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

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

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.

Study Overview

• Status: Completed
• Conditions: Hereditary Angioedema
• Intervention / Treatment: Drug: BCX7353 and probes

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Nottingham
    • Ruddington, Nottingham, United Kingdom, NG11 6JS
      • Quotient Clinical Ltd

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Metabolic Probes and BCX7353; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: BioCryst Pharmaceuticals
• Investigators: Principal Investigator: Litza McKenzie, MBChB, Quotient Clinical Ltd

Study record dates

Study Major Dates

• Study Start: March 1, 2016
• Primary Completion (Actual): June 1, 2016
• Study Completion (Actual): June 1, 2016

Study Registration Dates

• First Submitted: June 28, 2016
• First Submitted That Met QC Criteria: June 28, 2016
• First Posted (Estimate): June 30, 2016

Study Record Updates

• Last Update Posted (Estimate): January 31, 2017
• Last Update Submitted That Met QC Criteria: January 30, 2017
• Last Verified: June 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Hypersensitivity, Immediate; Genetic Diseases, Inborn; Skin Diseases, Vascular; Hypersensitivity; Urticaria; Hereditary Complement Deficiency Diseases; Primary Immunodeficiency Diseases; Angioedema; Angioedemas, Hereditary; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Berotralstat
• Other Study ID Numbers: BCX7353-102