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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Drug Interactions, Pharmacokinetics

Intervention / Treatment
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* Drug: Daptomycin
* Drug: Rifampin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Daptomycin and Rifampin<br>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: Daptomycin<br> <br> * Other names: Cubicin;Drug: Rifampin<br> <br> * Other names: Rifadin;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Daptomycin, Rifampin, P-glycoprotein, Pharmacokinetic