Alisertib (MLN8237) is an investigational potent Aurora A kinase inhibitor currently under clinical trials for
hematological and nonhematological malignancies. Nonclinical investigation showed that alisertib is a highly permeable
compound with high plasma protein binding, low plasma clearance, and moderate volume of distribution in rats, dogs,
monkeys and chimpanzees. Consistent with the above properties, the oral bioavailability in animals was greater than 82%.
The predicted human oral pharmacokinetic (PK) profile was constructed using allometric scaling of plasma clearance and
volume of distribution in the terminal phase from animals. The chimpanzee PK profiles were extremely useful to model
absorption rate constant, which was assumed to be similar to that in humans, based on the fact that chimpanzees are
phylogenetically closest to humans. The human plasma clearance was projected to be low of 0.12 L/hr/kg, with half-life of
approximately 10 hr.
For human efficacious dose estimation, the tumor growth inhibition as a measure of efficacy (E) was assessed in HCT116
xenograft mice at several oral QD or BID dose levels. Additionally, subcutaneous mini-pump infusion studies were
conducted to assess mitotic index in tumor samples as a pharmacodynamic (PD) marker. PK/PD/E modeling showed that
for optimal efficacy and PD in the xenograft mice maintaining a plasma concentration exceeding 1 µM for at least 8-12 hr
would be required. These values in conjunction with the projected human PK profile estimated the optimal oral dose of
approximately 103 mg QD or 62.4 mg BID in humans. Notably, the recommended Phase 2 dose being pursued in the
clinic is close to the projected BID dose.