Drug-Drug Interaction Between Rifampin and Fluvastatin

• Sponsor: University of California, San Francisco (Other)
• Overall Status: Completed
• CT.gov ID: NCT04029584
• Collaborator: (none)
• Enrollment: 10
• Location: 1
• Arms: 2
• Actual Duration (Months): 12
• Patients Per Site Per Month: 0.8

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Drug-drug Interaction	Drug: rifampin IV; Drug: Rifadin 300Mg Capsule; Drug: Fluvastatin 20 MG	Phase 4

Detailed Description

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention 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.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)
• Masking Description: No masking will be employed because it is very difficult to mask the effects of rifampin (range discoloration) on subjects.
• Primary Purpose: Basic Science
• Official Title: The Effects of Single Dose Rifampin on Pharmacokinetics of Fluvastatin in Uninduced and Hepatically Induced Healthy Volunteers
• Actual Study Start Date: Apr 25, 2019
• Actual Primary Completion Date: Apr 25, 2020
• Actual Study Completion Date: Apr 25, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Fluvastatin Alone First, Then Fluvastatin +IV Rifampin 600 mg 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; A 30-min intravenous infusion of rifampin 600mg in 10ml Normal Saline will be used to inhibit hepatic OATP1B1 transporters.; Drug: Rifadin 300Mg Capsule; Rifadin 600mg by mouth as two 300mg rifadin capsules; Drug: Fluvastatin 20 MG; one oral dose of fluvastatin (Lescol ) 20mg capsule
Experimental: Fluvastatin +IV Rifampin 600 mg First, Then Fluvastatin Alone 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; A 30-min intravenous infusion of rifampin 600mg in 10ml Normal Saline will be used to inhibit hepatic OATP1B1 transporters.; Drug: Rifadin 300Mg Capsule; Rifadin 600mg by mouth as two 300mg rifadin capsules; Drug: Fluvastatin 20 MG; one oral dose of fluvastatin (Lescol ) 20mg capsule

Outcome Measures

Primary Outcome Measures

1. AUC [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]

   The primary outcome will be fluvastatin Area under the concentration vs time curve (AUC0-12h and AUC0-INF)

Secondary Outcome Measures

1. Cmax [Cmax will be assessed over a 12 hour study period.]

   Secondary outcomes will include fluvastatin maximum plasma concentration (Cmax).

2. Tmax [Tmax will be assessed over a 12 hour study period.]

   Secondary outcomes will include time to Cmax (Tmax).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. 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.

2. 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.

3. 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.

4. 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.

5. 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).

6. BMI between 18.0 - 30 kg/m2 o Subjects capable of fasting from food and beverages at least 8 hours prior to medication dosing.

7. Be able to read, speak, and understand English.

8. Subjects capable of providing informed consent and completing the requirements of the study.

Exclusion Criteria:

1. Subjects with active medical problems

2. Subjects on chronic prescription or over the counter (OTC) medication that cannot be stopped 2 weeks prior to and during the study.

3. Subjects incapable of multiple blood draws (HCT < 30mg/dL)

4. Subjects with a history of rhabdomyolysis

5. Subjects with a history of drug-related myalgias

6. Subjects with a history or diagnosis of hemorrhagic tendencies or blood dyscrasias

7. Subjects with a history of GI bleed or peptic ulcer disease

8. Subjects who smoke tobacco or have ongoing alcohol or illegal drug use

9. Subjects who are pregnant, lactating, or trying to conceive during the study period

10. Subjects allergic to fluvastatin or rifampin or any known component of the medications

11. Anyone who in the opinion of the study investigators is unable to do the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California San Francisco	San Francisco	California	United States	94143

Sponsors and Collaborators

• University of California, San Francisco

Investigators

• Principal Investigator: Leslie Benet, PhD, University of California, San Francisco

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 26, 2019
• Informed Consent Form - Dec 26, 2018

More Information

Publications

None provided.

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT04029584
• Other Study ID Numbers: 18-27008
• First Posted: Jul 23, 2019
• Last Update Posted: Sep 8, 2021
• Last Verified: Aug 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by University of California, San Francisco: drug-drug interaction; statin; rifampin
• Additional relevant MeSH terms: Rifampin

Study Results

Participant Flow

Recruitment Details	Flyer on campus and Craiglist
Pre-assignment Detail	During the uninduced and induced study interventions there were separate randomization procedures.

Arm/Group Title	Fluvastatin Alone First, Then Fluvastatin +IV Rifampin 600 mg	Fluvastatin +IV Rifampin 600 mg First, Then Fluvastatin Alone
Arm/Group Description	Subjects received one oral dose of fluvastatin (Lescol®) 20mg capsule.	Subjects received one oral dose of fluvastatin (Lescol®) 20mg capsule immediately following a 30-min intravenous infusion of rifampin 600mg in 10ml Normal Saline.
Period Title: Uninduced Study 1st Intervention (1 Day)
STARTED	4	6
COMPLETED	4	6
NOT COMPLETED	0	0
Period Title: Uninduced Study 1st Intervention (1 Day)
STARTED	4	6
COMPLETED	4	6
NOT COMPLETED	0	0
Period Title: Uninduced Study 1st Intervention (1 Day)
STARTED	4	6
COMPLETED	4	6
NOT COMPLETED	0	0
Period Title: Uninduced Study 1st Intervention (1 Day)
STARTED	4	6
COMPLETED	4	6
NOT COMPLETED	0	0
Period Title: Uninduced Study 1st Intervention (1 Day)
STARTED	2	8
COMPLETED	2	8
NOT COMPLETED	0	0
Period Title: Uninduced Study 1st Intervention (1 Day)
STARTED	2	8
COMPLETED	2	8
NOT COMPLETED	0	0
Period Title: Uninduced Study 1st Intervention (1 Day)
STARTED	2	8
COMPLETED	2	8
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	All Subjects
Arm/Group Description	Subjects were randomized to one of two treatment groups: 1) a single oral dose of fluvastatin (Lescol®) 20 mg capsule or 2) a single oral dose of fluvastatin (Lescol®) 20 mg capsule immediately following a 30-min intravenous infusion of rifampin 600 mg in 10 mL normal saline.
Overall Participants	10
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	38 (13)
Sex: Female, Male (Count of Participants)
Female	4 40%
Male	6 60%
Race/Ethnicity, Customized (participants) [Number]
Caucasian	4 40%
African American	2 20%
Asian	2 20%
Hispanic	2 20%
Region of Enrollment (participants) [Number]
United States	10 100%
Serum creatinine (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	0.79 (0.13)

Outcome Measures

1. Primary Outcome

Title	AUC
Description	The primary outcome will be fluvastatin Area under the concentration vs time curve (AUC0-12h and AUC0-INF)
Time Frame	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

Outcome Measure Data

Analysis Population Description

healthy volunteer

Arm/Group Title	Fluvastatin Control	Fluvastatin and IV Rifampin	Fluvastatin + Oral Rifampin Induction	Fluvastatin +Oral Rifampin Induced +IV Rifampin
Arm/Group Description	healthy volunteer take a single dose fluvastatin	Healthy volunteer takes a single IV rifampin prior to oral fluvastatin	Healthy volunteers who take oral rifampin for 5 days prior to oral fluvastatin	Healthy takes five days oral rifampin, and then take one oral dose of fluvastatin (Lescol®) 20mg capsule immediately following a 30-min intravenous infusion of rifampin 600mg in 10ml Normal Saline
Measure Participants	10	10	10	10
AUC(0-12)	242 (83)	642 (269)	124 (33.7)	371 (217)
AUC(0-INF)	266 (86)	679 (274)	136 (35.9)	385 (222)

2. Secondary Outcome

Title	Cmax
Description	Secondary outcomes will include fluvastatin maximum plasma concentration (Cmax).
Time Frame	Cmax will be assessed over a 12 hour study period.

Outcome Measure Data

Analysis Population Description

healthy volunteers

Arm/Group Title	Fluvastatin Control	Fluvastatin and IV Rifampin	Fluvastatin + Oral Rifampin Induction	Fluvastatin +Oral Rifampin Induced +IV Rifampin
Arm/Group Description	healthy volunteer take a single dose fluvastatin	Healthy volunteer takes a single IV rifampin prior to oral fluvastatin	Healthy volunteers who take oral rifampin for 5 days prior to oral fluvastatin	Healthy takes five days oral rifampin, and then take one oral dose of fluvastatin (Lescol®) 20mg capsule immediately following a 30-min intravenous infusion of rifampin 600mg in 10ml Normal Saline
Measure Participants	10	10	10	10
Mean (Standard Deviation) [ng/mL]	176 (149)	447 (342)	87.8 (37.3)	379 (446)

3. Secondary Outcome

Title	Tmax
Description	Secondary outcomes will include time to Cmax (Tmax).
Time Frame	Tmax will be assessed over a 12 hour study period.

Outcome Measure Data

Analysis Population Description

healthy volunteer

Arm/Group Title	Fluvastatin Control	Fluvastatin and IV Rifampin	Fluvastatin + Oral Rifampin Induction	Fluvastatin +Oral Rifampin Induced +IV Rifampin
Arm/Group Description	healthy volunteer take a single dose fluvastatin	Healthy volunteer takes a single IV rifampin prior to oral fluvastatin	Healthy volunteers who take oral rifampin for 5 days prior to oral fluvastatin	Healthy takes five days oral rifampin, and then take one oral dose of fluvastatin (Lescol®) 20mg capsule immediately following a 30-min intravenous infusion of rifampin 600mg in 10ml Normal Saline
Measure Participants	10	10	10	10
Mean (Standard Deviation) [hr]	1.20 (0.62)	1.17 (0.72)	1.28 (0.545)	1.23 (0.960)

Adverse Events

Time Frame	Adverse event was monitored in uninduced arm from study day 1 to day 3. Adverse event was monitored in induced arm from study day -5 to day 3.
Arm/Group Title	Uninduced Healthy Volunteer Fluvastatin Alone		Uninduced Healthy Volunteer Fluvastatin and Rifampin		Hepatic Induced Healthy Volunteer Fluvastatin Alone		Hepatic Induced Healthy Volunteer Fluvastatin and Rifampin
Arm/Group Description	Subjects randomized to receive one oral dose of fluvastatin (Lescol®) 20mg capsule		Subjects randomized to receive one oral dose of fluvastatin 20mg immediately after a 30-min IV infusion of rifampin 600mg.		Subjects pretreated with 5 days with 600mg oral rifampin for enzyme and transporter induction. Subjects randomized to receive one oral dose of fluvastatin 20mg		Subjects pretreated with 5 days with 600mg oral rifampin for enzyme and transporter induction. Subjects randomized to receive one oral dose of fluvastatin 20mg immediately after a 30-min IV infusion of rifampin 600mg.
All Cause Mortality
	Uninduced Healthy Volunteer Fluvastatin Alone		Uninduced Healthy Volunteer Fluvastatin and Rifampin		Hepatic Induced Healthy Volunteer Fluvastatin Alone		Hepatic Induced Healthy Volunteer Fluvastatin and Rifampin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/10 (0%)		0/10 (0%)
Serious Adverse Events
	Uninduced Healthy Volunteer Fluvastatin Alone		Uninduced Healthy Volunteer Fluvastatin and Rifampin		Hepatic Induced Healthy Volunteer Fluvastatin Alone		Hepatic Induced Healthy Volunteer Fluvastatin and Rifampin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/10 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Uninduced Healthy Volunteer Fluvastatin Alone		Uninduced Healthy Volunteer Fluvastatin and Rifampin		Hepatic Induced Healthy Volunteer Fluvastatin Alone		Hepatic Induced Healthy Volunteer Fluvastatin and Rifampin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/10 (0%)		0/10 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.