PHARMACOKINETICS AND PHARMACODYNAMICS OF BCX7353, AN ORAL PLASMA KALLIKREIN INHIBITOR, IN HEALTHY JAPANESE SUBJECTS

Abstract

Introduction BCX7353 is an oral kallikrein inhibitor being studied for prevention and treatment of hereditary angioedema (HAE) attacks in Western patients. HAE afflicts all ethnic groups. An ethnobridging study was conducted in healthy Japanese subjects to support development of BCX7353 in Japanese HAE patients. Methods BCX7353 was administered as a single dose (100mg or 500mg) or as 7 daily doses (250mg) to healthy subjects born in Japan living abroad The pharmacokinetic and kallikrein inhibition profiles were determined up to 96-hours post-last dose. BCX7353 concentrations were determined using a validated mass spectrometry assay and kallikrein inhibition was assessed with an ellagic acid-initiated contact activation assay. Results Median BCX7353 Cmax was 5-6h post-dose; concentrations declined with a half-life of 46-73h (geometric mean across groups). Compared with Western subjects, geometric mean BCX7353 AUC and Cmax for Japanese subjects were higher by 84% and 66% at 100mg x1, 19% and 27% at 500mg x1, and 13% and 20% for 250mg QD, respectively. At 500mg single doses, mean kallikrein activity was fully suppressed (>80%) from 2-16 and 2-12h post-500mg dose for Western and Japanese subjects, respectively; post-Day 7 250mg dose, kallikrein activity was suppressed from 2-16h and for 24h in Western and Japanese subjects, respectively. Conclusions Ethnic, healthy Japanese subjects have profiles for BCX7353 pharmacokinetics and kallikrein inhibition comparable to Western subjects at doses similar to those under evaluation in Western HAE patients enrolled in attack prevention and treatment trials. These data support administration of similar doses to Japanese HAE patients. BCX7353 is an oral kallikrein inhibitor being studied for prevention and treatment of hereditary angioedema (HAE) attacks in Western patients. HAE afflicts all ethnic groups. An ethnobridging study was conducted in healthy Japanese subjects to support development of BCX7353 in Japanese HAE patients. BCX7353 was administered as a single dose (100mg or 500mg) or as 7 daily doses (250mg) to healthy subjects born in Japan living abroad The pharmacokinetic and kallikrein inhibition profiles were determined up to 96-hours post-last dose. BCX7353 concentrations were determined using a validated mass spectrometry assay and kallikrein inhibition was assessed with an ellagic acid-initiated contact activation assay. Median BCX7353 Cmax was 5-6h post-dose; concentrations declined with a half-life of 46-73h (geometric mean across groups). Compared with Western subjects, geometric mean BCX7353 AUC and Cmax for Japanese subjects were higher by 84% and 66% at 100mg x1, 19% and 27% at 500mg x1, and 13% and 20% for 250mg QD, respectively. At 500mg single doses, mean kallikrein activity was fully suppressed (>80%) from 2-16 and 2-12h post-500mg dose for Western and Japanese subjects, respectively; post-Day 7 250mg dose, kallikrein activity was suppressed from 2-16h and for 24h in Western and Japanese subjects, respectively. Ethnic, healthy Japanese subjects have profiles for BCX7353 pharmacokinetics and kallikrein inhibition comparable to Western subjects at doses similar to those under evaluation in Western HAE patients enrolled in attack prevention and treatment trials. These data support administration of similar doses to Japanese HAE patients.