm: Inje Cocktail + Belatacept Caffeine Inje Cocktail consisting of (200 mg Caffeine, 50 mg losartan tablet, 40 mg Omeprazole capsule, 30 mg Dextromethorphan capsule and 5 mg Midazolam oral syrup) administered on Days 1, 4, 7 and 11 Belatacept 10 mg/kg Intravenous (IV) solution, administered on Day 4 Arm: Inje Cocktail + Belatacept Losartan Inje Cocktail consisting of (200 mg Caffeine, 50 mg losartan tablet, 40 mg Omeprazole capsule, 30 mg Dextromethorphan capsule and 5 mg Midazolam oral syrup) administered on Days 1, 4, 7 and 11 Belatacept 10 mg/kg Intravenous (IV) solution, administered on Day 4 Arm: Inje Cocktail + Belatacept Omeprazole Inje Cocktail consisting of (200 mg Caffeine, 50 mg losartan tablet, 40 mg Omeprazole capsule, 30 mg Dextromethorphan capsule and 5 mg Midazolam oral syrup) administered on Days 1, 4, 7 and 11 Belatacept 10 mg/kg Intravenous (IV) solution, administered on Day 4 Arm: Inje Cocktail + Belatacept Dextromethorphan Inje Cocktail consisting of (200 mg Caffeine, 50 mg losartan tablet, 40 mg Omeprazole capsule, 30 mg Dextromethorphan capsule and 5 mg Midazolam oral syrup) administered on Days 1, 4, 7 and 11 Belatacept 10 mg/kg Intravenous (IV) solution, administered on Day 4 Arm: Inje Cocktail + Belatacept Midazolam Inje Cocktail consisting of (200 mg Caffeine, 50 mg losartan tablet, 40 mg Omeprazole capsule, 30 mg Dextromethorphan capsule and 5 mg Midazolam oral syrup) administered on Days 1, 4, 7 and 11 Belatacept 10 mg/kg Intravenous (IV) solution, administered on Day 4
- Primary Outcome Measures
Name Time Method Adjusted Geometric Mean Maximum Drug Concentration (Cmax) of Midazolam With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 Samples for the assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for midazolam with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Cmax measured in nanograms per milliliter (ng/mL). Inje cocktail components (Midazolam) measured using High Performance Liquid Chromatography (HPLC) with Tandem Mass Spectrometry (MS/MS) Detection.
Adjusted Geometric Mean Area Under the Concentration Time Curve (AUC) From Zero to Last Concentration (0-T) and AUC Extrapolated to Infinity (INF) of Midazolam With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7and 11 AUC(0-T): area under the plasma concentration-time curve from zero to the last time of the last quantifiable concentration and AUC (INF): AUC from time zero extrapolated to infinite time were measured in ng\*h/mL. Samples for the assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for midazolam with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Midazolam measured using HPLC with MS/MS Detection.
Adjusted Geometric Mean AUC (0-T) and AUC (INF) of Losartan With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 AUC (0-T): area under the concentration curve from time 0 to the time of the last quantifiable concentration and AUC (INF) extrapolated to infinity were measured in ng\*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for losartan with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Inje cocktail components (losartan) measured using HPLC with MS/MS Detection.
Adjusted Geometric Mean Cmax of Dextromethorphan With and Without the Coadministration of Belatacept - PK Evaluable Population Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 Cmax was measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for dextromethorphan with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. The poor metabolizer of CYP2D6 was excluded from the statistical analysis. Inje cocktail components (dextromethorphan) measured using HPLC with MS/MS Detection.
Adjusted Geometric Mean Cmax of Losartan With and Without the Coadministration of Belatacept - PK Evaluable Population Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for losartan with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Inje cocktail components (losartan) measured using HPLC with MS/MS Detection.
Adjusted Geometric Mean Cmax of Omeprazole With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 Cmax: Maximum observed plasma concentration was measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for omeprazole with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Inje cocktail components (omeprazole) measured using HPLC with MS/MS Detection.
Adjusted Geometric Mean Cmax of Caffeine With and Without the Coadministration of Belatacept - PK Evaluable Population Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection. Cmax was measured in ng/mL.
Adjusted Geometric Mean AUC (0-T) and AUC (INF) of Omeprazole With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 AUC(0-T): Area under the plasma concentration-time curve from time zero zero to the time of the last quantifiable concentration and AUC (INF): AUC extrapolated to infinity were measured in ng\*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for omeprazole with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Inje cocktail components (omeprazole) measured using HPLC with MS/MS Detection.
Adjusted Geometric Mean AUC (0-T) and AUC (INF) of Dextromethorphan With and Without the Coadministration of Belatacept - PK Evaluable Population Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 AUC(0-T): area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration and AUC (INF): AUC extrapolated to infinity, were measured as ng\*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for dextromethorphan with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. The poor metabolizer of CYP2D6 was excluded from the statistical analysis. Inje cocktail components (dextromethorphan) measured using HPLC with MS/MS Detection.
Adjusted Geometric Mean AUC (0-T) and AUC (INF) of Caffeine With and Without the Coadministration of Belatacept - PK Evaluable Population Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection. AUC (0-T) and AUC (INF) were measured as ng\*h/mL.
- Secondary Outcome Measures
Name Time Method Time of Maximum Observed Plasma Concentration (Tmax) of the Inje Cocktail Components (Midazolam, Losartan, Omeprazole, Dextromethorphan, and Caffeine) With and Without Coadministration of Belatacept - PK Evaluable Population Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of dextromethorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. Tmax was measured in hours (h).
Apparent Total Body Clearance (CLT/F) of the Inje Cocktail Components (Midazolam, Losartan, Omeprazole, Dextromethorphan and Caffeine) With and Without Coadministration of Belatacept - PK Evaluable Population Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of dextromethorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. CLT/F was measured as liters/hour (L/h)
Plasma Half-Life (T-HALF) of the Inje Cocktail Components (Midazolam, Losartan, Omeprazole, Dextromethorphan, and Caffeine) With and Without Coadministration of Belatacept - PK Evaluable Population Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of dextromethorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. T-HALF was measured in hours (h).
Cmax of Inje Cocktail Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without Coadministration of Belatacept - PK Evaluable Population Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 Samples for assessment of plasma concentrations of Inje cocktail component metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail component metabolites were each measured using HPLC with MS/MS detection. Cmax was measured in ng/mL.
Tmax of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without the Coadministration of Belatacept - PK Evaluable Population Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 Samples for assessment of plasma concentrations of Inje cocktail components metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. Time of maximum observed plasma concentration (Tmax) was measured in hours (h).
T-HALF of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without the Coadministration of Belatacept - PK Evaluable Population Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 Plasma half-life (T-HALF) was measured in hours (h). Samples for assessment of plasma concentrations of Inje cocktail components metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection.
Ratio of Paraxanthine AUC(0-T) to Caffeine AUC(0-T) and Paraxanthine AUC (INF) to Caffeine AUC (INF), Corrected for Molecular Weight [MR_AUC(0-T) and MR_AUC (INF)] With and Without Coadministration of Belatacept - PK Evaluable Population Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 Metabolite (paraxanthine) to parent (caffeine) ratio was corrected for molecular weight. AUC (0-T) and AUC (INF) measured in ng\*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.
Ratio of Paraxanthine (Cmax) to Caffeine (Cmax), Corrected for Molecular Weight (MR_Cmax) With and Without Coadministration of Belatacept - PK Evaluable Population Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 Metabolite (paraxanthine) to parent (caffeine) ratio was corrected for molecular weight. Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components and their metabolites were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.
Ratio of E-3174 AUC(0-T) to Losartan AUC(0-T) and E3174 AUC (INF) to Losartan AUC (INF) Corrected for Molecular Weight [MR_AUC(0-T), MR_AUC(INF)] With and Without Coadministration of Belatacept - PK Evaluable Population Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 Metabolite (E-3174) to parent (losartan) ratio was corrected for molecular weight. AUC (0-T) and AUC (INF) measured in ng\*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.
AUC(0-T) of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without Coadministration of Belatacept - PK Evaluable Population Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 Area under the plasma concentration-time curve from zero to the last time of the last quantifiable concentration \[AUC(0-T)\] was measured in ng\*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection.
AUC(INF) of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without Coadministration of Belatacept - PK Evaluable Population Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 Area under the plasma concentration-time curve from time zero extrapolated to infinite time \[AUC(INF)\] was measured in ng\*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection.
Ratio of E-3174 (Cmax) to Losartan (Cmax), Corrected for Molecular Weight (MR_Cmax) With and Without Coadministration of Belatacept - PK Evaluable Population Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 Metabolite (E-3174) to parent (losartan) ratio was corrected for molecular weight. Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.
Ratio of 5-Hydroxyomeprazole AUC(0-T) to Omeprazole AUC(0-T) and 5-Hydroxyomeprazole AUC(INF) to Omeprazole AUC(INF) , Corrected for Molecular Weight [MR_AUC(0-T), MR_AUC(INF)] With and Without Coadministration of Belatacept - PK Evaluable Population Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 Metabolite (5-Hydroxyomeprazole) to parent (omeprazole) ratio was corrected for molecular weight. AUC (0-T) and AUC (INF) measured in ng\*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.
Ratio of 5-Hydroxyomeprazole (Cmax) to Omeprazole (Cmax), Corrected for Molecular Weight (MR_Cmax) With and Without Coadministration of Belatacept - PK Evaluable Population Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 Metabolite (5-hydroxyomeprazole) to parent (omeprazole) ratio was corrected for molecular weight. Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.
Ratio of 5-Dextrorphan AUC(0-T) to Dextromethorphan AUC(0-T) and 5-Dextrorphan AUC(INF) to Dextromethorphan AUC(INF), Corrected for Molecular Weight [MR_AUC(0-T), MR_AUC (INF)] With and Without Coadministration of Belatacept - PK Evaluable Population Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 Metabolite (5-dextrorphan ) to parent (dextromethorphan) ratio was corrected for molecular weight. AUC (0-T) and AUC (INF) measured in ng\*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection.
Ratio of 5-Dextrorphan (Cmax) to Dextromethorphan (Cmax), Corrected for Molecular Weight (MR_Cmax) With and Without Coadministration of Belatacept - PK Evaluable Population Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 Metabolite (5-dextrorphan) to parent (dextromethorphan) ratio was corrected for molecular weight. Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection.
Mean Change From Baseline in Heart Rate at Study Discharge (Day 46±2 Days) Baseline and Day 46 ±2 days Heart Rate was taken after the participant had been sitting quietly for at least 5 minutes and was measured in beats per minute (bpm). Hear rate was taken on Day 46 (day of discharge) during the follow up period. Baseline was defined as last non-missing result with a collection date-time less than the date-time of the first active dose of study drug.
Ratio of 1'-Hydroxy-Midazolam AUC(0-T) to Midazolam AUC(0-T) and 1'-Hydroxy-Midazolam AUC(INF) to Midazolam AUC(INF), Corrected for Molecular Weight [MR_AUC(0-T), MR_AUC (INF)] With and Without Coadministration of Belatacept - PK Evaluable Population Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 Metabolite (1'-hydroxy-midazolam) to parent (midazolam) ratio was corrected for molecular weight. AUC (0-T) and AUC (INF) measured in ng\*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.
Ratio of 1'-Hydroxy-Midazolam (Cmax) to Midazolam (Cmax), Corrected for Molecular Weight (MR_Cmax) With and Without Coadministration of Belatacept - PK Evaluable Population Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 Metabolite (1'-hydroxy-midazolam) to parent (midazolam) ratio was corrected for molecular weight. Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection.
Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and AEs Leading to Discontinuation - All Treated Participants Day 1 to Day of discharge (Day 46±2) Adverse events were coded according to the Medical Dictionary for Regulatory Activities (MedDRA), version 15.1. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Events captured from Day 1 (pre-dose) to last day prior to discharge (Day 46 ±2). In the total group, a participant with an AE is only counted once (ie, data reflected in Days 1, 4, 7, and 11 below could be the same participant with an AE on multiple days of the study).
Number of Participants With Marked Serum Chemistry Laboratory Abnormalities - All Treated Participants Day -1 to Day 46 ±2 days or at early termination Samples for laboratory tests were obtained at Screening visit, Day -1 or prior to dosing on Day 1, Days 3, 6, 10, 46, and at early termination, after 10 hours fasting. Upper limits of normal (ULN); Lower limits of normal (LLN); Pre-therapy (Rx); micromoles per liter (µmol/L); millimoles per liter (mmol/L); grams per liter (g/L); Units per liter (U/L); Aspartate Aminotransferase (AST); Blood Urea Nitrogen (BUN) Total Bilirubin: \>1.1\*ULN if Pre-Rx\<= ULN or Pre-Rx is missing, or \>1.2\*Pre-Rx if Pre-Rx \>ULN. AST: \>1.25\*Pre-Rx if Pre-Rx \>ULN or 1.25\*ULN if Pre-Rx \<= ULN or Pre-Rx is missing. BUN: \>1.1\*ULN if Pre-Rx\<= ULN or Pre-Rx is missing, or \>1.2\*Pre-Rx if Pre-Rx \>ULN. Phosphorus: \<0.85\*LLN if Pre-RX \>= LLN or is missing or if Pre-Rx \< LLN. total Protein: \<0.9\*LLN if Pre-Rx\>= LLN or is missing or Pre-Rx \> LLN. Creatine Kinase: \>1.5\*Pre-Rx if Pre-Rx \> ULN or is missing or Pre-Rx is \<= ULN. Lactate Dehydrogenase: \>1.25\*ULN if Pre-Rx \<= ULN or missing, \>1.5\*Pre-Rx if Pre-Rx \> ULN.
Number of Participants With Marked Hematology and Urinalysis Laboratory Abnormalities - All Treated Participants Day -1 to Day 46 ±2 days or at early termination Samples for laboratory tests were obtained at Screening visit, Day -1 or prior to dosing on Day 1, Days 3, 6, 10, 46 ±2, and at early termination, after 10 hours fasting. Leukocytes: \*10\^9 cells per liter (c/L) \< 0.85\*Pre-Rx if Pre-Rx \< LLN or \<0.9\*LLN if LLN \<= Pre-Rx or Pre-Rx is missing. Neutrophils (absolute): \*10\^12 c/L \< 0.85\* Pre-Rx if Pre-Rx \< 1.5, \<1.5 if Pre-Rx \>= 1.5, \< 1.5 if Pre-Rx missing. Urine blood from dipstick: \>=2 if Pre-Rx \<1 or was missing or if Pre-Rx \>=1. Urinary microscopic white blood cells (WBC) and red blood cells (RBC) \>= 2 if Pre-Rx \<2 or if Pre-Rx was missing or \>=4 if Pre-Rx \>=2.
Number of Participants With Out-of-Range Electrocardiogram Intervals - All Treated Participants Day 1 to Day 46 ±2 days or at early termination Participants had 12-Lead electrocardiograms (ECGs) performed at Screening Visit, Day 1 prior to dosing, Day 46 ±2, and at early termination. Definition of out-of-range: PR Interval \>210 milliseconds (msec); QRS \> 120 msec, QT \> 500 msec or \> 30 msec change from baseline (Day 1); QT with Fridericia correction (QTcF) \> 450 msec or change from baseline of \> 30 msec to \<= 60 msec or change from baseline \> 60 msec.
Mean Change From Baseline in Sitting Systolic and Diastolic Blood Pressure - All Treated Participants Baseline and 0.5 and 2.0 hours Post Dose on Days 1, 4, 7, and 11 Systolic and Diastolic blood pressures were taken after the participant had been sitting quietly for at least 5 minutes and the pressures were measured in millimeters of mercury (mm Hg). Pressures were obtained at screening visit, Day -1, and at 0 hour (pre-dose), 0.5 hour (post dose), and 2 hours (post dose) on Days 1, 4, 7, 11. Baseline was defined as last non-missing result with a collection date-time less than the date-time of the first active dose of study drug.
Mean Change From Baseline in Sitting Heart Rate - All Treated Participants Baseline and 0.5 and 2.0 hours Post Dose on Days 1, 4, 7, and 11 Heart Rate was taken after the participant had been sitting quietly for at least 5 minutes and the heart rate was measured in beats per minute (bpm). Heart Rates were obtained at screening visit, Day -1, and at 0 hour (pre-dose), 0.5 hour (post dose), and 2 hours (post dose) on Days 1, 4, 7, 11. Baseline was defined as last non-missing result with a collection date-time less than the date-time of the first active dose of study drug.
Mean Change From Baseline in Systolic and Diastolic Blood Pressure at Study Discharge (Day 46±2 Days) Baseline and Day 46 ±2 days Systolic and Diastolic blood pressures were taken after the participant had been sitting quietly for at least 5 minutes and the pressures were measured in millimeters of mercury (mm Hg). Systolic and Diastolic blood pressures were taken on Day 46 (day of discharge from the study). Baseline was defined as last non-missing result with a collection date-time less than the date-time of the first active dose of study drug.
Trial Locations
- Locations (1)
Healthcare Discoveries, Llc D/B/A Icon Development Solutions
🇺🇸San Antonio, Texas, United States