A Drug-Drug Interaction Study to Evaluate Drug Transporter Interactions

This is a single center, open-label, fixed-sequence, drug interaction study to evaluate the effect of BCX7353 on the pharmacokinetics of the P-gp substrate digoxin and the BCRP substrate rosuvastatin, as well as the effect of the P-gp inhibitor cyclosporine on the pharmacokinetics of BCX7353.

It is planned that 54 subjects will be enrolled into 3 cohorts of 18 subjects each. Cohort 1 will evaluate the effects of multiple doses of BCX7353 on single-dose pharmacokinetics of digoxin. Cohort 2 will evaluate the effect of multiple doses of BCX7353 on the pharmacokinetics of rosuvastatin. Cohort 3 will evaluate the effect of a single dose of cyclosporine on the pharmacokinetics of BCX7353. Cohorts may be dosed in parallel or in any order.

• BCX7353 (Drug): Day 11-18 for Cohort 1, Day 7-14 for Cohort 2, Day 1 for Cohort 3
• Digoxin (Drug): Day 1 of Cohort 1
• BCX7353 + digoxin (Drug): Day 19 of Cohort 1
• Rosuvastatin (Drug): Day 1 of Cohort 2
• rosuvastatin + BCX7353 (Drug): Day 15 of Cohort 1
• Cyclosporine + BCX7353 (Drug): Day 14 of Cohort 3

Primary outcomes

• Cmax of probe substrate [plasma pharmacokinetic parameters are based on blood sampling over a 48 - 72 hour period]
• AUClast of probe substrate [plasma pharmacokinetic parameters are based on blood sampling over a 48 - 72 hour period]
• AUCinf of probe substrate [plasma pharmacokinetic parameters are based on blood sampling over a 48 - 72 hour period]

Secondary outcomes

• adverse events [absolute and change from baseline through end of study, approximately 30 days]
• laboratory analyses [absolute and change from baseline through end of study, approximately 30 days]
• vital signs [absolute and change from baseline through end of study, approximately 30 days]
• physical examination findings [absolute and change from baseline through end of study, approximately 30 days]
• electrocardiograms [absolute and change from baseline throughend of study, approximately 30 days]

Sex: All, ages: 18 Years to 55 Years, accepts healthy volunteers

Key Inclusion Criteria:

* written informed consent
* acceptable birth control measures for male subjects and women of childbearing potential
* creatinine clearance of at least 80 mL/min by Cockcroft-Gault equation
* complies with all required study procedures and restrictions

Key Exclusion Criteria:

* clinically significant medical history, current medical or psychiatric condition
* clinically significant ECG finding, vital sign measurement or laboratory/urinalysis abnormality at screening or baseline
* current use, or use of any prescribed or over the counter medication, vitamins or herbal products within 14 days of Day 1
* use of medication 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 the previous 3 months
* history of severe hypersensitivity to any medicinal product
* for subjects enrolled in cohort 1, current use of antibiotics or probiotics, or use within 6 months prior to Day 1

• Firas Almazedi, MBChB, Msc, CPI, Principal investigator, Covance Clinical