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 (MSD)

Status and phase: Completed; Phase 1

Conditions: Renal Insufficiency

Treatments: Drug: Atorvastatin and rosuvastatin oral solution; Drug: Rifampin; Drug: Midazolam oral solution; Drug: Dabigatran and pitavastatin oral solution

Study type: Interventional

Funder types: Industry

Identifiers

NCT03311841

CA21005 (Other Identifier)

MK-0000-386 (Other Identifier)

0000-386

Details and patient eligibility

About

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).

Enrollment: 32 patients

Sex: All

Ages: 18 to 78 years old

Volunteers: Accepts Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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32 participants in 5 patient groups

End Stage Renal Disease

Experimental group

Description:

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.

Treatment:

Drug: Atorvastatin and rosuvastatin oral solution

Drug: Midazolam oral solution

Drug: Dabigatran and pitavastatin oral solution

Severe Impairment

Experimental group

Description:

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.

Treatment:

Drug: Atorvastatin and rosuvastatin oral solution

Drug: Midazolam oral solution

Drug: Rifampin

Drug: Dabigatran and pitavastatin oral solution

Moderate Impairment

Experimental group

Description:

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.

Treatment:

Drug: Atorvastatin and rosuvastatin oral solution

Drug: Midazolam oral solution

Drug: Rifampin

Drug: Dabigatran and pitavastatin oral solution

Mild Impairment

Experimental group

Description:

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.

Treatment:

Drug: Atorvastatin and rosuvastatin oral solution

Drug: Midazolam oral solution

Drug: Rifampin

Drug: Dabigatran and pitavastatin oral solution

Healthy Control

Active Comparator group

Description:

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.

Treatment:

Drug: Atorvastatin and rosuvastatin oral solution

Drug: Midazolam oral solution

Drug: Rifampin

Drug: Dabigatran and pitavastatin oral solution