Influence of Rifampin Co-Administration on the Pharmacokinetic Profile of Daptomycin

The purpose of this study is to understand how an antibiotic, rifampin, may change the blood levels of another antibiotic, daptomycin, in the body. In addition, the effect of polymorphisms in P-glycoprotein (a protein involved in the removal of daptomycin from the body) on the blood levels of daptomycin will be evaluated. The hypotheses are that rifampin will decrease the blood levels of daptomycin and that the effect will be greater for certain P-glycoprotein polymorphisms.

Study Overview

• Status: Completed
• Conditions: Pharmacokinetics; Drug Interactions
• Intervention / Treatment: Drug: Rifampin; Drug: Daptomycin

Detailed Description

This will be an open-label, sequential pharmacokinetic study in 12 healthy volunteers. After providing informed consent, participants meeting inclusion criteria will be administered daptomycin 6 mg/kg over 2 minutes and blood and urine samples will be collected over a 24 hour period after infusion. Following this, participants will be given a 13 day supply of rifampin 600 mg/day to be taken at home. After completion of the rifampin course, a second pharmacokinetic sampling will be performed (day 15 overall). Participants will be administered a dose of rifampin 600 mg then once again be administered daptomycin 6 mg/kg over 2 minutes and blood and urine samples will be collected over a second 24 hour period. A blood sample will be obtained at the first study visit for determination of each participant's P-glycoprotein genotype.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Ability to provide informed consent
• If female of child bearing potential, on reliable method of contraception and negative pregnancy test at enrollment

Exclusion Criteria:

• Obesity (body mass index > 30)
• Creatinine clearance < 80 ml/min
• Creatine phosphokinase > 2 times upper limit of normal at enrollment
• Aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase > 3 times upper limit of normal at enrollment
• History of liver disease or cirrhosis
• History of congestive heart failure
• Allergy or intolerance to rifampin or daptomycin
• Need for concomitant non-study medications during the study period
• Inability to abstain from grapefruit juice or herbal supplements (such as St. John's wort) during the study period
• Receipt of study drugs within 30 days prior to enrollment
• Pregnancy or lactation
• Inability to adhere to study procedures

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Daptomycin and Rifampin; Drug: Daptomycin Daptomycin 6 mg/kg will be given by IV infusion on the first study day Drug: Rifampin Rifampin 600 mg capsules will be given orally once daily for 14 days starting on study day 2 Drug: Daptomycin Daptomycin 6 mg/kg will be given by IV infusion on study day 15	Drug: Rifampin; Other Names: Rifadin; Drug: Daptomycin; Other Names: Cubicin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Daptomycin total, renal, and non-renal clearance	Total, renal, and non-renal clearance of daptomycin before and after administration of rifampin	14 days
Daptomycin Volume of Distribution	The volume of distribution of daptomycin before and after administration of rifampin	14 days
Daptomycin Elimination Rate Constant	The elimination rate constant of daptomycin before and after administration of rifampin	14 days
Daptomycin Free and Total Peak Concentrations	The free and total peak concentrations of daptomycin before and after administration of rifampin	14 days
Daptomycin Free and Total 24 hour Concentrations	The free and total 24 hour concentrations of daptomycin before and after administration of rifampin	14 days
Daptomycin Free and Total Area Under the Concentration-Time Curve (AUC) from 0 to 24 hours	The free and total AUC from 0 to 24 hours of daptomycin before and after administration of rifampin	14 days
Daptomycin Free and Total AUC from 0 to Infinity	The free and total AUC from 0 to infinity of daptomycin before and after administration of rifampin	14 days
Percent Protein Binding of Daptomycin	The percent protein binding of daptomycin before and after administration of rifampin	14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
P-glycoprotein Polymorphism	The effect of different P-glycoprotein polymorphisms on the pharmacokinetic profile of daptomycin before and after administration of rifampin will be assessed	14 days
Number of Participants with Adverse Events	Safety monitoring will be done by regular adverse event assessment, laboratory and vital sign monitoring, and physical exam.	45 days

Collaborators and Investigators

• Sponsor: University of Utah
• Collaborators: Cubist Pharmaceuticals LLC
• Investigators: Principal Investigator: Russell Benefield, Pharm.D., University of Utah

Study record dates

Study Major Dates

• Study Start: May 1, 2014
• Primary Completion (Actual): June 1, 2015
• Study Completion (Actual): July 1, 2016

Study Registration Dates

• First Submitted: March 24, 2014
• First Submitted That Met QC Criteria: March 24, 2014
• First Posted (Estimate): March 27, 2014

Study Record Updates

• Last Update Posted (Estimate): December 12, 2016
• Last Update Submitted That Met QC Criteria: December 9, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Keywords: Pharmacokinetic; Rifampin; P-glycoprotein; Daptomycin
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Rifampin; Daptomycin
• Other Study ID Numbers: 00069136