A Single-Dose Study to Investigate the Pharmacokinetics of MK-7655 in Participants With Impaired Renal Function (MK-7655-005)

Merck Sharp & Dohme LLC49 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Infectious Disease

Interventions

MK-7655DRUG

125 mg intravenous (IV) over 30 minutes as a single dose

Imipenem + CilastatinDRUG

250 mg IV over 30 minutes as a single dose

CaffeineDRUG

Caffeine caplet, single 200 mg dose, orally

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion criteria * Participants of reproductive potential (male or female) must be willing to use contraception. * Body Mass Index (BMI) ≤40 kg/m\^2 * Weight \>60 kg at screening visit * No clinically significant abnormality on electrocardiogram (ECG) at screening visit and/or prior to administration of the initial dose of study drug * Panels A-D: smokers will be limited to no more that 10 cigarettes per day. * Panels E-H: nonsmoker or has not used nicotine for at least 6 months * In good health (stable health for participants with renal impairment) Exclusion criteria * Pregnant or breastfeeding. * History of recent stroke, chronic seizures, or major neurological disorder * History of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, immunological, respiratory, or genitourinary abnormalities or diseases * History of malignant neoplastic disease. Exceptions: (1) adequately treated non-melanomatous skin carcinoma or carcinoma in situ of the cervix; (2) other malignancies that have been successfully treated ≥10 years prior to the screening visit * Panels A-D: Use of any medication (prescription or non-prescription) or herbal remedies (such as St. John's Wort \[Hypericum perforatum\]) beginning approximately 2 weeks (or 5 half-lives) prior to administration of the initial dose of study drug to the post study visit * Panels E-H: Use of any medication (prescription or non-prescription) or herbal remedies (such as St. John's Wort \[Hypericum perforatum\]) that are inhibitors or inducers of CYP1A2, CYP2C19, CYP34A, or substrates of CYP2C19, beginning approximately 2 weeks (or 5 half-lives) prior to administration of the probe cocktail, until the post-study visit * Consumption of greater than 3 glasses of alcoholic beverages (1 glass is approximately equivalent to: beer \[284 mL/10 ounces\], wine \[125 mL/4 ounces\], or distilled spirits \[25 mL/1 ounce\]) per day * Consumption of greater than 6 servings (1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, or other caffeinated beverages per day * Major surgery, donation or loss of 1 unit of blood (approximately 500 mL), or participation in another investigational study within 4 weeks prior to the screening visit * History of multiple and/or severe allergies (including latex allergy), or prior anaphylactic reaction or intolerability to prescription or non-prescription drugs or food * History of hypersensitivity to PRIMAXIN® IV or other beta lactam antibiotic (including but not limited to penicillins, cephalosporins, monobactams and carbapenems) * Regular user (including recreational use of drugs \[including alcohol\]) within approximately 12 months of screening visit * History of kidney removal and/or renal transplant * History of Clostridium difficile colitis or known C. difficile colonization

Outcomes

Primary Outcomes

Part 1: Area Under the Plasma Concentration-time Curve From Dosing to Infinity (AUC0-inf) of MK-7655 in Combination With PRIMAXIN®

AUC0-∞ is a measure of the mean (extrapolated) plasma drug concentration after dosing to infinity.

Time frame: Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose

Dialysis Clearance (CLD) of MK-7655 in Participants With End-stage Renal Diseases Requiring Hemodialysis (ESRD/HD)

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.

Time frame: 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours postdose

Extraction Coefficient of MK-7655 in Participants With End-stage Renal Diseases Requiring Hemodialysis (ESRD/HD)

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\[100\*(post-dialyzer concentration - pre-dialyzer concentration) / pre-dialyzer concentration\].

Time frame: 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours postdose

Secondary Outcomes

Part 1: Concentration at End of Infusion (Ceoi) of MK-7655 in Combination With PRIMAXIN®

Ceoi is the observed plasma drug concentration at the end of IV infusion.

Time frame: At 0.5 hours postdose

Part 1: Predicted Clearance (CLpred) of MK-7655 in Combination With PRIMAXIN®

CLpred is the predicted apparent total body clearance of drug.

Time frame: Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose

Data from ClinicalTrials.gov

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Midazolam hcl syrup single 2.0 mg dose by mouth.

OmeprazoleDRUG

Omeprazole tablets, single 40 mg dose (as two 20 mg tablets), orally

Part 1: Predicted Volume of Distribution During the Terminal Phase (VZpred) of MK-7655 in Combination With PRIMAXIN®

VZpred is the predicted volume of distribution during the terminal phase.

Time frame: Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose

Part 1: Time of Maximum Plasma Concentration (Tmax) of MK-7655 in Combination With PRIMAXIN®

Tmax is the time at which the highest plasma drug concentration was observed.

Time frame: Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose

Part 1: Apparent Plasma Half-life (t½) of MK-7655 in Combination With PRIMAXIN®

Apparent t½ is the amount of time for the maximum drug concentration to decrease by 50%.

Time frame: Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose

Part 1: AUC0-inf of Imipenem in Combination With MK-7655

Imipenem is 1 of the 2 constituents of PRIMAXIN®. AUC0-∞ is a measure of the mean (extrapolated) plasma drug concentration after dosing to infinity.

Time frame: Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose

Part 1: Ceoi of Imipenem in Combination With MK-7655

Imipenem is 1 of the 2 constituents of PRIMAXIN®. Ceoi is the observed plasma drug concentration at the end of IV infusion.

Time frame: At 0.5 hours postdose

Part 1: CLpred of Imipenem in Combination With MK-7655

Imipenem is 1 of the 2 constituents of PRIMAXIN®. CLpred is the predicted apparent total body clearance of drug.

Time frame: Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose

Part 1: VZpred of Imipenem in Combination With MK-7655

Imipenem is 1 of the 2 constituents of PRIMAXIN®. VZpred is the predicted volume of distribution during the terminal phase.

Time frame: Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose

Part 1: Tmax of Imipenem in Combination With MK-7655

Tmax is the time at which the highest plasma drug concentration was observed.

Time frame: Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose

Part 1: Apparent t½ of Imipenem in Combination With MK-7655

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%.

Time frame: Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose

Part 1: AUC0-inf of Cilastin in Combination With MK-7655

Cilastin is 1 of the 2 constituents of PRIMAXIN®. AUC0-∞ is a measure of the mean (extrapolated) plasma drug concentration after dosing to infinity.

Time frame: Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose

Part 1: Ceoi of Cilastin in Combination With MK-7655

Cilastin is 1 of the 2 constituents of PRIMAXIN®. Ceoi is the observed plasma drug concentration at the end of IV infusion.

Time frame: At 0.5 hours postdose

Part 1: CLpred of Cilastin in Combination With MK-7655

Cilastin is 1 of the 2 constituents of PRIMAXIN®. CLpred is the predicted apparent total body clearance of drug.

Time frame: Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose

Part 1: VZpred of Cilastin in Combination With MK-7655

Cilastin is 1 of the 2 constituents of PRIMAXIN®. VZpred is the predicted volume of distribution during the terminal phase.

Time frame: Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose

Part 1: Tmax of Cilastin in Combination With MK-7655

Tmax is the time at which the highest plasma drug concentration was observed.

Time frame: Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose

Part 1: Apparent t½ of Cilastin in Combination With MK-7655

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%.

Time frame: Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose

Part 1: Renal Clearance (CLR) of MK-7655 in Urine

CLR represents renal clearance in urine. Urine was collected for 24 hours postdose.

Time frame: Predose to 24 hours postdose

Part 1: CLR of Imipenem in Urine

CLR represents renal clearance in urine. Urine was collected for 24 hours postdose.

Time frame: Predose to 24 hours postdose

Part 1: CLR of Cilastin in Urine

CLR represents renal clearance in urine. Urine was collected for 24 hours postdose.

Time frame: Predose to 24 hours postdose

Part 2: Plasma AUC0-∞ of Caffeine as a Probe Substrate of Cytochrome P450 Enzyme (CYP)1A2

Caffeine was selected as a substrate of CYP1A2. AUC0-∞ was determined in participants with severe renal impairment and ESRD/HD participants.

Time frame: Predose and 0.5, 1, 2,3, 4, 8, 12, and 24 hours postdose

Part 2: Plasma AUC0-∞ of Midazolam as a Probe Substrate of Cytochrome P450 Enzyme (CYP)3A4

Midazolam was selected as a substrate of CYP3A4. AUC0-∞ was determined in participants with severe renal impairment and ESRD/HD participants.

Time frame: Predose and 0.5, 1, 2,3, 4, 8, 12, and 24 hours postdose

Part 2: Plasma AUC0-∞ of Omeprazole as a Probe Substrate of Cytochrome P450 Enzyme (CYP)2C19

Omeprazole was selected as a substrate of CYP2C19. AUC0-∞ was determined in participants with severe renal impairment and ESRD/HD participants.

Time frame: Predose and 0.5, 1, 2,3, 4, 8, 12, and 24 hours postdose

Parts 1 and 2: Percentage of Participants With ≥1 Adverse Events (AEs)

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.

Time frame: Up to 14 days after the last dose of study drug in Part 2 (up to 11 weeks)