Effects of rifampin, itraconazole and esomeprazole on the pharmacokinetics of alisertib, an investigational aurora a kinase inhibitor in patients with advanced malignancies

Xiaofei Zhou, Shubham Pant, John Nemunaitis, A. Craig Lockhart, Gerald Falchook, Todd M. Bauer, Manish Patel, John Sarantopoulos, Michael Bargfrede, Andreas Muehler, Lakshmi Rangachari, Bin Zhang, Karthik Venkatakrishnan

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Aim Two studies investigated the effect of gastric acid reducing agents and strong inducers/inhibitors of CYP3A4 on the pharmacokinetics of alisertib, an investigational Aurora A kinase inhibitor, in patients with advanced malignancies. Methods In Study 1, patients received single doses of alisertib (50 mg) in the presence and absence of either esomeprazole (40 mg once daily [QD]) or rifampin (600 mg QD). In Study 2, patients received single doses of alisertib (30 mg) in the presence and absence of itraconazole (200 mg QD). Blood samples for alisertib and 2 major metabolites were collected up to 72 h (Study 1) and 96 h (Study 2) postdose. Area under the curve from time zero extrapolated to infinity (AUC0-inf) and maximum concentrations (Cmax) were calculated and compared using analysis of variance to estimate least squares (LS) mean ratios and 90% confidence intervals (CIs). Results The LS mean ratios (90% CIs) for alisertib AUC0-inf and Cmax in the presence compared to the absence of esomeprazole were 1.28 (1.07, 1.53) and 1.14 (0.97, 1.35), respectively. The LS mean ratios (90% CIs) for alisertib AUC0-inf and Cmax in the presence compared to the absence of rifampin were 0.53 (0.41, 0.70) and 1.03 (0.84, 1.26), respectively. The LS mean ratios (90% CIs) for alisertib AUC0-inf and Cmax in the presence compared to the absence of itraconazole were 1.39 (0.99, 1.95) and 0.98 (0.82, 1.19), respectively. Conclusions The use of gastric acid reducing agents, strong CYP3A inhibitors or strong metabolic enzyme inducers should be avoided in patients receiving alisertib.

Original languageEnglish (US)
Pages (from-to)248-258
Number of pages11
JournalInvestigational New Drugs
Volume36
Issue number2
DOIs
StatePublished - Apr 1 2018

Keywords

  • Alisertib
  • Aurora A kinase
  • CYP3A4
  • Drug-drug interactions
  • Induction
  • Inhibition

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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    Zhou, X., Pant, S., Nemunaitis, J., Craig Lockhart, A., Falchook, G., Bauer, T. M., Patel, M., Sarantopoulos, J., Bargfrede, M., Muehler, A., Rangachari, L., Zhang, B., & Venkatakrishnan, K. (2018). Effects of rifampin, itraconazole and esomeprazole on the pharmacokinetics of alisertib, an investigational aurora a kinase inhibitor in patients with advanced malignancies. Investigational New Drugs, 36(2), 248-258. https://doi.org/10.1007/s10637-017-0499-z