Clinical trial NCT01275170: A Single-Dose Study to Investigate the Pharmacokinetics of MK-7655 in Participants With Impaired Renal Function (MK-7655-005)
Official title: A Single-Dose Study to Investigate the Pharmacokinetics of MK-7655 in Subjects With Impaired Renal Function
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Infectious Disease
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2011-01-12
Enrollment: 49
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Part 1: Area Under the Plasma Concentration-time Curve From Dosing to Infinity (AUC0-inf) of MK-7655 in Combination With PRIMAXIN®
timeFrame: Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose
measure: Dialysis Clearance (CLD) of MK-7655 in Participants With End-stage Renal Diseases Requiring Hemodialysis (ESRD/HD)
timeFrame: 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours postdose
measure: Extraction Coefficient of MK-7655 in Participants With End-stage Renal Diseases Requiring Hemodialysis (ESRD/HD)
timeFrame: 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours postdose
Secondary outcomes:
measure: Part 1: Concentration at End of Infusion (Ceoi) of MK-7655 in Combination With PRIMAXIN®
timeFrame: At 0.5 hours postdose
measure: Part 1: Predicted Clearance (CLpred) of MK-7655 in Combination With PRIMAXIN®
timeFrame: Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose
measure: Part 1: Predicted Volume of Distribution During the Terminal Phase (VZpred) of MK-7655 in Combination With PRIMAXIN®
timeFrame: Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose
measure: Part 1: Time of Maximum Plasma Concentration (Tmax) of MK-7655 in Combination With PRIMAXIN®
timeFrame: Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose
measure: Part 1: Apparent Plasma Half-life (t½) of MK-7655 in Combination With PRIMAXIN®
timeFrame: Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose
measure: Part 1: AUC0-inf of Imipenem in Combination With MK-7655
timeFrame: Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose
measure: Part 1: Ceoi of Imipenem in Combination With MK-7655
timeFrame: At 0.5 hours postdose
measure: Part 1: CLpred of Imipenem in Combination With MK-7655
timeFrame: Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose
measure: Part 1: VZpred of Imipenem in Combination With MK-7655
timeFrame: Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose
measure: Part 1: Tmax of Imipenem in Combination With MK-7655
timeFrame: Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose
measure: Part 1: Apparent t½ of Imipenem in Combination With MK-7655
timeFrame: Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose
measure: Part 1: AUC0-inf of Cilastin in Combination With MK-7655
timeFrame: Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose
measure: Part 1: Ceoi of Cilastin in Combination With MK-7655
timeFrame: At 0.5 hours postdose
measure: Part 1: CLpred of Cilastin in Combination With MK-7655
timeFrame: Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose
measure: Part 1: VZpred of Cilastin in Combination With MK-7655
timeFrame: Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose
measure: Part 1: Tmax of Cilastin in Combination With MK-7655
timeFrame: Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose
measure: Part 1: Apparent t½ of Cilastin in Combination With MK-7655
timeFrame: Predose and 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, and 14 hours postdose
measure: Part 1: Renal Clearance (CLR) of MK-7655 in Urine
timeFrame: Predose to 24 hours postdose
measure: Part 1: CLR of Imipenem in Urine
timeFrame: Predose to 24 hours postdose
measure: Part 1: CLR of Cilastin in Urine
timeFrame: Predose to 24 hours postdose
measure: Part 2: Plasma AUC0-∞ of Caffeine as a Probe Substrate of Cytochrome P450 Enzyme (CYP)1A2
timeFrame: Predose and 0.5, 1, 2,3, 4, 8, 12, and 24 hours postdose
measure: Part 2: Plasma AUC0-∞ of Midazolam as a Probe Substrate of Cytochrome P450 Enzyme (CYP)3A4
timeFrame: Predose and 0.5, 1, 2,3, 4, 8, 12, and 24 hours postdose
measure: Part 2: Plasma AUC0-∞ of Omeprazole as a Probe Substrate of Cytochrome P450 Enzyme (CYP)2C19
timeFrame: Predose and 0.5, 1, 2,3, 4, 8, 12, and 24 hours postdose
measure: Parts 1 and 2: Percentage of Participants With ≥1 Adverse Events (AEs)
timeFrame: Up to 14 days after the last dose of study drug in Part 2 (up to 11 weeks)
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.