An Open-label Drug-Drug Interaction Study to Evaluate the Effect of BCX7353 on Cytochrome P450 Enzyme Activity Using Probe Substrates

Study Overview
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Brief Summary
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This is an open-label, single sequence study to evaluate the effect of BCX7353 on hepatic and intestinal cytochrome P450 enzymes using probe substrate drugs in healthy subjects. Pharmacokinetics of the probe substrate drugs will be measured prior to and following administration of multiple doses of BCX7353.

Detailed Description
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This is a single centre, single sequence, open-label, study to evaluate the effect of BCX7353 on hepatic and intestinal cytochrome P450 (CYP) 3A4 (midazolam IV and PO, respectively), CYP2C9 (tolbutamide), CYP2C19 (omeprazole) and CYP2D6 (dextromethorphan) enzyme activity using probe substrate drugs in healthy subjects. Pharmacokinetics of the probe substrate drugs will be measured prior to and following administration of multiple doses of BCX7353. Twenty healthy male and female subjects are planned for dosing. Each subject will receive the following treatments: Day 1: 1 mg midazolam will be administered as an IV bolus simultaneously to administration of 500 mg tolbutamide, 40 mg omeprazole, and 30 mg dextromethorphan orally. Day 2: a single oral dose of 2 mg midazolam. Days 3 to 9: 350 mg BCX7353 once a day. Day 10: 1 mg midazolam will be administered as an IV bolus simultaneously to administration of 500 mg tolbutamide, 40 mg omeprazole, 30 mg dextromethorphan and 350 mg BCX7353, orally. Day 11: a single oral dose of 2 mg of midazolam along with 350 mg BCX7353.

Official Title
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A Single Sequence, Open-Label Drug-Drug Interaction Study to Evaluate the Effect of BCX7353 on Cytochrome P450 3A4, 2C9, 2C19 and 2D6 Enzyme Activity Using Probe Substrates in Healthy Subjects

Conditions
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Hereditary Angioedema

Intervention / Treatment
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* Drug: BCX7353 and probes


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Written informed consent Body mass index 18 to 32 kg/m2 Abides by study restrictions Attends all study visits and agrees to remain in study center for the confinement period Acceptable birth control measures for male subjects and women of childbearing potential Key Exclusion Criteria: Clinically significant medical history, current medical or psychiatric condition. This includes a history of clinically significant gastrointestinal, hematologic, renal, hepatic, bronchopulmonary, neurological, or cardiac disease Clinically significant ECG finding, vital sign measurement or laboratory/urinalysis abnormality at screening or baseline Poor or ultra- metabolizers of CYP2C19 or CYP2D6 Use of over the counter or prescription medication within 14 days of dosing and anticipated use through the follow-up visit Use of medication or consumption of any substance that is known to inhibit or induce metabolic enzymes or transporters within 30 days of dosing Participation in any other investigational drug study within 90 days of screening Recent or current history of alcohol or drug abuse Regular recent use of tobacco or nicotine products Positive serology for HBV, HCV, or HIV Pregnant or nursing Donation or loss of greater than 400 mL of blood within 3 months Serious adverse reaction or serious hypersensitivity to any drug

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: Metabolic Probes and BCX7353<br>Day 1: 1 mg midazolam will be administered as an IV bolus simultaneously to administration of 500 mg tolbutamide, 40 mg omeprazole, and 30 mg dextromethorphan orally. Day 2: a single oral dose of 2 mg midazolam. Days 3 to 9: 350 mg BCX7353 once a day. Day 10: 1 mg midazolam will be administered as an IV bolus simultaneously to administration of 500 mg tolbutamide, 40 mg omeprazole, 30 mg dextromethorphan and 350 mg BCX7353, orally. Day 11: a single oral dose of 2 mg of midazolam along with 350 mg BCX7353. | Drug: BCX7353 and probes<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of probe substrates |  | plasma pharmacokinetic parameters are based on blood sampling through 24 hours on Day 1, 2, 10 and 11 | 
| Tmax of probe substrates |  | plasma pharmacokinetic parameters are based on blood sampling through 24 hours on Day 1, 2, 10 and 11 | 
| AUClast of probe substrates |  | plasma pharmacokinetic parameters are based on blood sampling through 24 hours on Day 1, 2, 10 and 11 | 
| AUCinf of probe substrates |  | plasma pharmacokinetic parameters are based on blood sampling through 24 hours on Day 1, 2, 10 and 11 | 
| t1/2 of probe substrates |  | plasma pharmacokinetic parameters are based on blood sampling through 24 hours on Day 1, 2, 10 and 11 | 
| Cl of intravenous midazolam |  | plasma pharmacokinetic parameters are based on blood sampling through 24 hours on Day 1, 2, 10 and 11 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| adverse events |  | absolute and change from baseline through study day 11 | 
| laboratory analyses |  | absolute and change from baseline through study day 11 | 
| Vital signs |  | absolute and change from baseline through study day 11 | 
| physical examination findings |  | absolute and change from baseline through study day 11 | 
| electrocardiograms |  | absolute and change from baseline through study day 11 | 
| C24 for tolbutamide |  | plasma pharmacokinetic parameters are based on blood sampling through 24 hours on Day 1, 2, 10 and 11 | 
| C6 for IV and oral midazolam |  | plasma pharmacokinetic parameters are based on blood sampling through 24 hours on Day 1, 2, 10 and 11 | 
| Probe/metabolite AUC24 ratio |  | plasma pharmacokinetic parameters are based on blood sampling through 24 hours on Day 1, 2, 10 and 11 | 
| Tlag of probe substrates |  | plasma pharmacokinetic parameters are based on blood sampling through 24 hours on Day 1, 2, 10 and 11 | 
| VdF of probe substrates |  | plasma pharmacokinetic parameters are based on blood sampling through 24 hours on Day 1, 2, 10 and 11 | 
| CL/F of oral probe substrates |  | plasma pharmacokinetic parameters are based on blood sampling through 24 hours on Day 1, 2, 10 and 11 | 
| Vss of intravenous midazolam |  | plasma pharmacokinetic parameters are based on blood sampling through 24 hours on Day 1, 2, 10 and 11 |