Abstract
SHetA2 is a small molecule drug with promising cancer prevention and therapeutic activity and a high preclinical safety profile. The study objectives were to perform interspecies scaling and pharmacokinetic (PK) modeling of SHetA2 for human PK prediction. The PK data obtained from mice, rats, and dogs after intravenous and oral doses were used for simultaneous fitting to PK models. The disposition of SHetA2 was best described by a two-compartment model. The absorption kinetics was well characterized with a first-order absorption model for mice and rats, and a gastrointestinal transit model for dogs. Oral administration of SHetA2 showed a relatively fast absorption in mice, prolonged absorption (i.e., flip-flop kinetics) toward high doses in rats, and an early peak followed by a secondary peak at high doses in dogs. The oral bioavailability was 17.7-19.5% at 20-60 mg/kg doses in mice, <1.6% at 100-2000 mg/kg in rats, and 11.2% at 100 mg/kg decreasing to 3.45% at 400 mg/kg and 1.11% at 1500 mg/kg in dogs. The disposition parameters were well correlated with the body weight for all species using the allometric equation, which predicted values of CL (17.3 L/h), V1 (36.2 L), V2 (68.5 L) and CLD (15.2 L/h) for a 70-kg human. The oral absorption rate and bioavailability of SHetA2 was highly dependent on species, doses, formulations, and possibly other factors. The limited bioavailability at high doses was taken into consideration for the suggested first-in-human dose, which was much lower than the dose estimated based on toxicology studies. In summary, the present study provided the PK model for SHetA2 that depicted the disposition and absorption kinetics in preclinical species, and computational tools for human PK prediction.