title: Preclinical Pharmacokinetics, Pharmacodynamics, Tissue Distribution, and Interspecies Scaling of Recombinant Human Coagulation Factor XaI16L.
abstract: FXaI16Lis 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 FXaI16Lin preclinical species, and to understand its potential implication in human. Pharmacokinetics of FXaI16Lwas examined using active site probes and the results showed that FXaI16Ldisplayed 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 FXaI16Lon shortening of active partial prothrombin time and formation of thrombin-antithrombin complex were observed. Furthermore, biodistribution study was conducted in mice using radiolabeled FXaI16L, and showed that125I-FXaI16Lhas 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 FXaI16L.
authors.affiliation: Biomedicine Design, Pfizer Research and Development, Andover, Massachussetts 01810. Electronic address: chuenlei.parng@pfizer.com.
authors.forename: Chuenlei
authors.initials: C
authors.lastname: Parng
authors.affiliation: Pfizer Drug Safety Research and Development, Groton, Connecticut 06340.
authors.forename: Victoria
authors.initials: V
authors.lastname: Markiewicz
authors.affiliation: Pfizer Quantitative Medicine, Cambridge, Massachussetts 02140.
authors.forename: Jianqing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Biomedicine Design, Pfizer Research and Development, Andover, Massachussetts 01810.
authors.forename: Beth
authors.initials: B
authors.lastname: Leary
authors.affiliation: Biomedicine Design, Pfizer Research and Development, Andover, Massachussetts 01810.
authors.forename: Nicole
authors.initials: N
authors.lastname: Duriga
authors.affiliation: Biomedicine Design, Pfizer Research and Development, Andover, Massachussetts 01810.
authors.forename: Lisa
authors.initials: L
authors.lastname: Dyleski
authors.affiliation: Biomedicine Design, Pfizer Research and Development, Andover, Massachussetts 01810.
authors.forename: Teresa
authors.initials: T
authors.lastname: Caiazzo
authors.affiliation: Pfizer Drug Safety Research and Development, Groton, Connecticut 06340.
authors.forename: Michael
authors.initials: M
authors.lastname: Bolt
authors.affiliation: Biomedicine Design, Pfizer Research and Development, Andover, Massachussetts 01810.
authors.forename: Alison
authors.initials: A
authors.lastname: Joyce
authors.affiliation: Biomedicine Design, Pfizer Research and Development, Andover, Massachussetts 01810.
authors.forename: Boris
authors.initials: B
authors.lastname: Gorovits
authors.affiliation: Pfizer Rare Disease Research Unit, Hematology, Cambridge, Massachussetts 02140.
authors.forename: Debra D
authors.initials: DD
authors.lastname: Pittman
authors.affiliation: Biomedicine Design, Pfizer Research and Development, Andover, Massachussetts 01810.
authors.forename: Robert
authors.initials: R
authors.lastname: Webster
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D001798:Blood Proteins / Q000378:metabolism; D015951:Factor Xa / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008954:Models, Biological; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: D001798:Blood Proteins; D011994:Recombinant Proteins; D015951:Factor Xa
keywords: FXa(I16L); coagulation factor Xa; interspecies scaling; metabolism; pharmacodynamics; pharmacokinetics; tissue distribution