title: Prediction of drug concentration-time data in humans from animals: a comparison of three methods.
abstract: The main objective of this work is to evaluate three methods to predict concentration-time data of drugs in humans in a multi-compartment system using animal pharmacokinetic parameters following intravenous administration. The prediction of concentration-time data in humans in a multi-compartment system was based on two proposed methods of Mordenti. The third method was based on the assumption that all drugs follow a single-compartment system. Ten drugs from the literature were chosen that were described by two-compartment model in both human and animals. Two-compartment model parameters (CL, V(c), V(ss), V(β), α, A, β and B) of at least 3 animals were scaled to humans and then were used to predict plasma concentrations-time data in humans. Allometrically scaled pharmacokinetic parameters from animals were also used to predict human profile using one-compartment model as a comparison. The results indicated that in a multi-compartment system, application of pharmacokinetic constants provided better prediction of concentration-time data in humans than the assumption that all drugs follow a single-compartment model. Both the proposed methods of Mordenti provided almost similar concentration-time profiles for most of the drugs. For some drugs, predicted α values were substantially higher than the observed values. This prediction error in α resulted in under-prediction of drug concentrations in distribution phase. In order to reduce the prediction error in α, Waijma's method for the prediction of α was modified which resulted in an improved prediction of concentration-time data in humans. Overall, Mordenti's proposed 2 methods and where necessary by modifying Waijma's method for the prediction of α can be used for reasonably accurate prediction of concentration-time data of drugs in humans.
authors.affiliation: Office of Blood Review & Research-OBRR, Center for Biologic Evaluation and Research, Food & Drug Administration, 1401 Rockville Pike, Rockville, MD, USA. iftekhar.mahmood@fda.hhs.gov
authors.forename: Iftekhar
authors.initials: I
authors.lastname: Mahmood
authors.forename: Kosalaram
authors.initials: K
authors.lastname: Goteti
mesh_terms: D000818:Animals; D001835:Body Weight; D006801:Humans; D007275:Injections, Intravenous; D008657:Metabolic Clearance Rate; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism*; D010599:Pharmacokinetics; D010601:Pharmacology, Clinical / Q000379:methods*; D013997:Time Factors
chemical_list: D004364:Pharmaceutical Preparations