Pharmacokinetics of Midazolam, Dabigatran, Pitavastatin, Atorvastatin, and Rosuvastatin in Participants With Renal Insufficiency in the Presence and Absence of Rifampin (MK-0000-386)

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1

Total Enrollment

32 participants

Study Classification

INTERVENTIONAL

Study Start Date

2018-03-01

Study Completion Date

2018-08-02

Brief Summary

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The purpose of this open-label, 2-period, fixed-sequence study is to characterize the plasma pharmacokinetic profiles of midazolam, dabigatran, pitavastatin, atorvastatin, and rosuvastatin following a single oral dose administration of a microdose cocktail in healthy participants, in participants with mild, moderate, severe (not on dialysis) renal impairment, and in participants with end-stage renal disease (ESRD; on dialysis).

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Detailed Description

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Conditions

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Renal Insufficiency

Study Design

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Allocation Method

NON_RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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End Stage Renal Disease

Participants requiring hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). A washout period of at least 14 days will separate dosings.

Group Type EXPERIMENTAL

Midazolam oral solution

Intervention Type DRUG

Midazolam hydrochloride 10 μg (1 mL of 10 μg/mL oral solution), administered orally as part of a microdose cocktail

Dabigatran and pitavastatin oral solution

Intervention Type DRUG

375/10 μg dabigatran etexilate and pitavastatin (1 mL of 375/10 μg/mL oral solution), administered orally as part of a microdose cocktail

Atorvastatin and rosuvastatin oral solution

Intervention Type DRUG

100/50 μg atorvastatin and rosuvastatin (2 mL of 50/25 μg/mL oral solution), administered orally as part of a microdose cocktail

Severe Impairment

Participants with \<30 mL/min/1.73m\^2 estimated glomerular filtration rate (eGFR) not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.

Group Type EXPERIMENTAL

Midazolam oral solution

Intervention Type DRUG

Midazolam hydrochloride 10 μg (1 mL of 10 μg/mL oral solution), administered orally as part of a microdose cocktail

Dabigatran and pitavastatin oral solution

Intervention Type DRUG

375/10 μg dabigatran etexilate and pitavastatin (1 mL of 375/10 μg/mL oral solution), administered orally as part of a microdose cocktail

Atorvastatin and rosuvastatin oral solution

Intervention Type DRUG

100/50 μg atorvastatin and rosuvastatin (2 mL of 50/25 μg/mL oral solution), administered orally as part of a microdose cocktail

Rifampin

Intervention Type DRUG

Rifampin 600 mg single dose (two 300 mg capsules) administered orally

Moderate Impairment

Participants with 30 to \<60 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.

Group Type EXPERIMENTAL

Midazolam oral solution

Intervention Type DRUG

Midazolam hydrochloride 10 μg (1 mL of 10 μg/mL oral solution), administered orally as part of a microdose cocktail

Dabigatran and pitavastatin oral solution

Intervention Type DRUG

375/10 μg dabigatran etexilate and pitavastatin (1 mL of 375/10 μg/mL oral solution), administered orally as part of a microdose cocktail

Atorvastatin and rosuvastatin oral solution

Intervention Type DRUG

100/50 μg atorvastatin and rosuvastatin (2 mL of 50/25 μg/mL oral solution), administered orally as part of a microdose cocktail

Rifampin

Intervention Type DRUG

Rifampin 600 mg single dose (two 300 mg capsules) administered orally

Mild Impairment

Participants with 60 to \<90 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.

Group Type EXPERIMENTAL

Midazolam oral solution

Intervention Type DRUG

Midazolam hydrochloride 10 μg (1 mL of 10 μg/mL oral solution), administered orally as part of a microdose cocktail

Dabigatran and pitavastatin oral solution

Intervention Type DRUG

375/10 μg dabigatran etexilate and pitavastatin (1 mL of 375/10 μg/mL oral solution), administered orally as part of a microdose cocktail

Atorvastatin and rosuvastatin oral solution

Intervention Type DRUG

100/50 μg atorvastatin and rosuvastatin (2 mL of 50/25 μg/mL oral solution), administered orally as part of a microdose cocktail

Rifampin

Intervention Type DRUG

Rifampin 600 mg single dose (two 300 mg capsules) administered orally

Healthy Control

Participants with ≥90 mL/min creatinine clearance. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings.

Group Type ACTIVE_COMPARATOR

Midazolam oral solution

Intervention Type DRUG

Midazolam hydrochloride 10 μg (1 mL of 10 μg/mL oral solution), administered orally as part of a microdose cocktail

Dabigatran and pitavastatin oral solution

Intervention Type DRUG

375/10 μg dabigatran etexilate and pitavastatin (1 mL of 375/10 μg/mL oral solution), administered orally as part of a microdose cocktail

Atorvastatin and rosuvastatin oral solution

Intervention Type DRUG

100/50 μg atorvastatin and rosuvastatin (2 mL of 50/25 μg/mL oral solution), administered orally as part of a microdose cocktail

Rifampin

Intervention Type DRUG

Rifampin 600 mg single dose (two 300 mg capsules) administered orally

Interventions

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Midazolam oral solution

Midazolam hydrochloride 10 μg (1 mL of 10 μg/mL oral solution), administered orally as part of a microdose cocktail

Intervention Type DRUG

Dabigatran and pitavastatin oral solution

375/10 μg dabigatran etexilate and pitavastatin (1 mL of 375/10 μg/mL oral solution), administered orally as part of a microdose cocktail

Intervention Type DRUG

Atorvastatin and rosuvastatin oral solution

100/50 μg atorvastatin and rosuvastatin (2 mL of 50/25 μg/mL oral solution), administered orally as part of a microdose cocktail

Intervention Type DRUG

Rifampin

Rifampin 600 mg single dose (two 300 mg capsules) administered orally

Intervention Type DRUG

Eligibility Criteria

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Inclusion Criteria

All participants (with mild, moderate or severe renal impairment, end stage renal disease, or healthy):

* a female must be non-pregnant, non-breast feeding and if she is of reproductive potential: must agree to use (and/or have their partner use) two acceptable methods of birth control beginning at screening, throughout the study and until 2 weeks after the last dosing of study drug
* a female of non-childbearing potential: must have undergone a sterilization procedure at least 6 months prior to the first dose or be postmenopausal with amenorrhea for at least 1 year prior to the first dose
* a non-vasectomized male participant must agree to use a condom with spermicide or abstain from sexual intercourse from the first dose until 90 days after the last dose of study drug
* a male participant must agree not to donate sperm from dosing until 90 days after the last dose of study drug
* has a body mass index (BMI) ≤ 40.0 kg/m\^2
* is a non-smoker or moderate smoker (≤ 20 cigarettes/day or the equivalent)

Participants with mild, moderate or severe renal impairment or end stage renal disease:

* has a clinical diagnosis of renal impairment and meets the protocol-specified renal impairment function qualifications at the prestudy visit (screening)

Healthy participants:

* has baseline creatinine clearance ≥ 90 mL/min based on Cockcroft-Gault equation
* is judged to be in good health based on medical history, physical examination, vital signs, pulse oximetry, and laboratory safety tests

Exclusion Criteria

All participants (with mild, moderate or severe renal impairment, end stage renal disease, or healthy):

* is mentally or legally incapacitated or has significant emotional problems at the time of the screening visit or expected during the conduct of the study.
* history or presence of clinically significant medical or psychiatric condition or disease
* history of stroke, chronic seizures, or major neurological disorders
* history of malignant neoplastic disease
* history or presence of alcoholism or drug abuse within the past 6 months
* female participant who is pregnant or lactating

Participants with mild, moderate or severe renal impairment:

* has had a renal transplant or has had nephrectomy
* has uncontrolled type 2 diabetes mellitus (T2DM), a history of Type 1 diabetes, or ketoacidosis
* history of significant endocrine, gastrointestinal, cardiovascular, hematological, immunological, respiratory, or genitourinary diseases

Participants with end stage renal disease (ESRD):

* had a failed renal allograft within the last 2 years prior to the first dose, or a successful renal allograft
* has uncontrolled T2DM, a history of Type 1 diabetes, or ketoacidosis
* history of significant endocrine, gastrointestinal, cardiovascular, hematological, immunological, respiratory, or genitourinary diseases

Healthy participants:

* history of hypoglycemia, glucose intolerance, T2DM, or ketoacidosis
* history of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, or genitourinary abnormalities or diseases.

Minimum Eligible Age

18 Years

Maximum Eligible Age

78 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes