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

Merck Sharp & Dohme LLC32 enrolled

Overview

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).

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Renal Insufficiency

Interventions

Midazolam oral solutionDRUG

Eligibility

Sex: ALLMin age: 18 YearsMax age: 78 YearsHealthy volunteers:

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1

AUC0-inf is the area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease (ESRD) requiring hemodialysis.

Time frame: 0 hour (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose

Effect of Rifampin on AUC0-inf Post-dose Period 2

To evaluate the effect of a single oral dose of rifampin on the AUC0-inf of midazolam, dabigatran, pitavastatin, pitavastatin lactone, atorvastatin, ortho-hydroxyatorvastatin, and rosuvatatin. AUC0-inf is the area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail and rifampin in healthy participants and participants with renal impairment. As pre-specified in the protocol, this outcome measure does not include data from the end-stage renal disease participants as they did not receive rifampin during Period 2.

Time frame: Microdose cocktail: 0 hour (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose; rifampin: 0 hour (pre-dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose

Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1

AUC0-24 is the area under the plasma concentration-time curve from time 0 to 24 hours post-dose. This is a measure of the average amount of study drug in the blood plasma over a period of 24 hours after the dose. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease requiring hemodialysis.

Time frame: 0 hour (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post-dose

Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1

AUC0-last is the area under the plasma concentration-time curve from time zero to time of last measurable concentration. This is a measure of the amount of study drug in the blood plasma from pre-dose until the last measurable concentration of study drug could be determined. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease requiring hemodialysis.

Time frame: 0 hour (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose

Maximum Plasma Concentration (Cmax) Post-dose Period 1

Cmax is the peak plasma concentration of study drug after administration. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease requiring hemodialysis.