Drug-Drug Interaction Between Rifampin and Fluvastatin

Study Overview
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Brief Summary
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The effect of organic anion transporting polypeptide 1B1 (OATP1B1) transporter inhibition at clinical doses of fluvastatin, a biopharmaceutics drug disposition classification system (BDDCS) class 1 drug, has not been studied to date. A single dose of IV rifampin can be used as model OATP1B1 inhibitor to evaluate the significance of OATP1B1 transporter effects on fluvastatin disposition. A preinduction regimen of oral rifampin followed by a single IV infusion of rifampin can be used to evaluate the combined effects of enzyme induction and OATP1B1 transporter inhibition on fluvastatin disposition. A two arm, randomized, open label, crossover clinical study in healthy, volunteers will be conducted to evaluate the effects of IV rifampin on fluvastatin disposition in both hepatically induced and uninduced subjects.

Detailed Description
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The effect of rifampin on the pharmacokinetics of fluvastatin will be studied in healthy volunteers in a two arms, two-period, randomized, unblinded, crossover clinical trial. In the first arm, subjects will be randomized to one of two treatment groups: (i)fluvastatin (Lescol®) 20mg capsule (ii) one oral dose of fluvastatin (Lescol®) 20mg capsule immediately following a 30-min intravenous infusion of rifampin 600mg in 10ml Normal Saline. In the second arms, patients will be pretreated with 600mg oral rifampin (two 300mg rifadin capsule) once daily to induce hepatic enzymes (and transporters) for 5 years. Subjects will be randomized to one of two treatment groups: (i) one oral dose of fluvastatin (Lescol®) 20mg capsule (ii) one oral dose of fluvastatin (Lescol®) 20mg capsule immediately following a 30-min intravenous infusion of rifampin 600mg in 10ml Normal Saline

Official Title
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The Effects of Single Dose Rifampin on Pharmacokinetics of Fluvastatin in Uninduced and Hepatically Induced Healthy Volunteers

Conditions
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Drug-drug Interaction

Intervention / Treatment
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* Drug: rifampin IV
* Drug: Rifadin 300Mg Capsule
* Drug: Fluvastatin 20 MG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male or female, ages 18-65 years old, with no current medical conditions or active diagnoses as determined by the study doctor based on history, physical exam, and laboratory evaluations. Subjects who take no other medications two weeks prior to the study and during the time course of the study including prescription medications, over-the-counter medications, dietary supplements, or drugs of abuse. Subjects able to maintain adequate birth control during the study independent of hormonal contraceptives (including hormonal intrauterine devices (IUDs)). Adequate methods of contraception include use of condoms and copper IUDs. Subjects able to abstain from grapefruit, grapefruit juice, oranges, orange juice, caffeinated beverages and/or alcoholic beverages from 7am the day before the study to completion of that study day. Participants determined to have normal liver and kidney function as measured at baseline ( alanine aminotransferase (ALT): ≤ 2x upper level of normal (ULN), aspartate aminotransferase (AST): ≤ 2x ULN, serum creatinine (SCr): ≤ 1.5x ULN, T. Bili: 0.1-1.2mg/dL, Albumin: 3.4 - 4.7 mg/dL). BMI between 18.0 - 30 kg/m2 o Subjects capable of fasting from food and beverages at least 8 hours prior to medication dosing. Be able to read, speak, and understand English. Subjects capable of providing informed consent and completing the requirements of the study. Exclusion Criteria: Subjects with active medical problems Subjects on chronic prescription or over the counter (OTC) medication that cannot be stopped 2 weeks prior to and during the study. Subjects incapable of multiple blood draws (HCT < 30mg/dL) Subjects with a history of rhabdomyolysis Subjects with a history of drug-related myalgias Subjects with a history or diagnosis of hemorrhagic tendencies or blood dyscrasias Subjects with a history of GI bleed or peptic ulcer disease Subjects who smoke tobacco or have ongoing alcohol or illegal drug use Subjects who are pregnant, lactating, or trying to conceive during the study period Subjects allergic to fluvastatin or rifampin or any known component of the medications Anyone who in the opinion of the study investigators is unable to do the study

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: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This study is a two arm, randomized, open label, crossover, clinical trial. Arm 1 will be conducted in normal healthy volunteers; Arm 2 will be conducted in hepatically induced (by oral rifampin) healthy volunteers.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fluvastatin Alone First, Then Fluvastatin +IV Rifampin 600 mg<br>The effect of rifampin on the pharmacokinetics of fluvastatin will be studied in healthy volunteers with or without hepatic induction in a randomized, unblinded, crossover clinical trial. For uninduced periods, subjects will be randomized to receive one oral dose of fluvastatin (Lescol®) 20mg capsule first. Separated by one day of washout, they then receive one oral dose of fluvastatin (Lescol®) 20mg capsule immediately following a 30-min intravenous infusion of rifampin 600mg in 10ml Normal Saline. Before starting hepatic induced period, subjects will have a washout for greater than one week. To induce hepatic enzyme and transporter, Subjects will be pretreated with 5 days with 600mg oral rifampin. Subjects will be then randomized first to receive a single dose of fluvastatin 20mg. Separated by one day of washout, subject will then receive one oral dose of fluvastatin 20mg immediately after a 30-min IV infusion of rifampin 600mg. | Drug: rifampin IV<br>* A 30-min intravenous infusion of rifampin 600mg in 10ml Normal Saline will be used to inhibit hepatic OATP1B1 transporters.<br>Drug: Rifadin 300Mg Capsule<br>* Rifadin 600mg by mouth as two 300mg rifadin capsules<br>Drug: Fluvastatin 20 MG<br>* one oral dose of fluvastatin (Lescol ) 20mg capsule<br>|
| Experimental: Fluvastatin +IV Rifampin 600 mg First, Then Fluvastatin Alone<br>The effect of rifampin on the disposition of fluvastatin will be studied in healthy volunteers with or without hepatic induction in a randomized, unblinded, crossover clinical trial. For uninduced periods, subjects will be randomized to first receive one oral dose of fluvastatin (Lescol®) 20mg capsule immediately following a 30-min intravenous infusion of rifampin 600mg in 10ml Normal Saline.Separated by one day of washout, subjects will be then receive a single dose of fluvastatin (Lescol®) 20mg capsule. Before starting induction periods, subjects will have a washout greater than one week. To induce hepatic enzyme and transporter, subjects will be pretreated with 5 days with 600mg oral rifampin. subjects will be randomized to receive first one oral dose of fluvastatin 20mg immediately after a 30-min IV infusion of rifampin 600mg. Separated by one day of washout, subject will then receive one oral dose of fluvastatin 20mg. | Drug: rifampin IV<br>* A 30-min intravenous infusion of rifampin 600mg in 10ml Normal Saline will be used to inhibit hepatic OATP1B1 transporters.<br>Drug: Rifadin 300Mg Capsule<br>* Rifadin 600mg by mouth as two 300mg rifadin capsules<br>Drug: Fluvastatin 20 MG<br>* one oral dose of fluvastatin (Lescol ) 20mg capsule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC | The primary outcome will be fluvastatin Area under the concentration vs time curve (AUC0-12h and AUC0-INF) | AUC will be assessed over a 12 hour study at 0, 0.33, 0.67,1,1.5, 2, 2.5, 3, 4, 6, 9, 12h | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | Secondary outcomes will include fluvastatin maximum plasma concentration (Cmax). | Cmax will be assessed over a 12 hour study period. | 
| Tmax | Secondary outcomes will include time to Cmax (Tmax). | Tmax will be assessed over a 12 hour study period. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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drug-drug interaction, statin, rifampin