Preclinical Pharmacokinetics, Pharmacodynamics, Tissue Distribution, and Interspecies Scaling of Recombinant Human...

FXa^I16L is a recombinant human FXa variant which is currently being evaluated in the clinic for treating intracerebral hemorrhage. The aim of our studies is to investigate overall pharmacokinetics, pharmacodynamics, and distribution of FXa^I16L in preclinical species, and to understand its potential implication in human. Pharmacokinetics of FXa^I16L was examined using active site probes and the results showed that FXa^I16L displayed fast clearance, low volume of distribution, and a very short plasma resident time in mice, rats, and monkeys. When pharmacodynamics was examined in monkeys, concentration effects of FXa^I16L on shortening of active partial prothrombin time and formation of thrombin-antithrombin complex were observed. Furthermore, biodistribution study was conducted in mice using radiolabeled FXa^I16L, and showed that ¹²⁵I-FXa^I16L has high plasma protein binding and significant liver and kidney distribution. Human pharmacokinetic prediction for first-in-human dosing was evaluated using allometric scaling, liver blood flow, and a fixed coefficient method, and single species allometric scaling using monkey data was most predictive for human pharmacokinetics of FXa^I16L.