Voxelotor CYP and Transporter Cocktail Interaction Study

Sickle Cell Disease Clinical Trial

Official title:

A Phase 1, Open-Label, Two-Part, Fixed-Sequence, Drug-Drug Interaction Study to Evaluate the Effect of Voxelotor on the Pharmacokinetics of Selected CYP and Transporter Probe Substrates in Healthy Participants

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05981365
• Other study ID #: GBT440-0122
• Secondary ID: C5341029
• Status: Completed
• Phase: Phase 1
• Start date: April 17, 2023
• Est. completion date: October 4, 2023

Study information

• Verified date: January 2024
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 44
• Est. completion date: October 4, 2023
• Est. primary completion date: October 4, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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.

Related Conditions & MeSH terms

• Anemia, Sickle Cell
• Sickle Cell Disease

Intervention

Drug:
• Voxelotor
Drug drug interaction
• Bupropion
Drug drug interaction
• Repaglinide
Drug drug interaction
• Flurbiprofen
Drug drug interaction
• Omeprazole
Drug drug interaction
• Midazolam
Drug drug interaction
• Metformin
Drug drug interaction
• Furosemide
Drug drug interaction
• Rosuvastatin
Drug drug interaction

Locations

Country	Name	City	State
United States	ICON Early Phase Services, LLC	San Antonio	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part A- Maximum observed plasma concentration (Cmax) for bupropion		Up to 81 Days
Primary	Part A- area under the plasma concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUCt) for bupropion		Up to 81 Days
Primary	Part A- area under the plasma concentration-time curve (AUC) from time 0 extrapolated to infinity (AUCinf) for bupropion		Up to 81 Days
Primary	Part A- Maximum observed plasma concentration (Cmax) for repaglinide		Up to 81 Days
Primary	Part A- area under the plasma concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUCt) for repaglinide		Up to 81 Days
Primary	Part A- area under the plasma concentration-time curve (AUC) from time 0 extrapolated to infinity (AUCinf) for repaglinide		Up to 81 Days
Primary	Part A- Maximum observed plasma concentration (Cmax) for flurbiprofen		Up to 81 Days
Primary	Part A- area under the plasma concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUCt) for flurbiprofen		Up to 81 Days
Primary	Part A- area under the plasma concentration-time curve (AUC) from time 0 extrapolated to infinity (AUCinf) for flurbiprofen		Up to 81 Days
Primary	Part A- Maximum observed plasma concentration (Cmax) for omeprazole		Up to 81 Days
Primary	Part A- area under the plasma concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUCt) for omeprazole		Up to 81 Days
Primary	Part A- area under the plasma concentration-time curve (AUC) from time 0 extrapolated to infinity (AUCinf) for omeprazole		Up to 81 Days
Primary	Part A- Maximum observed plasma concentration (Cmax) for midazolam		Up to 81 Days
Primary	Part A- area under the plasma concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUCt) for midazolam		Up to 81 Days
Primary	Part A- area under the plasma concentration-time curve (AUC) from time 0 extrapolated to infinity (AUCinf) for midazolam		Up to 81 Days
Primary	Part B- Maximum observed plasma concentration (Cmax) for metformin		Up to 68 Days
Primary	Part B- area under the plasma concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUCt) for metformin		Up to 68 Days
Primary	Part B- area under the plasma concentration-time curve (AUC) from time 0 extrapolated to infinity (AUCinf) for metformin		Up to 68 Days
Primary	Part B- Maximum observed plasma concentration (Cmax) for furosemide		Up to 68 Days
Primary	Part B- area under the plasma concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUCt) for furosemide		Up to 68 Days
Primary	Part B- area under the plasma concentration-time curve (AUC) from time 0 extrapolated to infinity (AUCinf) for furosemide		Up to 68 Days
Primary	Part B- Maximum observed plasma concentration (Cmax) for rosuvastatin		Up to 68 Days
Primary	Part B- area under the plasma concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUCt) for rosuvastatin		Up to 68 Days
Primary	Part B- area under the plasma concentration-time curve (AUC) from time 0 extrapolated to infinity (AUCinf) for rosuvastatin		Up to 68 Days
Secondary	Part A- Maximum observed plasma concentration (Cmax) for 6-hydroxybupropion		Up to 81 Days
Secondary	Part A- area under the plasma concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUCt) for 6-hydroxybupropion		Up to 81 Days
Secondary	Part A- area under the plasma concentration-time curve (AUC) from time 0 extrapolated to infinity (AUCinf) for 6-hydroxybupropion		Up to 81 Days
Secondary	Part A- Maximum observed plasma concentration (Cmax) for 5-hydroxyomeprazole		Up to 81 Days
Secondary	Part A- area under the plasma concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUCt) for 5-hydroxyomeprazole		Up to 81 Days
Secondary	Part A- area under the plasma concentration-time curve (AUC) from time 0 extrapolated to infinity (AUCinf) for 5-hydroxyomeprazole		Up to 81 Days
Secondary	Part A- Maximum observed plasma concentration (Cmax) for 1-hydroxymidazolam		Up to 81 Days
Secondary	Part A- area under the plasma concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUCt) for 1-hydroxymidazolam		Up to 81 Days
Secondary	Part A- area under the plasma concentration-time curve (AUC) from time 0 extrapolated to infinity (AUCinf) for 1-hydroxymidazolam		Up to 81 Days
Secondary	Part A- The time that Cmax is observed (tmax) for bupropion in plasma		Up to 81 Days
Secondary	Part A- The time that Cmax is observed (tmax) for 6-hydroxybupropion in plasma		Up to 81 Days
Secondary	Part A- The time that Cmax is observed (tmax) for repaglinide in plasma		Up to 81 Days
Secondary	Part A- The time that Cmax is observed (tmax) for flurbiprofen in plasma		Up to 81 Days
Secondary	Part A- The time that Cmax is observed (tmax) for omeprazole in plasma		Up to 81 Days
Secondary	Part A- The time that Cmax is observed (tmax) for 5-hydroxyomeprazole in plasma		Up to 81 Days
Secondary	Part A- The time that Cmax is observed (tmax) for midazolam in plasma		Up to 81 Days
Secondary	Part A- The time that Cmax is observed (tmax) for 1-hydroxymidazolam in plasma		Up to 81 Days
Secondary	Part A- terminal elimination half-life (t½) for bupropion in plasma		Up to 81 Days
Secondary	Part A- terminal elimination half-life (t½) for 6-hydroxybupropion in plasma		Up to 81 Days
Secondary	Part A- terminal elimination half-life (t½) for repaglinide in plasma		Up to 81 Days
Secondary	Part A- terminal elimination half-life (t½) for flurbiprofen in plasma		Up to 81 Days
Secondary	Part A- terminal elimination half-life (t½) for omeprazole in plasma		Up to 81 Days
Secondary	Part A- terminal elimination half-life (t½) for 5-hydroxyomeprazole in plasma		Up to 81 Days
Secondary	Part A- terminal elimination half-life (t½) for midazolam in plasma		Up to 81 Days
Secondary	Part A- terminal elimination half-life (t½) for 1-hydroxymidazolamin plasma		Up to 81 Days
Secondary	Part A- Ratio of metabolite to parent AUCt corrected for molecular weight (AUCt M/P) for bupropion		Up to 81 Days
Secondary	Part A- Ratio of metabolite to parent AUCt corrected for molecular weight (AUCt M/P) for omeprazole		Up to 81 Days
Secondary	Part A- Ratio of metabolite to parent AUCt corrected for molecular weight (AUCt M/P) for midazolam		Up to 81 Days
Secondary	Part B- The time that Cmax is observed (tmax) for metformin in plasma		Up to 68 Days
Secondary	Part B- The time that Cmax is observed (tmax) for furosemide in plasma		Up to 68 Days
Secondary	Part B- The time that Cmax is observed (tmax) for rosuvastatin in plasma		Up to 68 Days
Secondary	Part B- terminal elimination half-life (t½) for metformin in plasma		Up to 68 Days
Secondary	Part B- terminal elimination half-life (t½) for furosemide in plasma		Up to 68 Days
Secondary	Part B- terminal elimination half-life (t½) for rosuvastatin in plasma		Up to 68 Days
Secondary	Part A- Incidence of Treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs)		Up to 81 Days
Secondary	Part B- Incidence of Treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs)		Up to 68 Days
Secondary	Part A- Incidence of clinically significant changes in clinical laboratory tests, physical examination findings, and vital signs		Up to 81 Days
Secondary	Part B- Incidence of clinically significant changes in clinical laboratory tests, physical examination findings, and vital signs		Up to 68 Days

External Links

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