Clinical trial NCT02819102: An Open-label Drug-Drug Interaction Study to Evaluate the Effect of BCX7353 on Cytochrome P450 Enzyme Activity Using Probe Substrates
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hereditary Angioedema
Lead sponsor: BioCryst Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2016-06-30
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Cmax of probe substrates
timeFrame: plasma pharmacokinetic parameters are based on blood sampling through 24 hours on Day 1, 2, 10 and 11
measure: Tmax of probe substrates
timeFrame: plasma pharmacokinetic parameters are based on blood sampling through 24 hours on Day 1, 2, 10 and 11
measure: AUClast of probe substrates
timeFrame: plasma pharmacokinetic parameters are based on blood sampling through 24 hours on Day 1, 2, 10 and 11
measure: AUCinf of probe substrates
timeFrame: plasma pharmacokinetic parameters are based on blood sampling through 24 hours on Day 1, 2, 10 and 11
measure: t1/2 of probe substrates
timeFrame: plasma pharmacokinetic parameters are based on blood sampling through 24 hours on Day 1, 2, 10 and 11
measure: Cl of intravenous midazolam
timeFrame: plasma pharmacokinetic parameters are based on blood sampling through 24 hours on Day 1, 2, 10 and 11
Secondary outcomes:
measure: adverse events
timeFrame: absolute and change from baseline through study day 11
measure: laboratory analyses
timeFrame: absolute and change from baseline through study day 11
measure: Vital signs
timeFrame: absolute and change from baseline through study day 11
measure: physical examination findings
timeFrame: absolute and change from baseline through study day 11
measure: electrocardiograms
timeFrame: absolute and change from baseline through study day 11
measure: C24 for tolbutamide
timeFrame: plasma pharmacokinetic parameters are based on blood sampling through 24 hours on Day 1, 2, 10 and 11
measure: C6 for IV and oral midazolam
timeFrame: plasma pharmacokinetic parameters are based on blood sampling through 24 hours on Day 1, 2, 10 and 11
measure: Probe/metabolite AUC24 ratio
timeFrame: plasma pharmacokinetic parameters are based on blood sampling through 24 hours on Day 1, 2, 10 and 11
measure: Tlag of probe substrates
timeFrame: plasma pharmacokinetic parameters are based on blood sampling through 24 hours on Day 1, 2, 10 and 11
measure: VdF of probe substrates
timeFrame: plasma pharmacokinetic parameters are based on blood sampling through 24 hours on Day 1, 2, 10 and 11
measure: CL/F of oral probe substrates
timeFrame: plasma pharmacokinetic parameters are based on blood sampling through 24 hours on Day 1, 2, 10 and 11
measure: Vss of intravenous midazolam
timeFrame: plasma pharmacokinetic parameters are based on blood sampling through 24 hours on Day 1, 2, 10 and 11
Other outcomes:
Locations:
city: Ruddington
country: United Kingdom
facility: Quotient Clinical Ltd
state: Nottingham
Study officials:
affiliation: Quotient Clinical Ltd
name: Litza McKenzie, MBChB
role: PRINCIPAL_INVESTIGATOR
References: