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

NCT03311841 | Completed Phase 1 Results FDA Drug

• 3 other identifiers: 0000-386MK-0000-386CA21005
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 2

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).

Conditions

Renal Insufficiency

Outcome Measures

Primary Outcomes (10)

• 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.

  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.

  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.

  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.

  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.

  0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose

• Plasma Concentration at 24 Hours (C24) Post-dose Period 1

  C24hr is a measure of the plasma study drug concentration 24 hours post-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.

  24 hours post-dose

• Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1

  Tmax is the amount of time to reach maximum (peak) plasma drug concentration following drug 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.

  0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose

• Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1

  T1/2 is the elimination half-life of study drug. T1/2 is the time it takes for half of the study drug in the blood plasma to dissipate. 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.

  0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose

• Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1

  CL/F is the rate at which study drug was removed from the body. 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. CL/F was to be calculated for the parent plasma analytes only, midazolam, dabigatran, pitavastatin, atorvastatin, and rosuvastatin.

  0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose

• Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1

  Vz/F is the distribution of study drug between the plasma and the rest of the body 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. Vz/F was to be calculated for the parent plasma analytes only, midazolam, dabigatran, pitavastatin, atorvastatin, and rosuvastatin.

  0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose

Secondary Outcomes (8)

• Effect of Rifampin on AUC0-24 Post-dose Period 2

  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

• Effect of Rifampin on AUC0-last Post-dose Period 2

  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

• Effect of Rifampin on Cmax Post-dose Period 2

  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

• Effect of Rifampin on C24 Post-dose Period 2

  24 hours post-dose

• Effect of Rifampin on Tmax Post-dose Period 2

  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

Study Arms (5)

End Stage Renal Disease

EXPERIMENTAL

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.

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

Severe Impairment

EXPERIMENTAL

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.

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

Moderate Impairment

EXPERIMENTAL

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.

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

Mild Impairment

EXPERIMENTAL

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.

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

Healthy Control

ACTIVE COMPARATOR

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.

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

Interventions

Midazolam oral solution DRUG

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

End Stage Renal Disease; Healthy Control; Mild Impairment; Moderate Impairment; Severe Impairment

Dabigatran and pitavastatin oral solution 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

End Stage Renal Disease; Healthy Control; Mild Impairment; Moderate Impairment; Severe Impairment

Atorvastatin and rosuvastatin oral solution DRUG

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

End Stage Renal Disease; Healthy Control; Mild Impairment; Moderate Impairment; Severe Impairment

Rifampin DRUG

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

Healthy Control; Mild Impairment; Moderate Impairment; Severe Impairment

Eligibility Criteria

• Age: 18 Years - 78 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Study Sites (2)

Clinical Pharmacology of Miami ( Site 0001)

Hialeah, Florida, 33014, United States

Location

Orlando Clinical Research Center ( Site 0002)

Orlando, Florida, 32809, United States

Location

MeSH Terms

Conditions

Renal Insufficiency

Interventions

Midazolam; Dabigatran; pitavastatin; Atorvastatin; Rosuvastatin Calcium; Rifampin

Condition Hierarchy (Ancestors)

Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Benzimidazoles; Pyrroles; Azoles; Heptanoic Acids; Fatty Acids; Lipids; Sulfonamides; Amides; Organic Chemicals; Fluorobenzenes; Hydrocarbons, Fluorinated; Hydrocarbons, Halogenated; Hydrocarbons; Sulfones; Sulfur Compounds; Pyrimidines; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 12, 2017
• First Posted: October 17, 2017
• Study Start: March 1, 2018
• Primary Completion: August 2, 2018
• Study Completion: August 2, 2018
• Last Updated: January 9, 2020
• Results First Posted: January 9, 2020

Record last verified: 2019-12

Data Sharing

• IPD Sharing: Will share

Locations

US (2)