Voxelotor CYP and Transporter Cocktail Interaction Study

Pfizer44 enrolled

Overview

This research study is examining multiple doses of voxelotor (a study drug intended for treatment of sickle cell disease) and how it interacts with additional substrates (substrates are drugs or other substances that are metabolized by cytochrome enzymes. The substrates used in this study are FDA approved medications). The study will help to determine the safety and tolerability of the study drugs taken together, as well as the pharmacokinetics (PK) on how your body processes and responds to the combination of the study drug and substrates. Although these drugs are FDA approved, their use in this study is experimental.

This is an open-label, fixed-sequence, 2-period evaluation study. This means the study doctor and participants in the study will know what study drugs they are taking. There will be approximately 46 healthy male and female participants between the ages of 18 - 55. There will be two parts of the study: parts A and B. Part A will consist of 26 healthy male and female participants (at least 20% African American). For Part A, participant involvement is expected to last approximately 81 days, including a 33-day screening period and a 48-day on study period (consisting of 2 study treatment periods, a washout period lasting 7 to 14 days, and the Follow-up visit). Part B will consist of 20 healthy male and female participants (at least 20% African American). For Part B, participant involvement is expected to last approximately 68 days, including a 33-day screening period and a 35-day on study period (consisting of 2 study treatment periods, a washout period lasting 7 to 14 days, and the Follow-up visit). You will only be allowed to be in one part of the study.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Enrollment

Conditions

Sickle Cell Disease

Interventions

VoxelotorDRUG

Drug drug interaction

BupropionDRUG

Drug drug interaction

RepaglinideDRUG

Drug drug interaction

Flurbiprofen

Eligibility

Sex: ALLMin age: 18 YearsMax age: 55 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * 1\. Males or females ≥ 18 and ≤ 55 years of age inclusive, at the time of signing the informed consent. 2\. No clinically significant findings as assessed by review of medical and surgical history, vital signs assessments, 12-lead electrocardiograms (ECG), physical examination, and clinical laboratory evaluations conducted at screening and day of admission. A single repeat measurement/test may be performed to confirm eligibility based upon initial vital signs, ECG, or clinical laboratory tests abnormalities. 3\. Body mass Index (BMI) ≥ 18.0 and ≤ 30.0 kg/m2, and body weight ≥ 50 kg at screening and Period 1 Day -1. BMI = weight (kg)/(height \[m\])2 4\. Females of childbearing potential must agree to use a highly effective method of contraception or practice abstinence from 2 weeks prior to study start through 30 days after the last dose of study drug. A highly effective method of contraception is defined as one that results in a low documented failure rate when used consistently and correctly such as: condom plus use of an intrauterine device; intrauterine system or hormonal method of contraception (oral, injected, implanted, or transdermal) for their female partner; or sexual abstinence. Males must be surgically sterilized, or agree to practice true abstinence, or use acceptable contraception if sexually active with a female partner of childbearing potential, throughout the study, and for at least 30 days after the last dose of study drug. 5\. Males must agree not to donate sperm during the study and for 30 days following last dose of study drug. Exclusion Criteria: 1. Positive pregnancy test or is lactating. 2. History or presence of clinically significant allergic diseases (except for untreated, asymptomatic, seasonal allergies) at time of screening in the opinion of the Investigator. 3. History or presence of conditions which, in the opinion of the Investigator, are known to interfere with the absorption, distribution, metabolism, or excretion of drugs, such as previous surgery on the gastrointestinal tract (including removal of parts of the stomach, bowel, liver, or pancreas). Participants who have a history of cholecystectomy and appendectomy are eligible for enrollment. 4. Any signs and/or symptoms of acute illness at screening or Day -1. 5. Abnormal ECG in any of the single ECGs collected at screening or Day -1, including QTcF \> 430 msec for males and \> 450 msec for females, or any cardiac rhythm other than sinus rhythm that is interpreted by the Investigator to be clinically significant. A single repeat measurement may be performed to re-evaluate ECG abnormalities (ie, to confirm that a participant is eligible). All the single ECGs must be not clinically significant to qualify for enrollment into the study. 6. Resting bradycardia (HR \< 45 bpm) or resting tachycardia (HR \> 100 bpm) at screening or Day -1. A single repeat measurement may be performed to re-evaluate vital signs abnormalities(ie, to confirm that a participant is ineligible). Each of the readings must be not clinically significant to qualify for enrollment into the study. 7. Hypertension, defined as resting (supine) systolic blood pressure (BP) \> 140 mmHg or resting diastolic BP \> 90 mmHg at screening or Day -1. A single repeat measurement may be performed to re-evaluate vital signs abnormalities (ie, to confirm that a participant is eligible). Each of the readings must be not clinically significant to qualify for enrollment into the study. 8. Use of prescription medications (with the exception of contraception), any over the counter drugs including herbal preparations including St. John's wort or dietary supplements, or any drugs that induce or inhibit study drug specific CYP450(s) within 14 days or 5 half-lives, whichever is longer, prior to Day -1, or requires continuing use during study participation. 9. Prior exposure to voxelotor/Oxbryta® within the past month. 10. Clinically significant anemia, or has donated blood or blood components exceeding 400 mL within 90 days prior to screening. 11. Positive screen for human immunodeficiency virus 1 (HIV-1) and HIV -2 antibodies, hepatitis A virus antibody, hepatitis B surface antigen, or hepatitis C virus antibody. 12. History or presence of contraindication to the use of midazolam including but not limited to hypersensitivity to benzodiazepines or formulation ingredients, acute narrow-angle glaucoma, myasthenia gravis, severe respiratory insufficiency, or sleep apnea syndrome. 13. Poor CYP2C9 or CYP2C19 metabolizer (determined at screening or available historical data). 14. Participant has an allergy or sensitivity to voxelotor, bupropion, repaglinide, flurbiprofen, omeprazole, or midazolam. Part B only 15. History of statin-induced myopathy or serious hypersensitivity reaction to other 3-hydroxy-3-methylglutaryl coenzyme A, reductase inhibitors (statins). 16. Heterozygous or homozygous variant allele carriers of SLCO1B1 (c.521T\>C, rs4149056), encoding the hepatic uptake transporter OATP1B1, resulting in decreased transport activity. 17. Participant has an allergy or sensitivity to voxelotor, metformin, furosemide, or rosuvastatin.

Locations (1)

ICON Early Phase Services, LLC

San Antonio, Texas, United States

Outcomes

Primary Outcomes

Part A: Maximum Observed Plasma Concentration (Cmax) for Bupropion

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively

Part A: Cmax for Repaglinide

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Period 1 Day 4 and Period 2 Day 6 for Treatment B and F, respectively

Part A: Cmax for Flurbiprofen

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Part A: Cmax for Omeprazole

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Part A: Cmax for Midazolam

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Part A: Area Under the Plasma Concentration-Time Curve From Time Zero (0) to the Time of the Last Quantifiable Concentration (AUCt) for Bupropion

AUCt was calculated using the linear/log trapezoidal rule.

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively

Part A: AUCt for Repaglinide

AUCt was calculated using the linear/log trapezoid rule.

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Period 1 Day 4 and Period 2 Day 6 for Treatment B and F, respectively

Part A: AUCt for Flurbiprofen

Data from ClinicalTrials.gov

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Secondary Outcomes

Part A: Cmax for 6-Hydroxybupropion

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively

Part A: Cmax for 5-Hydroxyomeprazole

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Part A: Cmax for 1-Hydroxymidazolam

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Part A: AUCt for 6-Hydroxybupropion

AUCt was calculated using the linear/log trapezoid rule.

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively

Part A: AUCt for 5-Hydroxyomeprazole

AUCt was calculated using the linear/log trapezoid rule.

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Part A: AUCt for 1-Hydroxymidazolam

AUCt was calculated using the linear/log trapezoid rule.

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Part A: AUCinf for 6-Hydroxybupropion

AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant.

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively

Part A: AUCinf for 5-Hydroxyomeprazole

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Part A: AUCinf for 1-Hydroxymidazolam

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Part A: Time at Which Cmax Was Observed (Tmax) for Bupropion

The time that Cmax was observed.

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively

Part A: Tmax for 6-Hydroxybupropion

The time that Cmax was observed for 6-Hydroxybupropion.

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively

Part A: Tmax for Repaglinide

The time that Cmax was observed for Repaglinide.

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Period 1 Day 4 and Period 2 Day 6 for Treatment B and F, respectively

Part A: Tmax for Flurbiprofen

The time that Cmax was observed for Flurbiprofen.

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Part A: Tmax for Omeprazole

The time that Cmax was observed for Omeprazole.

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Part A: Tmax for 5-Hydroxyomeprazole

The time that Cmax was observed for 5-Hydroxyomeprazole.

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Part A: Tmax for Midazolam

The time that Cmax was observed for Midazolam.

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Part A: Tmax for 1-Hydroxymidazolam

The time that Cmax was observed for 1-Hydroxymidazolam.

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Part A: Terminal Elimination Half-life (T½) for Bupropion

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively

Part A: t1/2 6-Hydroxybupropion

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively

Part A: T1/2 for Repaglinide

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Period 1 Day 4 and Period 2 Day 6 for Treatment B and F, respectively

Part A: T1/2 for Flurbiprofen

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Part A: T1/2 for Omeprazole

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Part A: T1/2 for 5-Hydroxyomeprazole

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Part A: T1/2 for Midazolam

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Part A: T1/2 for 1-Hydroxymidazolam

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight (AUCt M/P) for 6-Hydroxybupropion/Bupropion

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively

Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight for 5-Hydroxyomeprazole/Omeprazole

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight for Hydroxymidazolam/Midazolam

Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Part B: Tmax for Metformin

Time frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively

Part B: Tmax for Furosemide

Time frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively

Part B: Tmax for Rosuvastatin

Time frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively

Part B: T½ for Metformin

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Time frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively

Part B: T½ for Furosemide

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Time frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively

Part B: T½ for Rosuvastatin

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Time frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively