Factors affecting the pharmacokinetic profile of MS-275, a novel histone deacetylase inhibitor, in patients with cancer
- 210 Downloads
Aims: 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. Patients and Methods: 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). Results: 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. Conclusions: 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.
KeywordsMS-275 Histone deacetylation Pharmacokinetics Dosing strategy
Unable to display preview. Download preview PDF.
- 9.Ryan Q, Headlee D, Sparreboom A, Figg W, Zhai S, Murgo A, Elsayed Y, Karp J, Sausville E (2003) A phase I trial of an oral histone deacetylase inhibitor, MS-275, in advanced solid tumor and lymphoma patients. Proc Am Soc Clin Oncol 22:200Google Scholar
- 11.Hwang K, Acharya MR, Sausville EA, Zhai S, Woo EW, Venitz J, Figg WD, Sparreboom A (2004) Determination of MS-275, a novel histone deacetylase inhibitor, in human plasma by liquid chromatography-electrospray mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 804:289–294PubMedGoogle Scholar
- 12.Du Bois D, Du Bois EF (1916) A formula to estimate the approximate surface area if height and weight be known. Nutrition 5:303–111 (discussion 312–313)Google Scholar
- 19.Shitara Y, Sato H, Sugiyama Y (2004) Evaluation of drug-drug interaction in the hepatobiliary and renal transport of drugs. Annu Rev Pharmacol ToxicolGoogle Scholar
- 20.Karanam BV, Hop CE, Liu DQ, Wallace M, Dean D, Satoh H, Komuro M, Awano K,Vincent SH (2004) In vitro metabolism of MK-0767 [(±)-5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[(4-trifluoromet hyl) phenyl]methyl]benzamide], a peroxisome proliferator-activated receptor alpha/gamma agonist. I. Role of cytochrome P450, methyltransferases, flavin monooxygenases, and esterases. Drug Metab Dispos 32:1015–1022PubMedCrossRefGoogle Scholar
- 31.Acharya MR, Sparreboom A, Sausville EA, Conley BA, Doroshow JH, Venitz J, Figg WD (2005) Interspecies differences in plasma protein binding of MS-275, a histone deacetylase inhibitor. Proc Am Asc of Cancer Res (in press)Google Scholar