Drug-Drug Interaction Between Rifampin and Fluvastatin

NCT04029584 | Completed Phase 4 Results FDA Drug

• 1 other identifier: 18-27008
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Drug-drug Interaction

Keywords

drug-drug interaction; statin; rifampin

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• Cmax

  Cmax will be assessed over a 12 hour study period.

• Tmax

  Tmax will be assessed over a 12 hour study period.

Study Arms (2)

Fluvastatin Alone First, Then Fluvastatin +IV Rifampin 600 mg

EXPERIMENTAL

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; Drug: Rifadin 300Mg Capsule; Drug: Fluvastatin 20 MG

Fluvastatin +IV Rifampin 600 mg First, Then Fluvastatin Alone

EXPERIMENTAL

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; Drug: Rifadin 300Mg Capsule; Drug: Fluvastatin 20 MG

Interventions

rifampin IV DRUG

A 30-min intravenous infusion of rifampin 600mg in 10ml Normal Saline will be used to inhibit hepatic OATP1B1 transporters.

Fluvastatin +IV Rifampin 600 mg First, Then Fluvastatin Alone; Fluvastatin Alone First, Then Fluvastatin +IV Rifampin 600 mg

Rifadin 300Mg Capsule DRUG

Rifadin 600mg by mouth as two 300mg rifadin capsules

Fluvastatin +IV Rifampin 600 mg First, Then Fluvastatin Alone; Fluvastatin Alone First, Then Fluvastatin +IV Rifampin 600 mg

Fluvastatin 20 MG DRUG

one oral dose of fluvastatin (Lescol ) 20mg capsule

Fluvastatin +IV Rifampin 600 mg First, Then Fluvastatin Alone; Fluvastatin Alone First, Then Fluvastatin +IV Rifampin 600 mg

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of California, San Francisco: lead

Study Sites (1)

University of California San Francisco

San Francisco, California, 94143, United States

Location

MeSH Terms

Interventions

Rifampin; Fluvastatin

Intervention Hierarchy (Ancestors)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heptanoic Acids; Fatty Acids; Lipids

Results Point of Contact

• Title: Leslie Benet, PhD
• Organization: University of California, San Francisco

leslie.benet@ucsf.edu

(415) 476-3853

Study Officials

• Leslie Benet, PhD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: No masking will be employed because it is very difficult to mask the effects of rifampin (range discoloration) on subjects.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: July 16, 2019
• First Posted: July 23, 2019
• Study Start: April 25, 2019
• Primary Completion: April 25, 2020
• Study Completion: April 25, 2020
• Last Updated: September 8, 2021
• Results First Posted: September 8, 2021

Record last verified: 2021-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)