Drug Interaction Study of GBT440 With Caffeine, S-warfarin, Omeprazole, and Midazolam in Healthy Subjects

Study Overview
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Brief Summary
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The purpose of this study to evaluate the effect of concomitant administration of GBT440 on caffeine (a CYP1A2 probe substrate), S warfarin (a CYP2C9 probe substrate), omeprazole (a CYP2C19 probe substrate), and midazolam (a CYP3A4 probe substrate) plasma concentrations.

Official Title
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A Phase 1, Open-Label Study to Evaluate the Effect of Multiple Doses of GBT440 on the Pharmacokinetics of Probe Substrates for CYP1A2, CYP2C9, CYP2C19, and CYP3A4 in Healthy Subjects

Conditions
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Sickle Cell Disease

Intervention / Treatment
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* Drug: GBT440


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is a female of non-childbearing potential or male, who is healthy, nonsmoking, and 18 to 55 years old, inclusive, at screening Male subjects agree to use contraception Willing and able to give written informed consent Exclusion Criteria: Evidence or history of clinically significant metabolic, allergic, dermatological, hepatic, renal,hematological, pulmonary, cardiovascular, gastrointestinal, neurological, or psychiatric disorder History of hypersensitivity or allergy to drugs, foods, or other substances History or presence of abnormal electrocardiogram or hypertension History of alcohol abuse, illicit drug use, significant mental illness, physical dependence to any opioid, or any history of drug abuse or addiction within 1 year of screening Participated in another clinical trial of an investigational drug within 30 days (or 5 half-lives of the investigational drug, whichever is longer) prior to Screening

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fixed sequence, 2-periods<br>An open-label, fixed sequence, 2-period drug interaction study Period 1 Treatment A: Single dose of drug cocktail on Day 1 Period 2 Treatment B: GBT440 on Days 1 through 3 and Treatment C: Single dose of drug cocktail on Day 4 and GBT440 on Days 4 through 7 | Drug: GBT440<br>* GBT440 capsules followed by Caffeine, S-warfarin+vitamin K, Omeprazole, and Midazolam<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak plasma concentration(Cmax) for caffeine, S warfarin, omeprazole, and midazolam in plasma |  | 0 - 168 hours post dose in Period 1 and 0-408 hours post dose in Period 2 | 
| Area under the plasma concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUCt) for caffeine, S warfarin, omeprazole, and midazolam |  | 0 - 168 hours post dose in Period 1 and 0-408 hours post dose in Period 2 | 
| Area under the plasma concentration time curve from time 0 extrapolated to infinity (AUCinf) for caffeine, S warfarin, omeprazole, and midazolam |  | 0 - 168 hours post dose in Period 1 and 0-408 hours post dose in Period 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The time that Cmax was observed (tmax) for caffeine, S warfarin, omeprazole, and midazolam in plasma |  | 0 - 168 hours post dose in Period 1 and 0-408 hours post dose in Period 2 | 
| Terminal elimination half-life (t½) for caffeine, S warfarin, omeprazole, and midazolam in plasma |  | 0 - 168 hours post dose in Period 1 and 0-408 hours post dose in Period 2 | 
| Cmax for metabolites of caffeine, warfarin, omeprazole, and midazolam in plasma |  | 0 - 168 hours post dose in Period 1 and 0-408 hours post dose in Period 2 | 
| tmax, for metabolites of caffeine, warfarin, omeprazole, and midazolam in plasma |  | 0 - 168 hours post dose in Period 1 and 0-408 hours post dose in Period 2 | 
| AUCt for metabolites of caffeine, warfarin, omeprazole, and midazolam in plasma |  | 0 - 168 hours post dose in Period 1 and 0-408 hours post dose in Period 2 | 
| AUCinf for metabolites of caffeine, warfarin, omeprazole, and midazolam in plasma |  | 0 - 168 hours post dose in Period 1 and 0-408 hours post dose in Period 2 | 
| t1/2 for metabolites of caffeine, warfarin, omeprazole, and midazolam in plasma |  | 0 - 168 hours post dose in Period 1 and 0-408 hours post dose in Period 2 | 
| Ratio of metabolite to parent Cmax corrected for molecular weight (Cmax M/P) for metabolites of caffeine, warfarin, omeprazole, and midazolam in plasma |  | 0 - 168 hours post dose in Period 1 and 0-408 hours post dose in Period 2 | 
| Ratio of metabolite to parent AUCt corrected for molecular weight (AUCt M/P)for metabolites of caffeine, warfarin, omeprazole, and midazolam in plasma |  | 0 - 168 hours post dose in Period 1 and 0-408 hours post dose in Period 2 | 
| Ratio of metabolite to parent AUCinf corrected for molecular weight (AUCinf M/P) for metabolites of caffeine, warfarin, omeprazole, and midazolam in plasma |  | 0 - 168 hours post dose in Period 1 and 0-408 hours post dose in Period 2 | 
| Cmax for GBT440 in whole blood and plasma |  | 0 - 168 hours post dose in Period 1 and 0-408 hours post dose in Period 2 | 
| tmax for GBT440 in whole blood and plasma |  | 0 - 168 hours post dose in Period 1 and 0-408 hours post dose in Period 2 | 
| AUC from time 0 to 24 hours (AUC0-24) (Days 4 and 7) for GBT440 in whole blood and plasma |  | 0 - 168 hours post dose in Period 1 and 0-408 hours post dose in Period 2 | 
| t1/2 (Day7) for GBT440 in whole blood and plasma |  | 0 - 168 hours post dose in Period 1 and 0-408 hours post dose in Period 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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anemia, sickle cell