Sickle Cell Disease
Conditions
Keywords
Drug drug interaction
Brief 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.
Detailed 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.
Interventions
DRUGVoxelotor
Drug drug interaction
DRUGBupropion
Drug drug interaction
DRUGRepaglinide
Drug drug interaction
DRUGFlurbiprofen
Drug drug interaction
DRUGOmeprazole
Drug drug interaction
DRUGMidazolam
Drug drug interaction
DRUGMetformin
Drug drug interaction
DRUGFurosemide
Drug drug interaction
DRUGRosuvastatin
Drug drug interaction
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part B: AUCt for Metformin | 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 | AUCt was calculated using the linear/log trapezoid rule. |
| Part B: Cmax for Rosuvastatin | 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: AUCinf for Rosuvastatin | 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 | 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. |
| Part B: AUCinf for Furosemide | 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 | 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. |
| Part B: AUCinf for Metformin | 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 | 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. |
| Part B: AUCt for Rosuvastatin | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Day 1 and Day 4 for Treatment A and Treatment C, respectively | AUCt was calculated using the linear/log trapezoid rule. |
| Part B: AUCt for Furosemide | 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 | AUCt was calculated using the linear/log trapezoid rule. |
| Part B: Cmax for Furosemide | 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 A: Maximum Observed Plasma Concentration (Cmax) for Bupropion | 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 | 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 | 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 | 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 | 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 | 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 | AUCt was calculated using the linear/log trapezoidal rule. |
| Part A: AUCt for Repaglinide | 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 | AUCt was calculated using the linear/log trapezoid rule. |
| Part A: AUCt for Flurbiprofen | 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 | AUCt was calculated using the linear/log trapezoid rule. |
| Part A: AUCt for Omeprazole | 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 | AUCt was calculated using the linear/log trapezoid rule. |
| Part A: AUCt for Midazolam | 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 | AUCt was calculated using the linear/log trapezoid rule. |
| Part A: Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf) for Bupropion | 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 | 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. |
| Part A: AUCinf for Repaglinide | 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 | 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. |
| Part A: AUCinf for Flurbiprofen | 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 | 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. |
| Part A: AUCinf for Omeprazole | 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 | 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. |
| Part A: AUCinf for Midazolam | 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 | 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. |
| Part B: Cmax for Metformin | 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 | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part A: T1/2 for Midazolam | 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 | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. |
| Part A: T1/2 for 1-Hydroxymidazolam | 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 | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. |
| Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight (AUCt M/P) for 6-Hydroxybupropion/Bupropion | 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 | 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 | 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 | 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 | 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 | 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 | 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 | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. |
| Part B: T½ for Furosemide | 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 | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. |
| Part B: T½ for Rosuvastatin | 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 | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. |
| Part A: AUCt for 6-Hydroxybupropion | 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 | AUCt was calculated using the linear/log trapezoid rule. |
| Part A: Cmax for 6-Hydroxybupropion | 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 | 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 | 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 5-Hydroxyomeprazole | 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 | AUCt was calculated using the linear/log trapezoid rule. |
| Part A: AUCt for 1-Hydroxymidazolam | 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 | AUCt was calculated using the linear/log trapezoid rule. |
| Part A: AUCinf for 6-Hydroxybupropion | 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 | 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. |
| Part A: AUCinf for 5-Hydroxyomeprazole | 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 | 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. |
| Part A: AUCinf for 1-Hydroxymidazolam | 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 | 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. |
| Part A: Time at Which Cmax Was Observed (Tmax) for Bupropion | 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 | The time that Cmax was observed. |
| Part A: Tmax for 6-Hydroxybupropion | 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 | The time that Cmax was observed for 6-Hydroxybupropion. |
| Part A: Tmax for Repaglinide | 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 | The time that Cmax was observed for Repaglinide. |
| Part A: Tmax for Flurbiprofen | 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 | The time that Cmax was observed for Flurbiprofen. |
| Part A: Tmax for Omeprazole | 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 | The time that Cmax was observed for Omeprazole. |
| Part A: Tmax for 5-Hydroxyomeprazole | 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 | The time that Cmax was observed for 5-Hydroxyomeprazole. |
| Part A: Tmax for Midazolam | 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 | The time that Cmax was observed for Midazolam. |
| Part A: Tmax for 1-Hydroxymidazolam | 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 | The time that Cmax was observed for 1-Hydroxymidazolam. |
| Part A: Terminal Elimination Half-life (T½) for Bupropion | 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 | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. |
| Part A: t1/2 6-Hydroxybupropion | 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 | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. |
| Part A: T1/2 for Repaglinide | 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 | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. |
| Part A: T1/2 for Flurbiprofen | 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 | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. |
| Part A: T1/2 for Omeprazole | 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 | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. |
| Part A: T1/2 for 5-Hydroxyomeprazole | 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 | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | From start of study drug on Day 1 up to Day 28 (for a maximum of 30 days) | An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product during the course of a clinical investigation. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product, whether or not thought to be related to the investigational product. TEAE: any event that was not present before exposure to study drug (voxelotor or cocktail drugs \[probe substrates\]) or any event already present that worsened in either intensity or frequency after exposure to study drug. An SAE was defined as an AE that at any dose resulted in any of the following outcomes: death; life-threatening AE; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or disability; a congenital anomaly/birth defect; other important medical events. |
| Part B: Number of Participants With Clinically Significant Abnormalities in Vital Signs | From start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) | Vital signs included oral temperature, heart rate, respiratory rate (breaths per minute), and blood pressure. Blood pressure and heart rate were measured in a supine position using completely automated device after at least 5 minutes of rest for the participant in a quiet setting without distractions. Clinical significance of vital signs was determined by investigator. |
| Part B: Number of Participants With Clinically Significant Abnormalities in Physical Examinations | From start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) | A complete physical examination included cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and weight were also measured and recorded. Clinical significance of physical examinations was determined by investigator. |
| Part B: Number of Participants With Clinically Significant Abnormalities in Laboratory Tests | From start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) | The following laboratory parameters were assessed: hematology: hematocrit, hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, red blood cell count, neutrophils, monocytes, lymphocytes, basophils and eosinophils. coagulation: prothrombin time, partial thromboplastin time, international normalized ratio. Serum Chemistry: albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, creatinine, blood urea nitrogen, lactate dehydrogenase. Urinalysis: ketones, pH, protein, blood glucose, bilirubin, chloride, bicarbonate, phosphorous, potassium was assessed. Clinical significance of laboratory abnormalities was determined by investigator. |
| Part A: Number of Participants With Clinically Significant Abnormalities in Vital Signs | From start of study drug on Day 1 up to Day 28 (for a maximum of 30 days) | Vital signs included oral temperature, heart rate, respiratory rate (breaths per minute), and blood pressure. Blood pressure and heart rate were measured in a supine position using completely automated device after at least 5 minutes of rest for the participant in a quiet setting without distractions. Clinical significance of vital signs was determined by investigator. |
| Part A: Number of Participants With Clinically Significant Abnormalities in Physical Examinations | From start of study drug on Day 1 up to Day 28 (for a maximum of 30 days) | A complete physical examination included cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and weight were also measured and recorded. Clinical significance of physical examinations was determined by investigator. |
| Part A: Number of Participants With Clinically Significant Abnormalities in Laboratory Tests | From start of study drug on Day 1 up to Day 28 (for a maximum of 30 days) | The following laboratory parameters were assessed: hematology: hematocrit, hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, red blood cell count, neutrophils, monocytes, lymphocytes, basophils and eosinophils. coagulation: prothrombin time, partial thromboplastin time, international normalized ratio. Serum Chemistry: albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, creatinine, blood urea nitrogen, lactate dehydrogenase. Urinalysis: ketones, pH, protein, blood glucose, bilirubin, chloride, bicarbonate, phosphorous, potassium was assessed. Clinical significance of laboratory abnormalities was determined by investigator. |
| Part B: Number of Participants With TEAEs and SAEs | From start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) | An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product during the course of a clinical investigation. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product, whether or not thought to be related to the investigational product. TEAE: any event that was not present before exposure to study drug (voxelotor or cocktail drugs \[probe substrates\]) or any event already present that worsened in either intensity or frequency after exposure to study drug. An SAE was defined as an AE that at any dose resulted in any of the following outcomes: death; life-threatening AE; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or disability; a congenital anomaly/birth defect; other important medical events. |
Countries
United States
Participant flow
Pre-assignment details
A total of 44 participants (26 in Part A and 18 in Part B) were enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| Part A:Treatment Sequence ABCDEFG On Day 1 of Period 1, participants were administered a single oral dose of Treatment A (bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg, and midazolam 2 mg) and on Day 4, participants received a single oral dose of repaglinide 0.5 mg (Treatment B). Period 1 for Part A was of 5 days. In Period 2, participants were administered once daily oral dose of voxelotor 1500 mg (Treatment C) for 13 days. On Day 2, a single oral dose of bupropion 150 mg (Treatment D) was administered immediately following voxelotor administration. On Day 4, single oral dose of Treatment E (flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg) was administered immediately following voxelotor administration. Participants received Treatment F (single oral dose of repaglinide 0.5 mg) and Treatment G (single oral dose of bupropion 150 mg) on Day 6 and Day 12, immediately following voxelotor administration. Period 2 for Part A was of 15 days. There was a washout period of 7 to 14 days in between Period 1 and 2. Participants had a follow-up visit on Day 28. | 26 |
| Part B: Treatment Sequence ABCD On Day 1 of Period 1, participants were administered a single oral dose of Treatment A (metformin 10 mg, furosemide 1 mg, and rosuvastatin 10 mg). Period 1 for Part B was of 4 days. In Period 2, from Day 1 to Day 3, participants were administered Treatment B (oral doses of voxelotor 1500 mg) orally for 3 days. On Day 4, participants were administered Treatment C (single oral doses of metformin 10 mg, furosemide 1 mg, and rosuvastatin 10 mg) immediately following voxelotor administration. On Day 5, participants were administered Treatment D (single oral dose of voxelotor 1500 mg). Period 2 for Part B was of 7 days. There was a washout period of 7 to 14 days in between Period 1 and 2. Participants had a follow-up visit on Day 18. | 18 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | Part B: Treatment Sequence ABCD | Total | Part A:Treatment Sequence ABCDEFG |
|---|---|---|---|
| Age, Continuous | 36.9 Years STANDARD_DEVIATION 10.08 | 39.8 Years STANDARD_DEVIATION 9.61 | 41.9 Years STANDARD_DEVIATION 8.89 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 14 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 30 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 16 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 26 Participants | 16 Participants |
| Sex: Female, Male Female | 5 Participants | 14 Participants | 9 Participants |
| Sex: Female, Male Male | 13 Participants | 30 Participants | 17 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 / 26 | 0 / 25 | 0 / 18 | 0 / 18 |
| other Total, other adverse events | 4 / 26 | 9 / 25 | 1 / 18 | 2 / 18 |
| serious Total, serious adverse events | 0 / 26 | 0 / 25 | 0 / 18 | 0 / 18 |
Outcome results
Primary
Part A: Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf) for Bupropion
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter. Here Number of Participants Analyzed signifies the number of participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf) for Bupropion | 883.3 Hour*nanogram/milliliter | Geometric Coefficient of Variation 30 |
| Part A: Period 2: Treatment D | Part A: Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf) for Bupropion | 985.4 Hour*nanogram/milliliter | Geometric Coefficient of Variation 28 |
| Part A: Period 2: Treatment G | Part A: Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf) for Bupropion | 839.1 Hour*nanogram/milliliter | Geometric Coefficient of Variation 28 |
Comparison: Analysis was performed using linear mixed model, with treatment as fixed effect and participant as random effect.90% CI: [1.0672, 1.2122]
Comparison: Analysis was performed using linear mixed model, with treatment as fixed effect and participant as random effect.90% CI: [0.8643, 1.0162]
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
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | 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 Hour* nanogram/milliliter (h*ng/mL) | Geometric Coefficient of Variation 29 |
| Part A: Period 2: Treatment D | Part A: Area Under the Plasma Concentration-Time Curve From Time Zero (0) to the Time of the Last Quantifiable Concentration (AUCt) for Bupropion | 963.9 Hour* nanogram/milliliter (h*ng/mL) | Geometric Coefficient of Variation 28 |
| Part A: Period 2: Treatment G | Part A: Area Under the Plasma Concentration-Time Curve From Time Zero (0) to the Time of the Last Quantifiable Concentration (AUCt) for Bupropion | 812.1 Hour* nanogram/milliliter (h*ng/mL) | Geometric Coefficient of Variation 28 |
Comparison: Analysis was performed using linear mixed model, with treatment as fixed effect and participant as random effect.90% CI: [1.0807, 1.222]
Comparison: Analysis was performed using linear mixed model, with treatment as fixed effect and participant as random effect.90% CI: [0.8759, 1.0291]
Primary
Part A: AUCinf for Flurbiprofen
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, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: AUCinf for Flurbiprofen | 40047 h*ng/mL | Geometric Coefficient of Variation 26 |
| Part A: Period 2: Treatment D | Part A: AUCinf for Flurbiprofen | 45361 h*ng/mL | Geometric Coefficient of Variation 25 |
Comparison: Analysis was performed using linear mixed model, with treatment as fixed effect and participant as random effect.90% CI: [1.0688, 1.1883]
Primary
Part A: AUCinf for Midazolam
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, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: AUCinf for Midazolam | 27.15 h*ng/mL | Geometric Coefficient of Variation 40 |
| Part A: Period 2: Treatment D | Part A: AUCinf for Midazolam | 54.42 h*ng/mL | Geometric Coefficient of Variation 28 |
Comparison: Analysis was performed using linear mixed model, with treatment as fixed effect and participant as random effect.90% CI: [1.8496, 2.2193]
Primary
Part A: AUCinf for Omeprazole
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, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter. Here Number of Participants Analyzed signifies the number of participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: AUCinf for Omeprazole | 932.3 h*ng/mL | Geometric Coefficient of Variation 62 |
| Part A: Period 2: Treatment D | Part A: AUCinf for Omeprazole | 743.1 h*ng/mL | Geometric Coefficient of Variation 69 |
Comparison: Analysis was performed using linear mixed model, with treatment as fixed effect and participant as random effect.90% CI: [0.7039, 0.9031]
Primary
Part A: AUCinf for Repaglinide
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, and 24 hours post-dose on Period 1 Day 4 and Period 2 Day 6 for Treatment B and F, respectively
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter. Here Number of Participants Analyzed signifies the number of participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: AUCinf for Repaglinide | 16.49 h*ng/mL | Geometric Coefficient of Variation 40 |
| Part A: Period 2: Treatment D | Part A: AUCinf for Repaglinide | 21.74 h*ng/mL | Geometric Coefficient of Variation 33 |
Comparison: Analysis was performed using linear mixed model, with treatment as fixed effect and participant as random effect.90% CI: [1.1939, 1.3538]
Primary
Part A: AUCt for Flurbiprofen
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: AUCt for Flurbiprofen | 39639 h*ng/mL | Geometric Coefficient of Variation 26 |
| Part A: Period 2: Treatment D | Part A: AUCt for Flurbiprofen | 44940 h*ng/mL | Geometric Coefficient of Variation 24 |
Comparison: Analysis was performed using linear mixed model, with treatment as fixed effect and participant as random effect.90% CI: [1.07, 1.1896]
Primary
Part A: AUCt for Midazolam
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: AUCt for Midazolam | 25.78 h*ng/mL | Geometric Coefficient of Variation 42 |
| Part A: Period 2: Treatment D | Part A: AUCt for Midazolam | 52.58 h*ng/mL | Geometric Coefficient of Variation 27 |
Comparison: Analysis was performed using linear mixed model, with treatment as fixed effect and participant as random effect.90% CI: [1.8789, 2.2609]
Primary
Part A: AUCt for Omeprazole
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: AUCt for Omeprazole | 889.4 h*ng/mL | Geometric Coefficient of Variation 62 |
| Part A: Period 2: Treatment D | Part A: AUCt for Omeprazole | 721.8 h*ng/mL | Geometric Coefficient of Variation 68 |
Comparison: Analysis was performed using linear mixed model, with treatment as fixed effect and participant as random effect.90% CI: [0.7173, 0.9027]
Primary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: AUCt for Repaglinide | 15.47 h*ng/mL | Geometric Coefficient of Variation 40 |
| Part A: Period 2: Treatment D | Part A: AUCt for Repaglinide | 20.59 h*ng/mL | Geometric Coefficient of Variation 34 |
Comparison: Analysis was performed using linear mixed model, with treatment as fixed effect and participant as random effect.90% CI: [1.2558, 1.4121]
Primary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: Cmax for Flurbiprofen | 6923 ng/ml | Geometric Coefficient of Variation 25 |
| Part A: Period 2: Treatment D | Part A: Cmax for Flurbiprofen | 7820 ng/ml | Geometric Coefficient of Variation 20 |
Comparison: Analysis was performed using linear mixed model, with treatment as fixed effect and participant as random effect.90% CI: [1.0496, 1.2189]
Primary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: Cmax for Midazolam | 10.33 ng/ml | Geometric Coefficient of Variation 38 |
| Part A: Period 2: Treatment D | Part A: Cmax for Midazolam | 15.99 ng/ml | Geometric Coefficient of Variation 23 |
Comparison: Analysis was performed using linear mixed model, with treatment as fixed effect and participant as random effect.90% CI: [1.4523, 1.7054]
Primary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: Cmax for Omeprazole | 458.1 ng/ml | Geometric Coefficient of Variation 58 |
| Part A: Period 2: Treatment D | Part A: Cmax for Omeprazole | 374.3 ng/ml | Geometric Coefficient of Variation 57 |
Comparison: Analysis was performed using linear mixed model, with treatment as fixed effect and participant as random effect.90% CI: [0.6992, 0.9683]
Primary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: Cmax for Repaglinide | 10.85 ng/ml | Geometric Coefficient of Variation 41 |
| Part A: Period 2: Treatment D | Part A: Cmax for Repaglinide | 12.89 ng/ml | Geometric Coefficient of Variation 37 |
Comparison: Analysis was performed using linear mixed model, with treatment as fixed effect and participant as random effect.90% CI: [1.0215, 1.393]
Primary
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
Population: Pharmacokinetic (PK) evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: Maximum Observed Plasma Concentration (Cmax) for Bupropion | 160.5 Nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 31 |
| Part A: Period 2: Treatment D | Part A: Maximum Observed Plasma Concentration (Cmax) for Bupropion | 201.3 Nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 35 |
| Part A: Period 2: Treatment G | Part A: Maximum Observed Plasma Concentration (Cmax) for Bupropion | 191.1 Nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 36 |
Comparison: Analysis was performed using linear mixed model, with treatment as fixed effect and participant as random effect.90% CI: [1.1673, 1.3663]
Comparison: Analysis was performed using linear mixed model, with treatment as fixed effect and participant as random effect.95% CI: [1.0758, 1.3042]
Primary
Part B: AUCinf for Furosemide
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, 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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter. Here Number of Participants Analyzed signifies the number of participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part B: AUCinf for Furosemide | 108.4 h*ng/mL | Geometric Coefficient of Variation 29 |
| Part A: Period 2: Treatment D | Part B: AUCinf for Furosemide | 113.3 h*ng/mL | Geometric Coefficient of Variation 30 |
Comparison: Analysis was performed using linear mixed model, with treatment as fixed effect and participant as random effect.90% CI: [0.9888, 1.1427]
Primary
Part B: AUCinf for Metformin
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, 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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part B: AUCinf for Metformin | 310.5 h*ng/mL | Geometric Coefficient of Variation 25 |
| Part A: Period 2: Treatment D | Part B: AUCinf for Metformin | 249.0 h*ng/mL | Geometric Coefficient of Variation 29 |
Comparison: Analysis was performed using linear mixed model, with treatment as fixed effect and participant as random effect.90% CI: [0.7472, 0.8604]
Primary
Part B: AUCinf for Rosuvastatin
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, 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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter. Here Number of Participants Analyzed signifies the number of participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part B: AUCinf for Rosuvastatin | 50.87 h*ng/mL | Geometric Coefficient of Variation 45 |
| Part A: Period 2: Treatment D | Part B: AUCinf for Rosuvastatin | 63.16 h*ng/mL | Geometric Coefficient of Variation 43 |
Comparison: Analysis was performed using linear mixed model, with treatment as fixed effect and participant as random effect.90% CI: [1.1114, 1.3385]
Primary
Part B: AUCt for Furosemide
AUCt was calculated using the linear/log trapezoid rule.
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part B: AUCt for Furosemide | 105.0 h*ng/mL | Geometric Coefficient of Variation 28 |
| Part A: Period 2: Treatment D | Part B: AUCt for Furosemide | 108.4 h*ng/mL | Geometric Coefficient of Variation 33 |
Comparison: Analysis was performed using linear mixed model, with treatment as fixed effect and participant as random effect.90% CI: [0.9531, 1.1179]
Primary
Part B: AUCt for Metformin
AUCt was calculated using the linear/log trapezoid rule.
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part B: AUCt for Metformin | 303.8 h*ng/mL | Geometric Coefficient of Variation 26 |
| Part A: Period 2: Treatment D | Part B: AUCt for Metformin | 241.7 h*ng/mL | Geometric Coefficient of Variation 30 |
Comparison: Analysis was performed using linear mixed model, with treatment as fixed effect and participant as random effect.90% CI: [0.742, 0.8534]
Primary
Part B: AUCt for Rosuvastatin
AUCt was calculated using the linear/log trapezoid rule.
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 Day 1 and Day 4 for Treatment A and Treatment C, respectively
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part B: AUCt for Rosuvastatin | 50.29 h*ng/mL | Geometric Coefficient of Variation 46 |
| Part A: Period 2: Treatment D | Part B: AUCt for Rosuvastatin | 60.22 h*ng/mL | Geometric Coefficient of Variation 45 |
Comparison: Analysis was performed using linear mixed model, with treatment as fixed effect and participant as random effect.90% CI: [1.0972, 1.3069]
Primary
Part B: Cmax 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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part B: Cmax for Furosemide | 48.58 ng/mL | Geometric Coefficient of Variation 32 |
| Part A: Period 2: Treatment D | Part B: Cmax for Furosemide | 52.62 ng/mL | Geometric Coefficient of Variation 35 |
Comparison: Analysis was performed using linear mixed model, with treatment as fixed effect and participant as random effect.90% CI: [0.9723, 1.2065]
Primary
Part B: Cmax 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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part B: Cmax for Metformin | 55.84 ng/mL | Geometric Coefficient of Variation 35 |
| Part A: Period 2: Treatment D | Part B: Cmax for Metformin | 44.17 ng/mL | Geometric Coefficient of Variation 36 |
Comparison: Analysis was performed using linear mixed model, with treatment as fixed effect and participant as random effect.90% CI: [0.716, 0.8737]
Primary
Part B: Cmax 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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part B: Cmax for Rosuvastatin | 5.545 ng/mL | Geometric Coefficient of Variation 46 |
| Part A: Period 2: Treatment D | Part B: Cmax for Rosuvastatin | 7.286 ng/mL | Geometric Coefficient of Variation 53 |
Comparison: Analysis was performed using linear mixed model, with treatment as fixed effect and participant as random effect.90% CI: [1.1871, 1.4541]
Secondary
Part A: AUCinf for 1-Hydroxymidazolam
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, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter. Here Number of Participants Analyzed signifies the number of participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: AUCinf for 1-Hydroxymidazolam | 12.72 h*ng/mL | Geometric Coefficient of Variation 43 |
| Part A: Period 2: Treatment D | Part A: AUCinf for 1-Hydroxymidazolam | 20.92 h*ng/mL | Geometric Coefficient of Variation 26 |
Secondary
Part A: AUCinf for 5-Hydroxyomeprazole
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, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: AUCinf for 5-Hydroxyomeprazole | 510.3 h*ng/mL | Geometric Coefficient of Variation 21 |
| Part A: Period 2: Treatment D | Part A: AUCinf for 5-Hydroxyomeprazole | 615.5 h*ng/mL | Geometric Coefficient of Variation 22 |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter. Here Number of Participants Analyzed signifies the number of participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: AUCinf for 6-Hydroxybupropion | 11692 h*ng/mL | Geometric Coefficient of Variation 47 |
| Part A: Period 2: Treatment D | Part A: AUCinf for 6-Hydroxybupropion | 12407 h*ng/mL | Geometric Coefficient of Variation 44 |
| Part A: Period 2: Treatment G | Part A: AUCinf for 6-Hydroxybupropion | 14990 h*ng/mL | Geometric Coefficient of Variation 55 |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: AUCt for 1-Hydroxymidazolam | 12.73 h*ng/mL | Geometric Coefficient of Variation 43 |
| Part A: Period 2: Treatment D | Part A: AUCt for 1-Hydroxymidazolam | 20.07 h*ng/mL | Geometric Coefficient of Variation 27 |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: AUCt for 5-Hydroxyomeprazole | 504.1 h*ng/mL | Geometric Coefficient of Variation 21 |
| Part A: Period 2: Treatment D | Part A: AUCt for 5-Hydroxyomeprazole | 611.4 h*ng/mL | Geometric Coefficient of Variation 21 |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: AUCt for 6-Hydroxybupropion | 11529 h*ng/mL | Geometric Coefficient of Variation 49 |
| Part A: Period 2: Treatment D | Part A: AUCt for 6-Hydroxybupropion | 11223 h*ng/mL | Geometric Coefficient of Variation 44 |
| Part A: Period 2: Treatment G | Part A: AUCt for 6-Hydroxybupropion | 13453 h*ng/mL | Geometric Coefficient of Variation 53 |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: Cmax for 1-Hydroxymidazolam | 5.984 ng/ml | Geometric Coefficient of Variation 44 |
| Part A: Period 2: Treatment D | Part A: Cmax for 1-Hydroxymidazolam | 7.291 ng/ml | Geometric Coefficient of Variation 28 |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: Cmax for 5-Hydroxyomeprazole | 179.8 ng/mL | Geometric Coefficient of Variation 29 |
| Part A: Period 2: Treatment D | Part A: Cmax for 5-Hydroxyomeprazole | 216.8 ng/mL | Geometric Coefficient of Variation 27 |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: Cmax for 6-Hydroxybupropion | 351.1 ng/mL | Geometric Coefficient of Variation 45 |
| Part A: Period 2: Treatment D | Part A: Cmax for 6-Hydroxybupropion | 376.3 ng/mL | Geometric Coefficient of Variation 45 |
| Part A: Period 2: Treatment G | Part A: Cmax for 6-Hydroxybupropion | 489.1 ng/mL | Geometric Coefficient of Variation 49 |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight (AUCt M/P) for 6-Hydroxybupropion/Bupropion | 12.79 Ratio | Geometric Coefficient of Variation 40 |
| Part A: Period 2: Treatment D | Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight (AUCt M/P) for 6-Hydroxybupropion/Bupropion | 10.92 Ratio | Geometric Coefficient of Variation 39 |
| Part A: Period 2: Treatment G | Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight (AUCt M/P) for 6-Hydroxybupropion/Bupropion | 15.53 Ratio | Geometric Coefficient of Variation 47 |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight for 5-Hydroxyomeprazole/Omeprazole | 0.5417 Ratio | Geometric Coefficient of Variation 52 |
| Part A: Period 2: Treatment D | Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight for 5-Hydroxyomeprazole/Omeprazole | 0.8096 Ratio | Geometric Coefficient of Variation 60 |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight for Hydroxymidazolam/Midazolam | 0.4704 Ratio | Geometric Coefficient of Variation 43 |
| Part A: Period 2: Treatment D | Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight for Hydroxymidazolam/Midazolam | 0.3638 Ratio | Geometric Coefficient of Variation 26 |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: t1/2 6-Hydroxybupropion | 26.228 Hours | Standard Deviation 5.978 |
| Part A: Period 2: Treatment D | Part A: t1/2 6-Hydroxybupropion | 23.220 Hours | Standard Deviation 4.9391 |
| Part A: Period 2: Treatment G | Part A: t1/2 6-Hydroxybupropion | 21.500 Hours | Standard Deviation 4.3406 |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter. Here Number of Participants Analyzed signifies the number of participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: T1/2 for 1-Hydroxymidazolam | 3.346 Hours | Standard Deviation 4.0653 |
| Part A: Period 2: Treatment D | Part A: T1/2 for 1-Hydroxymidazolam | 3.172 Hours | Standard Deviation 0.9569 |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: T1/2 for 5-Hydroxyomeprazole | 1.455 Hours | Standard Deviation 0.5103 |
| Part A: Period 2: Treatment D | Part A: T1/2 for 5-Hydroxyomeprazole | 1.387 Hours | Standard Deviation 0.2029 |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: T1/2 for Flurbiprofen | 6.906 Hours | Standard Deviation 1.2545 |
| Part A: Period 2: Treatment D | Part A: T1/2 for Flurbiprofen | 6.855 Hours | Standard Deviation 1.2666 |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: T1/2 for Midazolam | 4.502 Hours | Standard Deviation 1.734 |
| Part A: Period 2: Treatment D | Part A: T1/2 for Midazolam | 5.497 Hours | Standard Deviation 0.6465 |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: T1/2 for Omeprazole | 0.945 Hours | Standard Deviation 0.324 |
| Part A: Period 2: Treatment D | Part A: T1/2 for Omeprazole | 0.891 Hours | Standard Deviation 0.2785 |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: T1/2 for Repaglinide | 4.684 Hours | Standard Deviation 1.6568 |
| Part A: Period 2: Treatment D | Part A: T1/2 for Repaglinide | 6.242 Hours | Standard Deviation 1.3469 |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter. Here Number of Participants Analyzed signifies the number of participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: Terminal Elimination Half-life (T½) for Bupropion | 20.577 Hours | Standard Deviation 2.6082 |
| Part A: Period 2: Treatment D | Part A: Terminal Elimination Half-life (T½) for Bupropion | 19.203 Hours | Standard Deviation 2.6331 |
| Part A: Period 2: Treatment G | Part A: Terminal Elimination Half-life (T½) for Bupropion | 19.383 Hours | Standard Deviation 2.6591 |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Period 1: Treatment A | Part A: Time at Which Cmax Was Observed (Tmax) for Bupropion | 1.500 Hours |
| Part A: Period 2: Treatment D | Part A: Time at Which Cmax Was Observed (Tmax) for Bupropion | 1.500 Hours |
| Part A: Period 2: Treatment G | Part A: Time at Which Cmax Was Observed (Tmax) for Bupropion | 1.500 Hours |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Period 1: Treatment A | Part A: Tmax for 1-Hydroxymidazolam | 1.000 Hours |
| Part A: Period 2: Treatment D | Part A: Tmax for 1-Hydroxymidazolam | 1.000 Hours |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Period 1: Treatment A | Part A: Tmax for 5-Hydroxyomeprazole | 2.000 Hours |
| Part A: Period 2: Treatment D | Part A: Tmax for 5-Hydroxyomeprazole | 2.000 Hours |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Period 1: Treatment A | Part A: Tmax for 6-Hydroxybupropion | 3.015 Hours |
| Part A: Period 2: Treatment D | Part A: Tmax for 6-Hydroxybupropion | 4.000 Hours |
| Part A: Period 2: Treatment G | Part A: Tmax for 6-Hydroxybupropion | 3.000 Hours |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Period 1: Treatment A | Part A: Tmax for Flurbiprofen | 2.000 Hours |
| Part A: Period 2: Treatment D | Part A: Tmax for Flurbiprofen | 1.500 Hours |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Period 1: Treatment A | Part A: Tmax for Midazolam | 1.000 Hours |
| Part A: Period 2: Treatment D | Part A: Tmax for Midazolam | 1.000 Hours |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Period 1: Treatment A | Part A: Tmax for Omeprazole | 2.000 Hours |
| Part A: Period 2: Treatment D | Part A: Tmax for Omeprazole | 2.000 Hours |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Period 1: Treatment A | Part A: Tmax for Repaglinide | 0.500 Hours |
| Part A: Period 2: Treatment D | Part A: Tmax for Repaglinide | 0.500 Hours |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part B: T½ for Furosemide | 7.786 Hours | Standard Deviation 5.1296 |
| Part A: Period 2: Treatment D | Part B: T½ for Furosemide | 4.757 Hours | Standard Deviation 2.1595 |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part B: T½ for Metformin | 3.554 Hours | Standard Deviation 0.9523 |
| Part A: Period 2: Treatment D | Part B: T½ for Metformin | 3.324 Hours | Standard Deviation 0.8515 |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part B: T½ for Rosuvastatin | 11.436 Hours | Standard Deviation 8.9813 |
| Part A: Period 2: Treatment D | Part B: T½ for Rosuvastatin | 8.852 Hours | Standard Deviation 3.1587 |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Period 1: Treatment A | Part B: Tmax for Furosemide | 0.510 Hours |
| Part A: Period 2: Treatment D | Part B: Tmax for Furosemide | 0.775 Hours |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Period 1: Treatment A | Part B: Tmax for Metformin | 1.500 Hours |
| Part A: Period 2: Treatment D | Part B: Tmax for Metformin | 2.000 Hours |
Secondary
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
Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Period 1: Treatment A | Part B: Tmax for Rosuvastatin | 5.000 Hours |
| Part A: Period 2: Treatment D | Part B: Tmax for Rosuvastatin | 2.500 Hours |
Other Pre-specified
Part A: Number of Participants With Clinically Significant Abnormalities in Laboratory Tests
The following laboratory parameters were assessed: hematology: hematocrit, hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, red blood cell count, neutrophils, monocytes, lymphocytes, basophils and eosinophils. coagulation: prothrombin time, partial thromboplastin time, international normalized ratio. Serum Chemistry: albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, creatinine, blood urea nitrogen, lactate dehydrogenase. Urinalysis: ketones, pH, protein, blood glucose, bilirubin, chloride, bicarbonate, phosphorous, potassium was assessed. Clinical significance of laboratory abnormalities was determined by investigator.
Time frame: From start of study drug on Day 1 up to Day 28 (for a maximum of 30 days)
Population: SAS included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Period 1: Treatment A | Part A: Number of Participants With Clinically Significant Abnormalities in Laboratory Tests | 0 Participants |
| Part A: Period 2: Treatment D | Part A: Number of Participants With Clinically Significant Abnormalities in Laboratory Tests | 0 Participants |
Other Pre-specified
Part A: Number of Participants With Clinically Significant Abnormalities in Physical Examinations
A complete physical examination included cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and weight were also measured and recorded. Clinical significance of physical examinations was determined by investigator.
Time frame: From start of study drug on Day 1 up to Day 28 (for a maximum of 30 days)
Population: SAS included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Period 1: Treatment A | Part A: Number of Participants With Clinically Significant Abnormalities in Physical Examinations | 1 Participants |
| Part A: Period 2: Treatment D | Part A: Number of Participants With Clinically Significant Abnormalities in Physical Examinations | 0 Participants |
Other Pre-specified
Part A: Number of Participants With Clinically Significant Abnormalities in Vital Signs
Vital signs included oral temperature, heart rate, respiratory rate (breaths per minute), and blood pressure. Blood pressure and heart rate were measured in a supine position using completely automated device after at least 5 minutes of rest for the participant in a quiet setting without distractions. Clinical significance of vital signs was determined by investigator.
Time frame: From start of study drug on Day 1 up to Day 28 (for a maximum of 30 days)
Population: SAS included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Period 1: Treatment A | Part A: Number of Participants With Clinically Significant Abnormalities in Vital Signs | 0 Participants |
| Part A: Period 2: Treatment D | Part A: Number of Participants With Clinically Significant Abnormalities in Vital Signs | 1 Participants |
Other Pre-specified
Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product during the course of a clinical investigation. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product, whether or not thought to be related to the investigational product. TEAE: any event that was not present before exposure to study drug (voxelotor or cocktail drugs \[probe substrates\]) or any event already present that worsened in either intensity or frequency after exposure to study drug. An SAE was defined as an AE that at any dose resulted in any of the following outcomes: death; life-threatening AE; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or disability; a congenital anomaly/birth defect; other important medical events.
Time frame: From start of study drug on Day 1 up to Day 28 (for a maximum of 30 days)
Population: Safety analysis set (SAS) included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 4 Participants |
| Part A: Period 1: Treatment A | Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| Part A: Period 2: Treatment D | Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 9 Participants |
| Part A: Period 2: Treatment D | Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
Other Pre-specified
Part B: Number of Participants With Clinically Significant Abnormalities in Laboratory Tests
The following laboratory parameters were assessed: hematology: hematocrit, hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, red blood cell count, neutrophils, monocytes, lymphocytes, basophils and eosinophils. coagulation: prothrombin time, partial thromboplastin time, international normalized ratio. Serum Chemistry: albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, creatinine, blood urea nitrogen, lactate dehydrogenase. Urinalysis: ketones, pH, protein, blood glucose, bilirubin, chloride, bicarbonate, phosphorous, potassium was assessed. Clinical significance of laboratory abnormalities was determined by investigator.
Time frame: From start of study drug on Day 1 up to Day 18 (for a maximum of 20 days)
Population: SAS included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Period 1: Treatment A | Part B: Number of Participants With Clinically Significant Abnormalities in Laboratory Tests | 0 Participants |
| Part A: Period 2: Treatment D | Part B: Number of Participants With Clinically Significant Abnormalities in Laboratory Tests | 0 Participants |
Other Pre-specified
Part B: Number of Participants With Clinically Significant Abnormalities in Physical Examinations
A complete physical examination included cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and weight were also measured and recorded. Clinical significance of physical examinations was determined by investigator.
Time frame: From start of study drug on Day 1 up to Day 18 (for a maximum of 20 days)
Population: SAS included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Period 1: Treatment A | Part B: Number of Participants With Clinically Significant Abnormalities in Physical Examinations | 0 Participants |
| Part A: Period 2: Treatment D | Part B: Number of Participants With Clinically Significant Abnormalities in Physical Examinations | 0 Participants |
Other Pre-specified
Part B: Number of Participants With Clinically Significant Abnormalities in Vital Signs
Vital signs included oral temperature, heart rate, respiratory rate (breaths per minute), and blood pressure. Blood pressure and heart rate were measured in a supine position using completely automated device after at least 5 minutes of rest for the participant in a quiet setting without distractions. Clinical significance of vital signs was determined by investigator.
Time frame: From start of study drug on Day 1 up to Day 18 (for a maximum of 20 days)
Population: SAS included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Period 1: Treatment A | Part B: Number of Participants With Clinically Significant Abnormalities in Vital Signs | 0 Participants |
| Part A: Period 2: Treatment D | Part B: Number of Participants With Clinically Significant Abnormalities in Vital Signs | 0 Participants |
Other Pre-specified
Part B: Number of Participants With TEAEs and SAEs
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product during the course of a clinical investigation. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product, whether or not thought to be related to the investigational product. TEAE: any event that was not present before exposure to study drug (voxelotor or cocktail drugs \[probe substrates\]) or any event already present that worsened in either intensity or frequency after exposure to study drug. An SAE was defined as an AE that at any dose resulted in any of the following outcomes: death; life-threatening AE; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or disability; a congenital anomaly/birth defect; other important medical events.
Time frame: From start of study drug on Day 1 up to Day 18 (for a maximum of 20 days)
Population: SAS included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Period 1: Treatment A | Part B: Number of Participants With TEAEs and SAEs | TEAEs | 1 Participants |
| Part A: Period 1: Treatment A | Part B: Number of Participants With TEAEs and SAEs | SAEs | 0 Participants |
| Part A: Period 2: Treatment D | Part B: Number of Participants With TEAEs and SAEs | TEAEs | 2 Participants |
| Part A: Period 2: Treatment D | Part B: Number of Participants With TEAEs and SAEs | SAEs | 0 Participants |