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

NCT01275170 | Completed Phase 1 Results

• 1 other identifier: 7655-005
• Study Type: interventional
• Target: 49
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Infectious Disease

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (24)

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

  At 0.5 hours postdose

• 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

• 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

• 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

• 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

Study Arms (8)

Panel A Mild Renal Impairment

EXPERIMENTAL

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; Drug: Imipenem + Cilastatin

Panel B Healthy Participants

EXPERIMENTAL

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; Drug: Imipenem + Cilastatin

Panel C Moderate Renal Impairment

EXPERIMENTAL

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; Drug: Imipenem + Cilastatin

Panel D Healthy Participants

EXPERIMENTAL

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; Drug: Imipenem + Cilastatin

Panel E Severe Renal Impairment

EXPERIMENTAL

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; Drug: Imipenem + Cilastatin; Drug: Caffeine; Drug: Midazolam; Drug: Omeprazole

Panel F Healthy Participants

EXPERIMENTAL

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; Drug: Imipenem + Cilastatin; Drug: Caffeine; Drug: Midazolam; Drug: Omeprazole

Panel G End Stage Renal Disease with Hemodialysis (ESRD/HD)

EXPERIMENTAL

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; Drug: Imipenem + Cilastatin; Drug: Caffeine; Drug: Midazolam; Drug: Omeprazole

Panel H Healthy Volunteers

EXPERIMENTAL

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; Drug: Imipenem + Cilastatin; Drug: Caffeine; Drug: Midazolam; Drug: Omeprazole

Interventions

MK-7655 DRUG

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

Also known as: RELEBACTAM®

Panel A Mild Renal Impairment; Panel B Healthy Participants; Panel C Moderate Renal Impairment; Panel D Healthy Participants; Panel E Severe Renal Impairment; Panel F Healthy Participants; Panel G End Stage Renal Disease with Hemodialysis (ESRD/HD); Panel H Healthy Volunteers

Imipenem + Cilastatin DRUG

250 mg IV over 30 minutes as a single dose

Also known as: PRIMAXIN®

Panel A Mild Renal Impairment; Panel B Healthy Participants; Panel C Moderate Renal Impairment; Panel D Healthy Participants; Panel E Severe Renal Impairment; Panel F Healthy Participants; Panel G End Stage Renal Disease with Hemodialysis (ESRD/HD); Panel H Healthy Volunteers

Caffeine DRUG

Caffeine caplet, single 200 mg dose, orally

Also known as: No Doz®

Panel E Severe Renal Impairment; Panel F Healthy Participants; Panel G End Stage Renal Disease with Hemodialysis (ESRD/HD); Panel H Healthy Volunteers

Midazolam DRUG

Midazolam hcl syrup single 2.0 mg dose by mouth.

Also known as: VERSED®

Panel E Severe Renal Impairment; Panel F Healthy Participants; Panel G End Stage Renal Disease with Hemodialysis (ESRD/HD); Panel H Healthy Volunteers

Omeprazole DRUG

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

Also known as: PRILOSEC®

Panel E Severe Renal Impairment; Panel F Healthy Participants; Panel G End Stage Renal Disease with Hemodialysis (ESRD/HD); Panel H Healthy Volunteers

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (1)

• 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.

  PMID: 31856304 RESULT

MeSH Terms

Conditions

Communicable Diseases

Interventions

relebactam; Cilastatin, Imipenem Drug Combination; Caffeine; Midazolam; Omeprazole

Condition Hierarchy (Ancestors)

Infections; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Imipenem; Thienamycins; Carbapenems; beta-Lactams; Lactams; Amides; Organic Chemicals; Cilastatin; Cyclopropanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Fatty Acids; Lipids; Drug Combinations; Pharmaceutical Preparations; Xanthines; Alkaloids; Purinones; Purines; Benzodiazepines; Benzazepines; 2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Sulfur Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Benzimidazoles

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 10, 2011
• First Posted: January 12, 2011
• Study Start: January 28, 2011
• Primary Completion: March 5, 2012
• Study Completion: March 5, 2012
• Last Updated: June 11, 2020
• Results First Posted: July 19, 2019

Record last verified: 2020-05

Data Sharing

• IPD Sharing: Will share