title: Designing first-in-human dose of coagulation factors: application of pharmacokinetic allometric scaling.
abstract: The objectives of this study were to (i) evaluate the predictive performance of pharmacokinetic interspecies scaling of coagulation factors to predict clearance (CL) and (ii) project first-in-human dose based on the predicted human CL. Human CL of nine coagulation factors was predicted using two or three animal species using two methods: (i) CL vs. body weight (simple allometry) and where applicable (ii) the product of CL and brain weight vs. body weight. Based on the predicted human CL, four methods were used to project the first-in-human dose. The predicted pharmacokinetic parameters and the estimated first-in-human dose of coagulation factors were compared with the observed human values obtained from clinical trials. The results of the study indicated that the CL of coagulation factors can be predicted with reasonable accuracy in humans and a good estimate of first-in-human dose can be obtained from the predicted human CL. The suggested methods in this study are not only time and cost-effective but also provide rational alternatives to the somewhat arbitrary dose selection process for coagulation factors often used.
authors.affiliation: Office of Blood Review & Research (OBRR), Center for Biologic Evaluation and Research, Food & Drug Administration, Rockville, MD, USA.
authors.forename: I
authors.initials: I
authors.lastname: Mahmood
mesh_terms: D000818:Animals; D001779:Blood Coagulation Factors / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001835:Body Weight; D004285:Dogs; D006801:Humans; D008252:Macaca fascicularis; D008657:Metabolic Clearance Rate; D051379:Mice; D011817:Rabbits; D051381:Rats; D013552:Swine
chemical_list: D001779:Blood Coagulation Factors
keywords: clearance; coagulation factors; first-in-human dose; interspecies scaling; pharmacokinetics; rule of exponent