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

Abstract

Summary 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 (AUC 0-inf ) and maximum concentrations (C max ) 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 AUC 0-inf and C max 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 AUC 0-inf and C max 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 AUC 0-inf and C max 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.

Pharmacokinetics of the Investigational Aurora A Kinase Inhibitor Alisertib in Adult Patients With Advanced Solid Tumors or Relapsed/Refractory Lymphoma With Varying Degrees of Hepatic Dysfunction

“…Plasma samples for alisertib, M1, and M2 were analyzed by validated liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) methods using solid‐phase extraction procedures. The dynamic ranges were 5.00 to 2500 ng/mL (9.6 to 4818 nM) for alisertib, 2.00 to 1000 ng/mL (2.9 to 1441 nM) for M1, and 0.500 to 250 ng/mL (0.99 to 495 nM) for M2 . For alisertib, assay precision (as measured by percent coefficient of variation [CV]) for the quality check (QC) samples (15.0 to 2000 ng/mL) ranged from 4.9% to 5.9%.…”

“…Following completion of equilibrium dialysis, aliquots of the dialysate and retentate samples were mixed with equal volumes of human plasma and PBS, respectively, prior to storage at ‐70°C for bioanalysis of alisertib concentrations. The concentration of free and bound alisertib in dialysate and retentate was determined using a mixed matrix calibration curve (50:50 human plasma:PBS) with the LC‐MS/MS methodology described above . The assay precision for the QC samples (1.5 to 200 ng/mL) ranged from 2.8% to 5%, and accuracy ranged from −4.8% to 4%.…”

“…The dynamic ranges were 5.00 to 2500 ng/mL (9.6 to 4818 nM) for alisertib, 2.00 to 1000 ng/mL (2.9 to 1441 nM) for M1, and 0.500 to 250 ng/mL (0.99 to 495 nM) for M2. 4,6,13 For alisertib, assay precision (as measured by percent coefficient of variation [CV]) for the quality check (QC) samples (15.0 to 2000 ng/mL) ranged from 4.9% to 5.9%. Accuracy (measured as percent bias) for the QC samples ranged from −4.7% to −4.2% for alisertib.…”

“…Results from a human absorption, distribution, metabolism, and excretion study confirmed that metabolism is the predominant route of elimination for alisertib, with renal excretion of unchanged alisertib representing a negligible (<0.1%) fraction of the administered dose. Alisertib undergoes parallel oxidative and conjugative biotransformation to an acyl glucuronide metabolite (M1) and O ‐desmethyl alisertib (M2) . The oxidative metabolite M2 is pharmacologically active in vitro as an Aurora A kinase inhibitor with approximately 4‐fold lesser potency than the parent drug (Takeda data on file).…”

“…Alisertib undergoes parallel oxidative and conjugative biotransformation to an acyl glucuronide metabolite (M1) and O-desmethyl alisertib (M2). 13,14 The oxidative metabolite M2 is pharmacologically active in vitro as an Aurora A kinase inhibitor with approximately 4-fold lesser potency than the parent drug (Takeda data on file). As hepatic impairment may increase the systemic exposure of alisertib, this study was designed to characterize the pharmacokinetics (PK) of alisertib in these special patient populations and to thereby guide development of posology adjustments that may be needed in patients with impaired hepatic function.…”