Global population pharmacokinetics of the investigational Aurora A kinase inhibitor alisertib in cancer patients: Rationale for lower dosage in Asia

Aims

This population pharmacokinetic analysis was conducted to quantitatively describe the regional differences and sources of inter-patient variability on the apparent oral clearance of alisertib.

Methods

A population pharmacokinetic analysis was performed on data from 671 cancer patients in Western countries and in Japan/ East Asia administered alisertib 5-150 mg once or twice daily in multiple dosing schedules. The final model was used to simulate alisertib pharmacokinetics in patients in the West and East Asian regions in the single agent schedule of 7 days of dosing in a 21 day cycle. Exposure-safety relationships for mechanism-related antiproliferative toxicities (neutropenia, mucositis and diarrhoea) were estimated by logistic regression.

Results

Alisertib pharmacokinetics were described by a 2-compartment model with 4-transit compartment absorption and linear elimination. The final model included a covariate effect of region on relative bioavailability, with patients in the East Asian region estimated to have a 52% higher bioavailability compared to Western patients. Population simulated exposure at 30 mg BID in patients in Asia was similar to that at 50 mg BID in Western patients (GM [CV] steady state AUC_(0-tau): 21.4 μM.h [52.3%] and 24.1 μM.h [53.6%], respectively). Exposure-adverse event relationships could be described for neutropenia, stomatitis and diarrhoea, supporting the lower dosage of alisertib in Asia for global clinical development.

Conclusions

Model-based simulations support achievement of similar alisertib exposures in patients in Asia administered a 40% lower dose compared to the Western population, thereby providing quantitative clinical pharmacology bridging and regional dosing rationale for global drug development.

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