A Single-Dose Study to Investigate the Pharmacokinetics of MK-7655 in Participants With Impaired Renal Function (MK-7655-005)
- Conditions
- Infectious Disease
- Interventions
- Registration Number
- NCT01275170
- Lead Sponsor
- Merck Sharp & Dohme LLC
- Brief Summary
This is a 2-part study of the pharmacokinetics (PK) of MK-7655. In Part I, the PK of a single 125 mg dose of MK-7655 given in combination with 250 mg of PRIMAXIN® (imipenem + cilastatin) will be determined in participants with impaired renal function and matched control participants. In Part II, the potential for renal insufficiency to affect non-renal clearance mechanisms will be investigated.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 49
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Panel H Healthy Volunteers Imipenem + Cilastatin A subset of healthy control participants were matched specifically to participants in Panel G and receive a single dose of MK-7655 125 mg + PRIMAXIN® 250 mg IV in Part 1. In Part 2, participants receive an oral cocktail containing caffeine 200 mg, midazolam 2 mg, and omeprazole 40 mg. Panel E Severe Renal Impairment Omeprazole Participants with an eGFR \<30 mL/min/1.73 m\^2 receive a single dose of MK-7655 125 mg + PRIMAXIN® 250 mg IV in Part 1. In Part 2, participants receive an oral cocktail containing caffeine 200 mg, midazolam 2 mg, and omeprazole 40 mg. Panel B Healthy Participants Imipenem + Cilastatin A subset of healthy control participants were matched specifically to participants in Panel A and receive a single dose of MK-7655 125 mg + PRIMAXIN® 250 mg IV in Part 1. Panel A Mild Renal Impairment Imipenem + Cilastatin Participants with an eGFR of \>50 to \<80 mL/min/1.73 m\^2 receive a single dose of MK-7655 125 mg + PRIMAXIN® 250 mg IV in Part 1. Panel C Moderate Renal Impairment Imipenem + Cilastatin Participants with an eGFR of 30 to 50 mL/min/1.73 m\^2 receive a single dose of MK-7655 125 mg + PRIMAXIN® 250 mg IV in Part 1. Panel F Healthy Participants Imipenem + Cilastatin A subset of healthy control participants were matched specifically to participants in Panel E and receive a single dose of MK-7655 125 mg + PRIMAXIN® 250 mg IV in Part 1. In Part 2, participants receive an oral cocktail containing caffeine 200 mg, midazolam 2 mg, and omeprazole 40 mg. Panel G End Stage Renal Disease with Hemodialysis (ESRD/HD) MK-7655 Participants with ESRD/HD receive a single dose of MK-7655 125 mg + PRIMAXIN® 250 mg IV postdialysis (Part 1, Period 1) and predialysis (Part 1, Period 2). In Part 2, participants receive an oral cocktail containing caffeine 200 mg, midazolam 2 mg, and omeprazole 40 mg predialysis (Part 2, Period 1) and postdialysis (Part 2, Period 2). Panel D Healthy Participants Imipenem + Cilastatin A subset of healthy control participants were matched specifically to participants in Panel C and receive a single dose of MK-7655 125 mg + PRIMAXIN® 250 mg IV in Part 1. Panel E Severe Renal Impairment Imipenem + Cilastatin Participants with an eGFR \<30 mL/min/1.73 m\^2 receive a single dose of MK-7655 125 mg + PRIMAXIN® 250 mg IV in Part 1. In Part 2, participants receive an oral cocktail containing caffeine 200 mg, midazolam 2 mg, and omeprazole 40 mg. Panel D Healthy Participants MK-7655 A subset of healthy control participants were matched specifically to participants in Panel C and receive a single dose of MK-7655 125 mg + PRIMAXIN® 250 mg IV in Part 1. Panel G End Stage Renal Disease with Hemodialysis (ESRD/HD) Imipenem + Cilastatin Participants with ESRD/HD receive a single dose of MK-7655 125 mg + PRIMAXIN® 250 mg IV postdialysis (Part 1, Period 1) and predialysis (Part 1, Period 2). In Part 2, participants receive an oral cocktail containing caffeine 200 mg, midazolam 2 mg, and omeprazole 40 mg predialysis (Part 2, Period 1) and postdialysis (Part 2, Period 2). Panel E Severe Renal Impairment MK-7655 Participants with an eGFR \<30 mL/min/1.73 m\^2 receive a single dose of MK-7655 125 mg + PRIMAXIN® 250 mg IV in Part 1. In Part 2, participants receive an oral cocktail containing caffeine 200 mg, midazolam 2 mg, and omeprazole 40 mg. Panel H Healthy Volunteers MK-7655 A subset of healthy control participants were matched specifically to participants in Panel G and receive a single dose of MK-7655 125 mg + PRIMAXIN® 250 mg IV in Part 1. In Part 2, participants receive an oral cocktail containing caffeine 200 mg, midazolam 2 mg, and omeprazole 40 mg. Panel A Mild Renal Impairment MK-7655 Participants with an eGFR of \>50 to \<80 mL/min/1.73 m\^2 receive a single dose of MK-7655 125 mg + PRIMAXIN® 250 mg IV in Part 1. Panel B Healthy Participants MK-7655 A subset of healthy control participants were matched specifically to participants in Panel A and receive a single dose of MK-7655 125 mg + PRIMAXIN® 250 mg IV in Part 1. Panel F Healthy Participants MK-7655 A subset of healthy control participants were matched specifically to participants in Panel E and receive a single dose of MK-7655 125 mg + PRIMAXIN® 250 mg IV in Part 1. In Part 2, participants receive an oral cocktail containing caffeine 200 mg, midazolam 2 mg, and omeprazole 40 mg. Panel C Moderate Renal Impairment MK-7655 Participants with an eGFR of 30 to 50 mL/min/1.73 m\^2 receive a single dose of MK-7655 125 mg + PRIMAXIN® 250 mg IV in Part 1. Panel E Severe Renal Impairment Caffeine Participants with an eGFR \<30 mL/min/1.73 m\^2 receive a single dose of MK-7655 125 mg + PRIMAXIN® 250 mg IV in Part 1. In Part 2, participants receive an oral cocktail containing caffeine 200 mg, midazolam 2 mg, and omeprazole 40 mg. Panel E Severe Renal Impairment Midazolam Participants with an eGFR \<30 mL/min/1.73 m\^2 receive a single dose of MK-7655 125 mg + PRIMAXIN® 250 mg IV in Part 1. In Part 2, participants receive an oral cocktail containing caffeine 200 mg, midazolam 2 mg, and omeprazole 40 mg. Panel F Healthy Participants Caffeine A subset of healthy control participants were matched specifically to participants in Panel E and receive a single dose of MK-7655 125 mg + PRIMAXIN® 250 mg IV in Part 1. In Part 2, participants receive an oral cocktail containing caffeine 200 mg, midazolam 2 mg, and omeprazole 40 mg. Panel F Healthy Participants Midazolam A subset of healthy control participants were matched specifically to participants in Panel E and receive a single dose of MK-7655 125 mg + PRIMAXIN® 250 mg IV in Part 1. In Part 2, participants receive an oral cocktail containing caffeine 200 mg, midazolam 2 mg, and omeprazole 40 mg. Panel F Healthy Participants Omeprazole A subset of healthy control participants were matched specifically to participants in Panel E and receive a single dose of MK-7655 125 mg + PRIMAXIN® 250 mg IV in Part 1. In Part 2, participants receive an oral cocktail containing caffeine 200 mg, midazolam 2 mg, and omeprazole 40 mg. Panel G End Stage Renal Disease with Hemodialysis (ESRD/HD) Caffeine Participants with ESRD/HD receive a single dose of MK-7655 125 mg + PRIMAXIN® 250 mg IV postdialysis (Part 1, Period 1) and predialysis (Part 1, Period 2). In Part 2, participants receive an oral cocktail containing caffeine 200 mg, midazolam 2 mg, and omeprazole 40 mg predialysis (Part 2, Period 1) and postdialysis (Part 2, Period 2). Panel G End Stage Renal Disease with Hemodialysis (ESRD/HD) Midazolam Participants with ESRD/HD receive a single dose of MK-7655 125 mg + PRIMAXIN® 250 mg IV postdialysis (Part 1, Period 1) and predialysis (Part 1, Period 2). In Part 2, participants receive an oral cocktail containing caffeine 200 mg, midazolam 2 mg, and omeprazole 40 mg predialysis (Part 2, Period 1) and postdialysis (Part 2, Period 2). Panel G End Stage Renal Disease with Hemodialysis (ESRD/HD) Omeprazole Participants with ESRD/HD receive a single dose of MK-7655 125 mg + PRIMAXIN® 250 mg IV postdialysis (Part 1, Period 1) and predialysis (Part 1, Period 2). In Part 2, participants receive an oral cocktail containing caffeine 200 mg, midazolam 2 mg, and omeprazole 40 mg predialysis (Part 2, Period 1) and postdialysis (Part 2, Period 2). Panel H Healthy Volunteers Midazolam A subset of healthy control participants were matched specifically to participants in Panel G and receive a single dose of MK-7655 125 mg + PRIMAXIN® 250 mg IV in Part 1. In Part 2, participants receive an oral cocktail containing caffeine 200 mg, midazolam 2 mg, and omeprazole 40 mg. Panel H Healthy Volunteers Caffeine A subset of healthy control participants were matched specifically to participants in Panel G and receive a single dose of MK-7655 125 mg + PRIMAXIN® 250 mg IV in Part 1. In Part 2, participants receive an oral cocktail containing caffeine 200 mg, midazolam 2 mg, and omeprazole 40 mg. Panel H Healthy Volunteers Omeprazole A subset of healthy control participants were matched specifically to participants in Panel G and receive a single dose of MK-7655 125 mg + PRIMAXIN® 250 mg IV in Part 1. In Part 2, participants receive an oral cocktail containing caffeine 200 mg, midazolam 2 mg, and omeprazole 40 mg.
- Primary Outcome Measures
Name Time Method Part 1: Area Under the Plasma Concentration-time Curve From Dosing to Infinity (AUC0-inf) of MK-7655 in Combination With PRIMAXIN® Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose AUC0-∞ is a measure of the mean (extrapolated) plasma drug concentration after dosing to infinity.
Extraction Coefficient of MK-7655 in Participants With End-stage Renal Diseases Requiring Hemodialysis (ESRD/HD) 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours postdose The extraction coefficient of MK-7655 was determined in ESRD/HD participants for 4.5 hours during HD. The formula for calculating extraction coefficient was: Extraction Coefficient = ABS\[100\*(post-dialyzer concentration - pre-dialyzer concentration) / pre-dialyzer concentration\].
Dialysis Clearance (CLD) of MK-7655 in Participants With End-stage Renal Diseases Requiring Hemodialysis (ESRD/HD) 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours postdose The CLD of MK-7655 was determined in ESRD/HD participants for 4.5 hours during HD. The formula for calculating CLD was: CLd = (1-Hct)\*QB\*\[(pre-dialyzer concentration - post-dialyzer concentration) / (pre-dialyzer concentration)\] where QB=350 mL/min and Hct=hematocrit.
- Secondary Outcome Measures
Name Time Method Part 1: Concentration at End of Infusion (Ceoi) of MK-7655 in Combination With PRIMAXIN® At 0.5 hours postdose Ceoi is the observed plasma drug concentration at the end of IV infusion.
Part 1: Apparent Plasma Half-life (t½) of MK-7655 in Combination With PRIMAXIN® Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose Apparent t½ is the amount of time for the maximum drug concentration to decrease by 50%.
Part 1: Ceoi of Imipenem in Combination With MK-7655 At 0.5 hours postdose Imipenem is 1 of the 2 constituents of PRIMAXIN®. Ceoi is the observed plasma drug concentration at the end of IV infusion.
Part 1: Time of Maximum Plasma Concentration (Tmax) of MK-7655 in Combination With PRIMAXIN® Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose Tmax is the time at which the highest plasma drug concentration was observed.
Part 1: Tmax of Imipenem in Combination With MK-7655 Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose Tmax is the time at which the highest plasma drug concentration was observed.
Part 1: VZpred of Cilastin in Combination With MK-7655 Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose Cilastin is 1 of the 2 constituents of PRIMAXIN®. VZpred is the predicted volume of distribution during the terminal phase.
Part 2: Plasma AUC0-∞ of Midazolam as a Probe Substrate of Cytochrome P450 Enzyme (CYP)3A4 Predose and 0.5, 1, 2,3, 4, 8, 12, and 24 hours postdose Midazolam was selected as a substrate of CYP3A4. AUC0-∞ was determined in participants with severe renal impairment and ESRD/HD participants.
Part 1: Predicted Clearance (CLpred) of MK-7655 in Combination With PRIMAXIN® Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose CLpred is the predicted apparent total body clearance of drug.
Part 1: Predicted Volume of Distribution During the Terminal Phase (VZpred) of MK-7655 in Combination With PRIMAXIN® Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose VZpred is the predicted volume of distribution during the terminal phase.
Part 1: AUC0-inf of Imipenem in Combination With MK-7655 Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose Imipenem is 1 of the 2 constituents of PRIMAXIN®. AUC0-∞ is a measure of the mean (extrapolated) plasma drug concentration after dosing to infinity.
Part 1: CLpred of Imipenem in Combination With MK-7655 Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose Imipenem is 1 of the 2 constituents of PRIMAXIN®. CLpred is the predicted apparent total body clearance of drug.
Part 1: VZpred of Imipenem in Combination With MK-7655 Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose Imipenem is 1 of the 2 constituents of PRIMAXIN®. VZpred is the predicted volume of distribution during the terminal phase.
Part 1: Apparent t½ of Imipenem in Combination With MK-7655 Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose Imipenem is 1 of the 2 constituents of PRIMAXIN®. Apparent t½ is the amount of time for the maximum drug concentration to decrease by 50%.
Part 1: AUC0-inf of Cilastin in Combination With MK-7655 Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose Cilastin is 1 of the 2 constituents of PRIMAXIN®. AUC0-∞ is a measure of the mean (extrapolated) plasma drug concentration after dosing to infinity.
Part 1: Ceoi of Cilastin in Combination With MK-7655 At 0.5 hours postdose Cilastin is 1 of the 2 constituents of PRIMAXIN®. Ceoi is the observed plasma drug concentration at the end of IV infusion.
Part 1: CLpred of Cilastin in Combination With MK-7655 Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose Cilastin is 1 of the 2 constituents of PRIMAXIN®. CLpred is the predicted apparent total body clearance of drug.
Part 1: CLR of Cilastin in Urine Predose to 24 hours postdose CLR represents renal clearance in urine. Urine was collected for 24 hours postdose.
Part 2: Plasma AUC0-∞ of Caffeine as a Probe Substrate of Cytochrome P450 Enzyme (CYP)1A2 Predose and 0.5, 1, 2,3, 4, 8, 12, and 24 hours postdose Caffeine was selected as a substrate of CYP1A2. AUC0-∞ was determined in participants with severe renal impairment and ESRD/HD participants.
Part 1: Apparent t½ of Cilastin in Combination With MK-7655 Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose Cilastin is 1 of the 2 constituents of PRIMAXIN®. Apparent t½ is the amount of time for the maximum drug concentration to decrease by 50%.
Parts 1 and 2: Percentage of Participants With ≥1 Adverse Events (AEs) Up to 14 days after the last dose of study drug in Part 2 (up to 11 weeks) An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
Part 1: Tmax of Cilastin in Combination With MK-7655 Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose Tmax is the time at which the highest plasma drug concentration was observed.
Part 1: Renal Clearance (CLR) of MK-7655 in Urine Predose to 24 hours postdose CLR represents renal clearance in urine. Urine was collected for 24 hours postdose.
Part 1: CLR of Imipenem in Urine Predose to 24 hours postdose CLR represents renal clearance in urine. Urine was collected for 24 hours postdose.
Part 2: Plasma AUC0-∞ of Omeprazole as a Probe Substrate of Cytochrome P450 Enzyme (CYP)2C19 Predose and 0.5, 1, 2,3, 4, 8, 12, and 24 hours postdose Omeprazole was selected as a substrate of CYP2C19. AUC0-∞ was determined in participants with severe renal impairment and ESRD/HD participants.