Investigational New Drugs

, Volume 24, Issue 5, pp 367–375 | Cite as

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

  • Milin R. Acharya
  • Judith E. Karp
  • Edward A. Sausville
  • Kyunghwa Hwang
  • Qin Ryan
  • Ivana Gojo
  • Jűrgen Venitz
  • William D. Figg
  • Alex Sparreboom
Preclinical Studies


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.


MS-275 Histone deacetylation Pharmacokinetics Dosing strategy 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Kouraklis G, Theocharis S (2002) Histone deacetylase inhibitors and anticancer therapy. Curr Med Chem Anti-Canc Agents 2:477–484CrossRefGoogle Scholar
  2. 2.
    Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK (2001) Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer 1:194–202PubMedCrossRefGoogle Scholar
  3. 3.
    Rosato RR, Almenara JA, Grant S (2003) The histone deacetylase inhibitor MS-275 promotes differentiation or apoptosis in human leukemia cells through a process regulated by generation of reactive oxygen species and induction of p21CIP1/WAF1 1. Cancer Res 63:3637–3645PubMedGoogle Scholar
  4. 4.
    Lucas DM, Davis ME, Parthun MR, Mone AP, Kitada S, Cunningham KD, Flax EL, Wickham J, Reed JC, Byrd JC, Grever MR (2004) The histone deacetylase inhibitor MS-275 induces caspase-dependent apoptosis in B-cell chronic lymphocytic leukemia cells. Leukemia 18:1207–1214PubMedCrossRefGoogle Scholar
  5. 5.
    Suzuki T, Ando T, Tsuchiya K, Fukazawa N, Saito A, Mariko Y, Yamashita T, Nakanishi O (1999) Synthesis and histone deacetylase inhibitory activity of new benzamide derivatives. J Med Chem 42:3001–3003PubMedCrossRefGoogle Scholar
  6. 6.
    Saito A, Yamashita T, Mariko Y, Nosaka Y, Tsuchiya K, Ando T, Suzuki T, Tsuruo T, Nakanishi O (1999) A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo antitumor activity against human tumors. Proc Natl Acad Sci USA 96:4592–4597PubMedCrossRefGoogle Scholar
  7. 7.
    Lee BI, Park SH, Kim JW, Sausville EA, Kim HT, Nakanishi O, Trepel JB, Kim SJ (2001) MS-275, a histone deacetylase inhibitor, selectively induces transforming growth factor beta type II receptor expression in human breast cancer cells. Cancer Res 61:931–934PubMedGoogle Scholar
  8. 8.
    Jaboin J, Wild J, Hamidi H, Khanna C, Kim CJ, Robey R, Bates SE, Thiele CJ (2002) MS-27-275, an inhibitor of histone deacetylase, has marked in vitro and in vivo antitumor activity against pediatric solid tumors. Cancer Res 62:6108–6115PubMedGoogle Scholar
  9. 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
  10. 10.
    Rudek MA, Venitz J, Ando Y, Reed E, Pluda JM, Figg WD (2003) Factors involved in the pharmacokinetics of COL-3, a matrix metalloproteinase inhibitor, in patients with refractory metastatic cancer: clinical and experimental studies. J Clin Pharmacol 43:1124–1135PubMedCrossRefGoogle Scholar
  11. 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. 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
  13. 13.
    Mosteller RD (1987) Simplified calculation of body-surface area. N Engl J Med 317:1098PubMedGoogle Scholar
  14. 14.
    Gibbs JP, Gooley T, Corneau B, Murray G, Stewart P, Appelbaum FR, Slattery JT (1999) The impact of obesity and disease on busulfan oral clearance in adults. Blood 93:4436–4440PubMedGoogle Scholar
  15. 15.
    Morgan DJ, Bray KM (1994) Lean body mass as a predictor of drug dosage. Implications for drug therapy. Clin Pharmacokinet 26:292–307PubMedGoogle Scholar
  16. 16.
    Felici A, Verweij J, Sparreboom A (2002) Dosing strategies for anticancer drugs: the good, the bad and body-surface area. Eur J Cancer 38:1677–1684PubMedCrossRefGoogle Scholar
  17. 17.
    Baker SD, Verweij J, Rowinsky EK, Donehower RC, Schellens JH, Grochow LB, Sparreboom A (2002) Role of body surface area in dosing of investigational anticancer agents in adults, 1991–2001. J Natl Cancer Inst 94:1883–1888PubMedGoogle Scholar
  18. 18.
    Marzolini C, Tirona RG, Kim RB (2004) Pharmacogenomics of the OATP and OAT families. Pharmacogenomics 5:273–282PubMedCrossRefGoogle Scholar
  19. 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. 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
  21. 21.
    Gurney H (2002) How to calculate the dose of chemotherapy. Br J Cancer 86:1297–1302PubMedCrossRefGoogle Scholar
  22. 22.
    Gurney H (1996) Dose calculation of anticancer drugs: a review of the current practice and introduction of an alternative. J Clin Oncol 14:2590–2611PubMedGoogle Scholar
  23. 23.
    Ratain MJ (1998) Body-surface area as a basis for dosing of anticancer agents: science, myth, or habit? J Clin Oncol 16:2297–2298PubMedGoogle Scholar
  24. 24.
    Grochow LB, Baraldi C, Noe D (1990) Is dose normalization to weight or body surface area useful in adults? J Natl Cancer Inst 82:323–325PubMedGoogle Scholar
  25. 25.
    Sawyer M, Ratain MJ (2001) Body surface area as a determinant of pharmacokinetics and drug dosing. Invest New Drugs 19:171–177PubMedCrossRefGoogle Scholar
  26. 26.
    Bruno R, Vivier N, Veyrat-Follet C, Montay G, Rhodes GR (2001) Population pharmacokinetics and pharmacokinetic-pharmacodynamic relationships for docetaxel. Invest New Drugs 19:163–169PubMedCrossRefGoogle Scholar
  27. 27.
    Gurney HP, Ackland S, Gebski V, Farrell G (1998) Factors affecting epirubicin pharmacokinetics and toxicity: evidence against using body-surface area for dose calculation. J Clin Oncol 16:2299–2304PubMedGoogle Scholar
  28. 28.
    Cosolo WC, Morgan DJ, Seeman E, Zimet AS, McKendrick JJ, Zalcberg JR (1994) Lean body mass, body surface area and epirubicin kinetics. Anticancer Drugs 5:293–297PubMedGoogle Scholar
  29. 29.
    Dobbs NA, Twelves CJ (1998) What is the effect of adjusting epirubicin doses for body surface area? Br J Cancer 78:662–666PubMedGoogle Scholar
  30. 30.
    de Jongh FE, Verweij J, Loos WJ, de Wit R, de Jonge MJ, Planting AS, Nooter K, Stoter G, Sparreboom A: Body-surface area-based dosing does not increase accuracy of predicting cisplatin exposure. J Clin Oncol 19:3733–3739, 2001PubMedGoogle Scholar
  31. 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
  32. 32.
    Egorin MJ (1998) Overview of recent topics in clinical pharmacology of anticancer agents. Cancer Chemother Pharmacol 42(Supp l):S22–S30PubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, LLC 2006

Authors and Affiliations

  • Milin R. Acharya
    • 1
    • 4
  • Judith E. Karp
    • 2
  • Edward A. Sausville
    • 3
  • Kyunghwa Hwang
    • 1
  • Qin Ryan
    • 1
  • Ivana Gojo
    • 3
  • Jűrgen Venitz
    • 4
  • William D. Figg
    • 1
  • Alex Sparreboom
    • 1
  1. 1.Clinical Pharmacology Research CoreNational Cancer InstituteBethesda
  2. 2.The Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimore
  3. 3.Greenebaum Cancer CenterUniversity of MarylandBaltimore
  4. 4.Department of PharmaceuticsVirginia Commonwealth UniversityRichmond

Personalised recommendations