PHARMACOKINETICS OF PHVS719, EXTENDED-RELEASE TABLET FORMULATION OF PHA121, A FIRST-IN-CLASS ORAL HUMAN BRADYKININ B2-RECEPTOR ANTAGONIST

Abstract

<h3>Introduction</h3> PHA121 is an orally bioavailable potent, competitive and selective antagonist of the human bradykinin B2 receptor (B2R) being developed in two formulations for treatment of hereditary angioedema (HAE): PHVS416 soft capsule for treatment of acute attacks and PHVS719 extended-release tablet for prophylaxis. <h3>Methods</h3> Bioavailability of the extended-release formulation PHVS719 in comparison with PHVS416 was evaluated in an open-label, crossover single-dose study. Eight healthy volunteers received treatment with PHVS416 (2x soft capsules each containing 10 mg-of PHA121) and PHVS719 (1x extended-release tablet containing 40 mg of PHA121) in randomized order and in variable experimental conditions. <h3>Results</h3> Administration of PHVS416 resulted in rapid clinically relevant exposure of PHA121 active ingredient above EC₈₅ determined from the bradykinin challenge (13.8 ng/mL) within 15 minutes. A single dose of PHVS719 yielded exposure of PHA121 above EC₈₅ by the 3-hour timepoint and maintained it for at least 28 hours with or without food. The 24-hour area under the curve exposure of PHA121 using PHVS719 was similar to that observed in studies with PHVS416 soft capsules dosed 20 mg twice a day with food (being investigated in the ongoing CHAPTER-1 prophylactic trial). PHVS416 and PHVS719 were well tolerated. <h3>Conclusions</h3> Findings from this study confirmed rapid achievement of clinically relevant exposure of PHA121 after administration of PHVS416. The observed pharmacokinetic of PHVS719 is consistent with the extended-release formulation designed to provide long-term exposure to PHA121. PHVS719 appears to be suitable for once-daily prophylactic dosing in HAE.