Phase 1
Completed N=44
Voxelotor CYP and Transporter Cocktail Interaction Study
Source: ClinicalTrials.gov NCT05981365 ↗Enrolled (actual)
44
Serious AEs
0.0%
Results posted
Nov 2024
Primary outcomePrimary: Part A: Maximum Observed Plasma Concentration (Cmax) for Bupropion — 160.5; 201.3; 191.1 Nanogram per milliliter (ng/mL)
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.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Part A: Maximum Observed Plasma Concentration (Cmax) for Bupropion |
160.5; 201.3; 191.1 | — |
| PRIMARY Part A: Cmax for Repaglinide |
10.85; 12.89 | — |
| PRIMARY Part A: Cmax for Flurbiprofen |
6923; 7820 | — |
| PRIMARY Part A: Cmax for Omeprazole |
458.1; 374.3 | — |
| PRIMARY Part A: Cmax for Midazolam |
10.33; 15.99 | — |
| PRIMARY Part A: Area Under the Plasma Concentration-Time Curve From Time Zero (0) to the Time of the Last Quantifiable Concentration (AUCt) for Bupropion |
845.3; 963.9; 812.1 | — |
| PRIMARY Part A: AUCt for Repaglinide |
15.47; 20.59 | — |
| PRIMARY Part A: AUCt for Flurbiprofen |
39639; 44940 | — |
| PRIMARY Part A: AUCt for Omeprazole |
889.4; 721.8 | — |
| PRIMARY Part A: AUCt for Midazolam |
25.78; 52.58 | — |
| PRIMARY Part A: Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf) for Bupropion |
883.3; 985.4; 839.1 | — |
| PRIMARY Part A: AUCinf for Repaglinide |
16.49; 21.74 | — |
| PRIMARY Part A: AUCinf for Flurbiprofen |
40047; 45361 | — |
| PRIMARY Part A: AUCinf for Omeprazole |
932.3; 743.1 | — |
| PRIMARY Part A: AUCinf for Midazolam |
27.15; 54.42 | — |
| PRIMARY Part B: Cmax for Metformin |
55.84; 44.17 | — |
| PRIMARY Part B: Cmax for Furosemide |
48.58; 52.62 | — |
| PRIMARY Part B: Cmax for Rosuvastatin |
5.545; 7.286 | — |
| PRIMARY Part B: AUCt for Metformin |
303.8; 241.7 | — |
| PRIMARY Part B: AUCt for Furosemide |
105.0; 108.4 | — |
| PRIMARY Part B: AUCt for Rosuvastatin |
50.29; 60.22 | — |
| PRIMARY Part B: AUCinf for Metformin |
310.5; 249.0 | — |
| PRIMARY Part B: AUCinf for Furosemide |
108.4; 113.3 | — |
| PRIMARY Part B: AUCinf for Rosuvastatin |
50.87; 63.16 | — |
| SECONDARY Part A: Cmax for 6-Hydroxybupropion |
351.1; 376.3; 489.1 | — |
| SECONDARY Part A: Cmax for 5-Hydroxyomeprazole |
179.8; 216.8 | — |
| SECONDARY Part A: Cmax for 1-Hydroxymidazolam |
5.984; 7.291 | — |
| SECONDARY Part A: AUCt for 6-Hydroxybupropion |
11529; 11223; 13453 | — |
| SECONDARY Part A: AUCt for 5-Hydroxyomeprazole |
504.1; 611.4 | — |
| SECONDARY Part A: AUCt for 1-Hydroxymidazolam |
12.73; 20.07 | — |
| SECONDARY Part A: AUCinf for 6-Hydroxybupropion |
11692; 12407; 14990 | — |
| SECONDARY Part A: AUCinf for 5-Hydroxyomeprazole |
510.3; 615.5 | — |
| SECONDARY Part A: AUCinf for 1-Hydroxymidazolam |
12.72; 20.92 | — |
| SECONDARY Part A: Time at Which Cmax Was Observed (Tmax) for Bupropion |
1.500; 1.500; 1.500 | — |
| SECONDARY Part A: Tmax for 6-Hydroxybupropion |
3.015; 4.000; 3.000 | — |
| SECONDARY Part A: Tmax for Repaglinide |
0.500; 0.500 | — |
| SECONDARY Part A: Tmax for Flurbiprofen |
2.000; 1.500 | — |
| SECONDARY Part A: Tmax for Omeprazole |
2.000; 2.000 | — |
| SECONDARY Part A: Tmax for 5-Hydroxyomeprazole |
2.000; 2.000 | — |
| SECONDARY Part A: Tmax for Midazolam |
1.000; 1.000 | — |
| SECONDARY Part A: Tmax for 1-Hydroxymidazolam |
1.000; 1.000 | — |
| SECONDARY Part A: Terminal Elimination Half-life (T½) for Bupropion |
20.577; 19.203; 19.383 | — |
| SECONDARY Part A: t1/2 6-Hydroxybupropion |
26.228; 23.220; 21.500 | — |
| SECONDARY Part A: T1/2 for Repaglinide |
4.684; 6.242 | — |
| SECONDARY Part A: T1/2 for Flurbiprofen |
6.906; 6.855 | — |
| SECONDARY Part A: T1/2 for Omeprazole |
0.945; 0.891 | — |
| SECONDARY Part A: T1/2 for 5-Hydroxyomeprazole |
1.455; 1.387 | — |
| SECONDARY Part A: T1/2 for Midazolam |
4.502; 5.497 | — |
| SECONDARY Part A: T1/2 for 1-Hydroxymidazolam |
3.346; 3.172 | — |
| SECONDARY Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight (AUCt M/P) for 6-Hydroxybupropion/Bupropion |
12.79; 10.92; 15.53 | — |
| SECONDARY Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight for 5-Hydroxyomeprazole/Omeprazole |
0.5417; 0.8096 | — |
| SECONDARY Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight for Hydroxymidazolam/Midazolam |
0.4704; 0.3638 | — |
| SECONDARY Part B: Tmax for Metformin |
1.500; 2.000 | — |
| SECONDARY Part B: Tmax for Furosemide |
0.510; 0.775 | — |
| SECONDARY Part B: Tmax for Rosuvastatin |
5.000; 2.500 | — |
| SECONDARY Part B: T½ for Metformin |
3.554; 3.324 | — |
| SECONDARY Part B: T½ for Furosemide |
7.786; 4.757 | — |
| SECONDARY Part B: T½ for Rosuvastatin |
11.436; 8.852 | — |
Eligibility Criteria
Inclusion Criteria
- 1. Males or females ≥ 18 and ≤ 55 years of age inclusive, at the time of signing the informed consent.
- 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.
- 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
- 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.
- Males must agree not to donate sperm during the study and for 30 days following last dose of study drug.
Exclusion Criteria
- Positive pregnancy test or is lactating.
- History or presence of clinically significant allergic diseases (except for untreated,
asymptomatic, seasonal allergies) at time of screening in the opinion of the Investigator.
- 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.
- Any signs and/or symptoms of acute illness at screening or Day -1.
- 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.
- Resting bradycardia (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.
- 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.
- 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.
- Prior exposure to voxelotor/Oxbryta® within the past month.
- Clinically significant anemia, or has donated blood or blood components exceeding 400 mL within 90 day
Data sourced from ClinicalTrials.gov (NCT05981365). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.