Drug-drug Interaction
Conditions
Keywords
drug-drug interaction, statin, rifampin
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.
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
Interventions
DRUGrifampin IV
A 30-min intravenous infusion of rifampin 600mg in 10ml Normal Saline will be used to inhibit hepatic OATP1B1 transporters.
DRUGRifadin 300Mg Capsule
Rifadin 600mg by mouth as two 300mg rifadin capsules
DRUGFluvastatin 20 MG
one oral dose of fluvastatin (Lescol ) 20mg capsule
Sponsors
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Masking description
No masking will be employed because it is very difficult to mask the effects of rifampin (range discoloration) on subjects.
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Cmax | Cmax will be assessed over a 12 hour study period. | Secondary outcomes will include fluvastatin maximum plasma concentration (Cmax). |
| Tmax | Tmax will be assessed over a 12 hour study period. | Secondary outcomes will include time to Cmax (Tmax). |
Countries
United States
Participant flow
Recruitment details
Flyer on campus and Craiglist
Pre-assignment details
During the uninduced and induced study interventions there were separate randomization procedures.
Participants by arm
| Arm | Count |
|---|---|
| All Subjects 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. | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | All Subjects |
|---|---|
| Age, Continuous | 38 years STANDARD_DEVIATION 13 |
| Race/Ethnicity, Customized African American | 2 participants |
| Race/Ethnicity, Customized Asian | 2 participants |
| Race/Ethnicity, Customized Caucasian | 4 participants |
| Race/Ethnicity, Customized Hispanic | 2 participants |
| Region of Enrollment United States | 10 participants |
| Serum creatinine | 0.79 mg/dL STANDARD_DEVIATION 0.13 |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 |
Outcome results
Primary
AUC
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
Population: healthy volunteer
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Fluvastatin Control | AUC | AUC(0-12) | 242 ng/mL·h | Standard Deviation 83 |
| Fluvastatin Control | AUC | AUC(0-INF) | 266 ng/mL·h | Standard Deviation 86 |
| Fluvastatin and IV Rifampin | AUC | AUC(0-INF) | 679 ng/mL·h | Standard Deviation 274 |
| Fluvastatin and IV Rifampin | AUC | AUC(0-12) | 642 ng/mL·h | Standard Deviation 269 |
| Fluvastatin + Oral Rifampin Induction | AUC | AUC(0-12) | 124 ng/mL·h | Standard Deviation 33.7 |
| Fluvastatin + Oral Rifampin Induction | AUC | AUC(0-INF) | 136 ng/mL·h | Standard Deviation 35.9 |
| Fluvastatin +Oral Rifampin Induced +IV Rifampin | AUC | AUC(0-12) | 371 ng/mL·h | Standard Deviation 217 |
| Fluvastatin +Oral Rifampin Induced +IV Rifampin | AUC | AUC(0-INF) | 385 ng/mL·h | Standard Deviation 222 |
Secondary
Cmax
Secondary outcomes will include fluvastatin maximum plasma concentration (Cmax).
Time frame: Cmax will be assessed over a 12 hour study period.
Population: healthy volunteers
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fluvastatin Control | Cmax | 176 ng/mL | Standard Deviation 149 |
| Fluvastatin and IV Rifampin | Cmax | 447 ng/mL | Standard Deviation 342 |
| Fluvastatin + Oral Rifampin Induction | Cmax | 87.8 ng/mL | Standard Deviation 37.3 |
| Fluvastatin +Oral Rifampin Induced +IV Rifampin | Cmax | 379 ng/mL | Standard Deviation 446 |
Secondary
Tmax
Secondary outcomes will include time to Cmax (Tmax).
Time frame: Tmax will be assessed over a 12 hour study period.
Population: healthy volunteer
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fluvastatin Control | Tmax | 1.20 hr | Standard Deviation 0.62 |
| Fluvastatin and IV Rifampin | Tmax | 1.17 hr | Standard Deviation 0.72 |
| Fluvastatin + Oral Rifampin Induction | Tmax | 1.28 hr | Standard Deviation 0.545 |
| Fluvastatin +Oral Rifampin Induced +IV Rifampin | Tmax | 1.23 hr | Standard Deviation 0.96 |