RT Journal Article
SR Electronic
T1 Assessment and Confirmation of Species Difference in Nonlinear Pharmacokinetics of Atipamezole with Physiologically Based Pharmacokinetic Modeling
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.119.089151
DO 10.1124/dmd.119.089151
A1 Zheng Li
A1 You Gao
A1 Chunmiao Yang
A1 Yanan Xiang
A1 Wenpeng Zhang
A1 Tianhong Zhang
A1 Ruibin Su
A1 Chuang Lu
A1 Xiaomei Zhuang
YR 2019
UL http://dmd.aspetjournals.org/content/early/2019/11/07/dmd.119.089151.abstract
AB Atipamezole, an α2-adrenoceptor antagonist, displayed nonlinear pharmacokinetics (PK) in rats. The aim of this study was to understand the underlying mechanisms of nonlinear PK in rats and linear PK in humans and develop physiologically based PK models (PBPK) to capture and validate this phenomenon. In vitro and in vivo data were generated to show that metabolism is the main clearance pathway of atipamezole and species differences exists. Where CYP was responsible for the metabolism in rats with a low Km, human specific UGT2B10 and 1A4 mediated N-glucuronidation was identified as the leading contributor to metabolism in humans with a high Vmax capacity. Saturation of metabolism was observed in rats at pharmacological relevant doses but not in humans at clinically relevant doses. PBPK models were developed using GastroPlus ™ software to predict the pharmacokinetic profile of atipamezole in rats after intravenous or intramuscular administration of 0.1-3 mg/kg doses. The model predicted the nonlinear PK of atipamezole in rats and predicted observed exposures within two-fold across dose levels. Under the same model structure, a human PBPK model was developed using human in vitro metabolism data. The PBPK model well described human concentration-time profiles at 10-100 mg doses showing dose proportional increases in exposure. This study demonstrated that PBPK is a useful tool to predict human PK when interspecies extrapolation is not applicable. The nonlinear PK in rat and linear PK in human were characterized in vitro and allowed the prospective human PK via i.m. dosing to be predicted at the preclinical stage.SIGNIFICANCE STATEMENT This study demonstrated that PBPK is a useful tool for predicting human PK when interspecies extrapolation is not applicable due to species unique metabolism. Atipamezole, for example, is metabolized by CYP in rats and by N-glucuronidation in humans that were hypothesized to be the underlying reasons for a nonlinear PK in rats and linear PK in humans. This was testified by PBPK simulation in this study.