Clinical trial NCT03311841: Pharmacokinetics of Midazolam, Dabigatran, Pitavastatin, Atorvastatin, and Rosuvastatin in Participants With Renal Insufficiency in the Presence and Absence of Rifampin (MK-0000-386)
Official title: A Study to Assess the Pharmacokinetics of Midazolam, Dabigatran, Pitavastatin, Atorvastatin, and Rosuvastatin Administered as Microdoses in Subjects With Varying Degrees of Renal Insufficiency in the Presence and Absence of Rifampin
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Renal Insufficiency
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2017-10-17
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Maximum age (years): 78
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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).


Eligibility criteria: 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.

Primary outcomes:
measure: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1
timeFrame: 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
measure: Effect of Rifampin on AUC0-inf Post-dose Period 2
timeFrame: 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
measure: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1
timeFrame: 0 hour (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post-dose
measure: Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1
timeFrame: 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
measure: Maximum Plasma Concentration (Cmax) Post-dose Period 1
timeFrame: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose
measure: Plasma Concentration at 24 Hours (C24) Post-dose Period 1
timeFrame: 24 hours post-dose
measure: Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1
timeFrame: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose
measure: Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1
timeFrame: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose
measure: Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1
timeFrame: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose
measure: Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1
timeFrame: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose
Secondary outcomes:
measure: Effect of Rifampin on AUC0-24 Post-dose Period 2
timeFrame: Microdose cocktail: 0 hour (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post-dose; rifampin: 0 hour (pre-dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose
measure: Effect of Rifampin on AUC0-last Post-dose Period 2
timeFrame: 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
measure: Effect of Rifampin on Cmax Post-dose Period 2
timeFrame: Microdose cocktail: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose; rifampin: 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose
measure: Effect of Rifampin on C24 Post-dose Period 2
timeFrame: 24 hours post-dose
measure: Effect of Rifampin on Tmax Post-dose Period 2
timeFrame: Microdose cocktail: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose; rifampin: 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose
measure: Effect of Rifampin on t1/2 Post-dose Period 2
timeFrame: Microdose cocktail: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose; rifampin: 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose
measure: Effect of Rifampin on CL/F Post-dose Period 2
timeFrame: Microdose cocktail: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose; rifampin: 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose
measure: Effect of Rifampin on Vz/F Post-dose Period 2
timeFrame: Microdose cocktail: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose; rifampin: 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose
Other outcomes:
Locations:
city: Hialeah
country: United States
facility: Clinical Pharmacology of Miami ( Site 0001)
state: Florida
city: Orlando
country: United States
facility: Orlando Clinical Research Center ( Site 0002)
state: Florida
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: