Pharmacokinetics of ABN401 and volitinib, specific inhibitors of c-MET receptor kinase, in preclinical animal species and the predictions in humans

Abstract

The objectives of this study were to determine the pharmacokinetics of ABN401, a specific inhibitor of c-MET receptor kinase, in animal species of preclinical studies and to predict the pharmacokinetics in humans. In addition, the kinetics of volitinib, a reference c-MET inhibitor for ABN401, was studied in rats and scaled to human for the comparison. The pharmacokinetic parameters for the elimination and tissue distribution of ABN401 were apparently linear in rats in the intravenous dose range of 1 to 10 mg/kg, as evidence by the lack of statistical differences in the systemic clearance (CL

15.9 ~ 20.3 mL/min/kg) and the volume of distribution (Vss

4.03 ~ 6.42 L/kg). Assuming the rat isolated hepatocyte to be an adequate model of the hepatic metabolism for ABN401 in rats, the metabolic clearance by the liver was expected to be approximately 48% of the systemic clearance. In addition, the fecal elimination, most likely via the biliary excretion, was found to be the secondary elimination pathway (i.e., 36% of the systemic clearance) to the hepatic metabolism. Amongst the nine major tissues tested, the important organs for ABN401 distribution (i.e., Kp greater than 20) were the spleen, liver, kidney and lung. Calculated Vss, based on the Kp values for the tissues and their anatomical volumes, were close to the measured (i.e., Vss = MRT x CL) value, suggesting ABN401 is primarily distributed to those nine tissues. Accordingly, a PBPK model, involving perfusion rate limited distribution to the 9 tissues and linear CL from the venous circulation, was constructed for rats. The calculated plasma concentration-time profile of ABN401 by the kinetic model assuming intravenous dose range of 1 to 10 mg/kg adequately predicted the observation (i.e., AUC ratio of 0.9 ~ 1.1) in rats. To predict human pharmacokinetics of ABN401, the allometric relationship for Vss and CL was constructed using the kinetic parameters obtained from four preclinical animal species (i.e., the mouse, rat, monkey and dog) and used to predict the parameter values in humans. In particular, Kp for the nine major tissues in humans were calculated from Kp,u of the rat, and estimated fu,p for human with the allometric relationship. For the case of CL estimation in humans, however, the allometric scaling predicted the unexpectedly high systemic clearance for the inhibitor. Therefore, the CL equivalent to the hepatic blood flow, as a lower reference of CL for ABN401, was also considered in subsequent calculations. The PBPK modeling and allometric scaling were also carried out for volitinib, using similar kinetic techniques. When the concentration of lung, i.e., the pharmacological target tissue, was estimated by the model assuming the oral dose of 5 mg/kg, the duration of the concentration exceeding the tentatively effective concentration (TEC, i.e., the IC50 divided by the free fraction of the inhibitor in the lung) was approximately 4 to 15 hours, depending on CL, while the duration was over 24 hours for the case of volitinib. Therefore, the pharmacokinetic rationale of this study for estimating of tissue distribution and in vivo PBPK model may be practically useful in predicting and interpreting pre-clinical/clinical pharmacokinetics of these two c-MET inhibitors.