Faculty Collaboration Database

Relative bioavailability of a prototype oral solution of the Aurora A kinase inhibitor alisertib (MLN8237) in patients with advanced solid tumors. Int J Clin Pharmacol Ther 2015 Jul;53(7):563-72

Date

06/16/2015

Pubmed ID

26073352

DOI

10.5414/CP202359

Scopus ID

2-s2.0-84936748326 (requires institutional sign-in at Scopus site)   7 Citations

Abstract

OBJECTIVES: Alisertib (MLN8237) is an investigational, oral, small-molecule, selective inhibitor of Aurora A kinase. Phase I/II studies of powder-in-capsule (PIC) and enteric-coated tablet formulations of alisertib have determined the recommended phase II dose and have demonstrated anti-tumor activity. This phase I relative bioavailability study characterized the pharmacokinetics of a prototype oral solution (OS) of alisertib (developed for patients unable to swallow solid dosage forms) in reference to the PIC formulation in adult cancer patients.

MATERIALS AND METHODS: A safety evaluation was undertaken first following a 3+3 design (OS starting dose, 15 mg). The relative bioavailability of alisertib OS vs. PIC was then evaluated following single dose administration of alisertib OS 25 mg and PIC 50 mg, using a 2-way crossover study design.

RESULTS: The relative bioavailability (geometric mean dose-normalized AUCinf ratio) of alisertib OS vs. PIC formulation was 1.26 (90% confidence interval (CI): 1.09-1.47 (OS, n=17; PIC, n=18 evaluable patients)). These results support a distinguishable difference in bioavailability of alisertib between the two formulations (lower bound of 90% CI>1), with an estimated 26% higher total systemic exposure with alisertib OS vs. PIC. Alisertib absorption from OS was faster than from PIC, with a shorter median tmax (OS, 1 hour; PIC, 2 hours) and a geometric mean dose-normalized Cmax ratio (OS vs. PIC) of 1.90 (90% CI: 1.52 - 2.37).

CONCLUSIONS: These findings inform the starting dose of alisertib OS to support further clinical evaluation of alisertib in patients unable to swallow solid dosage forms.

Author List

Falchook GS, Venkatakrishnan K, Sarantopoulos J, Kurzrock R, Mita AC, Fu S, Mita MM, Zhou X, Jung JA, Ullmann CD, Milch C, Rosen LS

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Administration, Oral
Adult
Aged
Antineoplastic Agents
Area Under Curve
Aurora Kinase A
Azepines
Biological Availability
Capsules
Chemistry, Pharmaceutical
Cross-Over Studies
Female
Gastrointestinal Absorption
Humans
Male
Middle Aged
Neoplasms
Pharmaceutical Solutions
Powders
Protein Kinase Inhibitors
Pyrimidines
Treatment Outcome
United States
Young Adult