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Dose selection for the investigational anticancer agent alisertib (MLN8237): Pharmacokinetics, pharmacodynamics, and

Karthik Venkatakrishnan1, Xiaofei Zhou1, Jeffrey Ecsedy2

  • 1Department of Clinical Pharmacology, Takeda Pharmaceuticals International Co., Cambridge, MA, USA.

Journal of Clinical Pharmacology
|October 11, 2014
PubMed

Insights

Alisertib, an Aurora A kinase (AAK) inhibitor, shows dose- and time-linear pharmacokinetics. These analyses support a safe and effective dose range for alisertib in future clinical trials.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Alisertib is a selective Aurora A kinase (AAK) inhibitor investigated for cancer treatment.
  • Phase I studies established dosing schedules and maximum tolerated doses (MTDs) for alisertib.

Purpose of the Study:

  • To conduct population pharmacokinetic, pharmacodynamic, and pharmacokinetic-safety analyses.
  • To support the selection of optimal doses and regimens for alisertib in Phase II/III trials.

Main Methods:

  • Population pharmacokinetic modeling was used to assess drug exposure and covariate effects.
  • Pharmacodynamic markers (skin mitotic index, tumor mitotic cells) were evaluated to confirm target engagement.
  • Pharmacokinetic-safety analyses correlated drug exposure with toxicity.

Main Results:

  • Pharmacokinetics of alisertib were dose- and time-linear, with no significant clinical covariates identified.
  • Pharmacodynamic analyses confirmed AAK inhibition at exposures achieved with the 7-day schedule at 50 mg BID.
  • Exposure-safety analysis predicted a low incidence (∼7%) of dose-limiting toxicity at 50 mg BID.

Conclusions:

  • Population pharmacokinetic and pharmacodynamic data support alisertib's mechanism of action.
  • The 50 mg BID dose on a 7-day schedule is predicted to achieve target inhibition with acceptable safety.
  • These findings support alisertib's continued clinical development within a defined dose range.
Keywords:
Aurora A kinaseMLN8237alisertibdoseoncology

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