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

A Single-Dose Study to Investigate the Pharmacokinetics of MK-7655 in Subjects With Impaired Renal Function

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 Overview

• Status: Completed
• Conditions: Infectious Disease
• Intervention / Treatment: Drug: MK-7655; Drug: Imipenem + Cilastatin; Drug: Caffeine; Drug: Midazolam; Drug: Omeprazole

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Panel A Mild Renal Impairment; 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.	Drug: MK-7655; 125 mg intravenous (IV) over 30 minutes as a single dose; Other Names: RELEBACTAM®; Drug: Imipenem + Cilastatin; 250 mg IV over 30 minutes as a single dose; Other Names: PRIMAXIN®
EXPERIMENTAL: Panel B Healthy Participants; 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.	Drug: MK-7655; 125 mg intravenous (IV) over 30 minutes as a single dose; Other Names: RELEBACTAM®; Drug: Imipenem + Cilastatin; 250 mg IV over 30 minutes as a single dose; Other Names: PRIMAXIN®
EXPERIMENTAL: Panel C Moderate Renal Impairment; 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.	Drug: MK-7655; 125 mg intravenous (IV) over 30 minutes as a single dose; Other Names: RELEBACTAM®; Drug: Imipenem + Cilastatin; 250 mg IV over 30 minutes as a single dose; Other Names: PRIMAXIN®
EXPERIMENTAL: Panel D Healthy Participants; 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.	Drug: MK-7655; 125 mg intravenous (IV) over 30 minutes as a single dose; Other Names: RELEBACTAM®; Drug: Imipenem + Cilastatin; 250 mg IV over 30 minutes as a single dose; Other Names: PRIMAXIN®
EXPERIMENTAL: Panel E Severe Renal Impairment; 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.	Drug: MK-7655; 125 mg intravenous (IV) over 30 minutes as a single dose; Other Names: RELEBACTAM®; Drug: Imipenem + Cilastatin; 250 mg IV over 30 minutes as a single dose; Other Names: PRIMAXIN®; Drug: Caffeine; Caffeine caplet, single 200 mg dose, orally; Other Names: No Doz®; Drug: Midazolam; Midazolam hcl syrup single 2.0 mg dose by mouth.; Other Names: VERSED®; Drug: Omeprazole; Omeprazole tablets, single 40 mg dose (as two 20 mg tablets), orally; Other Names: PRILOSEC®
EXPERIMENTAL: Panel F Healthy Participants; 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.	Drug: MK-7655; 125 mg intravenous (IV) over 30 minutes as a single dose; Other Names: RELEBACTAM®; Drug: Imipenem + Cilastatin; 250 mg IV over 30 minutes as a single dose; Other Names: PRIMAXIN®; Drug: Caffeine; Caffeine caplet, single 200 mg dose, orally; Other Names: No Doz®; Drug: Midazolam; Midazolam hcl syrup single 2.0 mg dose by mouth.; Other Names: VERSED®; Drug: Omeprazole; Omeprazole tablets, single 40 mg dose (as two 20 mg tablets), orally; Other Names: PRILOSEC®
EXPERIMENTAL: Panel G End Stage Renal Disease with Hemodialysis (ESRD/HD); 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).	Drug: MK-7655; 125 mg intravenous (IV) over 30 minutes as a single dose; Other Names: RELEBACTAM®; Drug: Imipenem + Cilastatin; 250 mg IV over 30 minutes as a single dose; Other Names: PRIMAXIN®; Drug: Caffeine; Caffeine caplet, single 200 mg dose, orally; Other Names: No Doz®; Drug: Midazolam; Midazolam hcl syrup single 2.0 mg dose by mouth.; Other Names: VERSED®; Drug: Omeprazole; Omeprazole tablets, single 40 mg dose (as two 20 mg tablets), orally; Other Names: PRILOSEC®
EXPERIMENTAL: Panel H Healthy Volunteers; 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.	Drug: MK-7655; 125 mg intravenous (IV) over 30 minutes as a single dose; Other Names: RELEBACTAM®; Drug: Imipenem + Cilastatin; 250 mg IV over 30 minutes as a single dose; Other Names: PRIMAXIN®; Drug: Caffeine; Caffeine caplet, single 200 mg dose, orally; Other Names: No Doz®; Drug: Midazolam; Midazolam hcl syrup single 2.0 mg dose by mouth.; Other Names: VERSED®; Drug: Omeprazole; Omeprazole tablets, single 40 mg dose (as two 20 mg tablets), orally; Other Names: PRILOSEC®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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].	1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours postdose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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: 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.	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.	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%.	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.	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.	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.	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.	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.	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%.	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.	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.	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.	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.	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.	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%.	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.	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.	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.	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.	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.	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.	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.	Up to 14 days after the last dose of study drug in Part 2 (up to 11 weeks)

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Bhagunde P, Colon-Gonzalez F, Liu Y, Wu J, Xu SS, Garrett G, Jumes P, Lasseter K, Marbury T, Rizk ML, Lala M, Rhee EG, Butterton JR, Boundy K. Impact of renal impairment and human organic anion transporter inhibition on pharmacokinetics, safety and tolerability of relebactam combined with imipenem and cilastatin. Br J Clin Pharmacol. 2020 May;86(5):944-957. doi: 10.1111/bcp.14204. Epub 2020 Jan 23.

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 28, 2011
• Primary Completion (ACTUAL): March 5, 2012
• Study Completion (ACTUAL): March 5, 2012

Study Registration Dates

• First Submitted: January 10, 2011
• First Submitted That Met QC Criteria: January 10, 2011
• First Posted (ESTIMATE): January 12, 2011

Study Record Updates

• Last Update Posted (ACTUAL): June 11, 2020
• Last Update Submitted That Met QC Criteria: May 28, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Kidney Diseases; Urologic Diseases; Disease Attributes; Infections; Communicable Diseases; Renal Insufficiency; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Central Nervous System Depressants; Enzyme Inhibitors; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Purinergic Antagonists; Purinergic Agents; Gastrointestinal Agents; Protease Inhibitors; Anti-Bacterial Agents; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Central Nervous System Stimulants; beta-Lactamase Inhibitors; Midazolam; Imipenem; Relebactam; Cilastatin; Caffeine; Omeprazole; Cilastatin, Imipenem Drug Combination
• Other Study ID Numbers: 7655-005

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf