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Phase 1 Completed N=44 Basic Science

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

OutcomeResultp-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
View full record on ClinicalTrials.gov →

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.

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