Factors affecting the pharmacokinetic profile of MS-275, a novel histone deacetylase inhibitor, in patients with cancer

Abstract

To evaluate elimination pathways of the histone deacetylase inhibitor MS-275 in vitro and screen for relationships between demographic factors that may affect its pharmacokinetics in vivo. Substrate specificity of MS-275 for the liver-specific organic anion transporting polypeptides (OATPs) was assessed using Xenopus laevis oocytes, and in vitro metabolism was evaluated using human liver microsomes. In vivo pharmacokinetic data were obtained from 64 adult patients (36 male/28 female; median age, 57 years) receiving MS-275 orally (dose range, 2 to 12 mg/m2). Accumulation of [G-3H]MS-275 by oocytes expressing OATP1B1 or OATP1B3 was not significantly different from water-injected controls (p = 0.82). Furthermore, no metabolites could be detected after incubation of MS-275 in human liver microsomes, suggesting that hepatic metabolism is a minor pathway of elimination. The mean (+/- SD) apparent oral clearance of MS-275 was 38.5 +/- 18.7 L/h, with a coefficient of variation (%CV) of 48.7%. When clearance was adjusted for body-surface area (BSA), the inter-individual variability was similar (%CV = 50.1%). In addition, in a linear-regression analysis, except for adjusted ideal body weight (p = 0.02, |r| = 0.29), none of the studied measures (BSA, lean-body mass, ideal body weight, body-mass index, height, weight, age, and sex) was a significant covariate (p > 0.13; |r| < 0.11) for oral clearance. The current analysis has eliminated a number of candidate covariates from further consideration as important determinants of MS-275 absorption and disposition. Furthermore, MS-275 can be added to the list of cancer drugs where BSA-based dosing is not more accurate than fixed dosing.