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Clinical pharmacology profile of vorinostat, a histone deacetylase inhibitor

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Abstract

Purpose

Vorinostat is a histone deacetylase inhibitor that has demonstrated preclinical activity in numerous cancer models. Clinical activity has been demonstrated in patients with a variety of malignancies. Vorinostat is presently indicated for the treatment of patients with advanced cutaneous T cell lymphoma (CTCL). Clinical investigation is ongoing for therapy of other solid tumors and hematological malignancies either as monotherapy or in combination with other chemotherapeutic agents. This review summarizes the pharmacokinetic properties of vorinostat.

Methods

Monotherapy pharmacokinetic data across a number of pharmacokinetic studies were reviewed, and data are presented. In addition, literature review was performed to obtain published Phase I and II pharmacokinetic combination therapy data to identify and characterize potential drug interactions with vorinostat. Pharmacokinetic data in special populations were also reviewed.

Results

The clinical pharmacology profile of vorinostat is favorable, exhibiting dose-proportional pharmacokinetics and modest food effect. There appear to be no major differences in the pharmacokinetics of vorinostat in special populations, including varying demographics and hepatic dysfunction. Combination therapy pharmacokinetic data indicate that vorinostat has a low propensity for drug interactions.

Conclusions

Vorinostat’s favorable clinical pharmacology and drug interaction profile aid in the ease of administration of vorinostat for the treatment of advanced CTCL and will be beneficial in continued assessment for other oncologic indications. Although a number of studies have been conducted to elucidate the detailed pharmacokinetic profile of vorinostat, more rigorous assessment of vorinostat pharmacokinetics, including clinical drug interaction studies, will be informative.

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Notes

  1. Pharmacokinetic data units were converted from mM to µM; mM units were likely a typographical error in the Badros et al. manuscript.

References

  1. Marks PA, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK (2001) Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer 1:194–202. doi:10.1038/35106079

    Article  PubMed  CAS  Google Scholar 

  2. Bolden JE, Peart MJ, Johnstone RW (2006) Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 5:769–784

    Article  PubMed  CAS  Google Scholar 

  3. Zolinza (vorinostat) [package insert] (2011) Merck & Co., Inc., Whitehouse Station, NJ

  4. Olsen EA, Kim YH, Kuzel TM, Pacheco TR, Ross FM, Parker S, Frankel SR, Chen C, Ricker JL, Arduino JM, Duvic M (2007) Phase IIB multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol 25:3109–3115. doi:10.1200/JCO.2006.10.2434

    Article  PubMed  CAS  Google Scholar 

  5. Duvic M, Talpur R, Ni X, Zhang C, Hazarika P, Kelly C, Chiao JH, Reilly JF, Ricker JL, Richon VM, Frankel SR (2007) Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood 109:31–39. doi:10.1182/blood-2006-06-025999

    Article  PubMed  CAS  Google Scholar 

  6. Rubin EH, Agrawal NGB, Friedman EJ, Scott P, Mazina KE, Sun L, Du L, Ricker JL, Frankel SR, Gottesdiener KM, Wagner JA, Iwamoto M (2006) A study to determine the effects of food and multiple dosing on the pharmacokinetics of vorinostat given orally to patients with advanced cancer. Clin Cancer Res 12(23):7039–7045. doi:10.1158/1078-0432.CCR-06-1802

    Article  PubMed  CAS  Google Scholar 

  7. Fujiwara Y, Yamamoto N, Yamada Y, Yamada K, Otsuki T, Kanazu S, Iwasa T, Hardwick JS, Tamura T (2009) Phase I and pharmacokinetic study of vorinostat (suberoylanilide hydroxamic acid) in Japanese patients with solid tumors. Cancer Sci 100(9):1728–1734. doi:10.1111/j.1349-7006.2009.01237.x

    Article  PubMed  CAS  Google Scholar 

  8. Ramalingam SS, Parise RA, Ramananthan RK, Lagattuta TF, Musguire LA, Stoller RG, Potter DM, Argiris AE, Zweibel JA, Egorin MJ, Belani CP (2007) Phase I and pharmacokinetic study of vorinostat, a histone deacetylase inhibitor, in combination with carboplatin and paclitaxel for advanced solid malignancies. Clin Cancer Res 13(12):3605–3610. doi:10.1158/1078-0432.CCR-07-0162

    Article  PubMed  CAS  Google Scholar 

  9. Kelly WK, O’Connor OA, Krug LM, Chiao JH, Heaney M, Curley T, MacGregore-Cortelli B, Tong W, Secrist JP, Schwartz L, Richardson S, Chu E, Olgac S, Marks PA, Scher H, Richon VM (2005) Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol 23:3923–3931. doi:10.1200/JCO.2005.14.167

    Article  PubMed  CAS  Google Scholar 

  10. Munster PN, Rubin EH, Van Belle S, Friedman E, Patterson JK, Van Dyck K, Li X, Comisar W, Chodakewitz JA, Wagner JA, Iwamoto M (2009) A single supratherapeutic dose of vorinostat does not prolong the QTc interval in patients with advanced cancer. Clin Cancer Res 15(22):7077–7084. doi:10.1158/1078-0432.CCR-09-1214

    Article  PubMed  CAS  Google Scholar 

  11. Galanis E, Jaeckle KA, Maurer MJ, Reid JM, Ames MM, Hardwick JS, Reilly JF, Loboda A, Nebozhyn M, Fantin VR, Richon VM, Scheithauer B, Giannini C, Flynn PJ, Moore DF, Zwiebel J, Buckner JC (2009) Phase II trial of vorinostat in recurrent glioblastoma multiforme: a north central cancer treatment group study. J Clin Oncol 27(12):2052–2058. doi:10.1200/JCO.2008.19.0694

    Article  PubMed  CAS  Google Scholar 

  12. Fouladi M, Park JR, Stewart CF, Gilbertson RJ, Schaiquevich P, Sun J, Reid MJ, Ames MM, Speights R, Ingle AM, Zweibel J, Blaney SM, Adamson PC (2010) Pediatric phase I trial and pharmacokinetic study of vorinostat: a Children’s Oncology Group phase I consortium report. J Clin Oncol 28:3623–3629. doi:12.1200/JCO.2009.25.9119

    Article  PubMed  CAS  Google Scholar 

  13. Zolinza (vorinostat) [Japan package insert] (2011) Taiho Pharmaceutical Co., Ltd., Tokyo, Japan

  14. Balliet RM, Chen G, Gallagher CJ, Dellinger RW, Sun D, Lazarus P (2009) Characterization of UGTs active against SAHA and association between SAHA glucuronidation activity phenotype with UGT genotype. Cancer Res 69:2981–2989. doi:10.1158/0008-5472.CAN-08-4143

    Article  PubMed  CAS  Google Scholar 

  15. Pajkovic N, Koeplinger KA, Baker MP, Soli ED, Fauty SE, Sandhu P (2006) In vitro metabolism of vorinostat (suberoylanilide hydroxamic acid), a novel anticancer agent [abstract]. In: Proceedings of the 54th ASMS Meeting, Seattle, Washington

  16. Sandhu P, Andrews P, Baker MP, Koeplinger KA, Soli ED, Miller T, Baillie TA (2007) Disposition of vorinostat, a novel histone deacetylase inhibitor and anticancer agent, in preclinical species. Drug Metab Lett 1:153–161

    Article  PubMed  CAS  Google Scholar 

  17. Watanabe T, Kato H, Kobayashi Y, Yamasaki S, Morita-Hoshi Y, Yokoyama H, Morishima Y, Ricker JL, Otsuki T, Miyagi-Maesima A, Matsuno Y, Tobinai K (2010) Potential efficacy of the oral histone deacetylase inhibitor vorinostat in a phase I trial in follicular and mantle cell lymphoma. Cancer Sci 101:196–200. doi:10.1111/j.1349-7006.2009.01360.x

    Article  PubMed  CAS  Google Scholar 

  18. Wong NS, Seah EZH, Wang LZ, Yeo WL, Yap HL, Chuah B, Lim YW, Ang PCS, Tai BC, Lim R, Goh BC, Lee SC (2011) Impact of UDP-gluconoryltransferase 2B17 genotype on vorinostat metabolism and clinical outcomes in Asian women with breast cancer. Pharmacogenet Genomics 21:760–768. doi:10.1097/FPC.0b013e32834a8639

    Article  PubMed  CAS  Google Scholar 

  19. Kelly WK, Richon VM, O’Connor OA, Curley T, MacGregor-Curtelli B, Tong W, Klang M, Schwartz L, Richardson S, Rosa E, Drobnjak M, Cordon-Cordo C, Chiao JH, Rifkind R, Marks PA, Scher H (2003) Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously. Clin Cancer Res 9:3578–3588

    PubMed  CAS  Google Scholar 

  20. Ramalingam SS, Kummar S, Sarantopoulos J, Shibata S, LoRusso P, Yerk M, Holleran J, Lin Y, Beumer JH, Harvey RD, Ivy SP, Belani CP, Egorin MJ (2010) Phase I study of vorinostat in patients with advanced solid tumors and hepatic dysfunction: a National Cancer Institute Organ Dysfunction working group study. J Clin Oncol 28:4507–4512. doi:10.1200/JCO.2010.30.2307

    Article  PubMed  CAS  Google Scholar 

  21. Piekarz RL, Frye AR, Wright JJ, Steinberg SM, Liewehr DJ, Rosing DR, Sachdev V, Fojo T, Bates SE (2006) Cardiac studies in patients treated with depsipeptide, FK228, in a phase II trial for T-cell lymphoma. Clin Cancer Res 12:3762–3773

    Article  PubMed  CAS  Google Scholar 

  22. Bates SE, Rosing DR, Fojo T, Piekarz RL (2006) Challenges of evaluating the cardiac effects of anticancer agents. Clin Cancer Res 12:3871–3874

    Article  PubMed  CAS  Google Scholar 

  23. Badros A, Burger AM, Phillip S, Niesvizky R, Kolla SS, Goloubeva O, Harris C, Zwiebel J, Wright JJ, Espinoza-Delgado I, Baer MR, Holleran JL, Egorin MJ, Grant S (2009) Phase I study of vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma. Clin Cancer Res 15(16):5250–5257. doi:10.1158/1078-0432.CCR-08-2850

    Article  PubMed  CAS  Google Scholar 

  24. Velcade (bortezomib) [package insert] (2010) Millennium Pharmaceuticals, Inc., Cambridge, MA

  25. Carboplatin [package insert] (2005) Spectrum Pharmaceuticals, Inc., Irvine, CA

  26. Taxol (paclitaxel) [package insert] (2011) Bristol-Myers Squibb Company, Princeton, NJ

  27. Beijnen JH, Schellens JHM (2004) Drug interactions in oncology. Lancet Oncol 5:489–496

    Article  PubMed  CAS  Google Scholar 

  28. Zhu WG, Lakshmanan RR, Beal MD, Otterson GA (2001) DNA methyltransferase inhibition enhances apoptosis induced by histone deacetylase inhibitors. Cancer Res 61:1327–1333

    PubMed  CAS  Google Scholar 

  29. Stathis A, Hotte SJ, Chen EX, Hirte HW, Oza AM, Moretto P, Webster S, Laughlin A, Stayner LA, McGill S, Wang L, Zhang WJ, Espinoza-Delgado I, Holleran JL, Egorin MJ, Siu LL (2011) Phase I study of decitabine in combination with vorinostat in patients with advanced solid tumors and non-Hodgkin’s lymphomas. Clin Cancer Res 17:1582–1590. doi:10.1158/1078-0432.CCR-10-1893

    Article  PubMed  CAS  Google Scholar 

  30. Dacogen (decitabine) [package insert] (2010) Eisai Inc., Woodcliff Lake, NJ

  31. Fakih MG, Pendyala L, Fetterly G, Toth K, Zwiebel JA, Espinoza-Delgado I, Litwin A, Rustum YM, Ross ME, Holleran JL, Egorin MJ (2009) A phase I, pharmacokinetic and pharmacodynamic study on vorinostat in combination with 5-fluorouracil, leucovorin, and oxaliplatin in patient with refractory colorectal cancer. Clin Cancer Res 15(9):3189–3195. doi:10.1158/1078-0432.CCR-08-2999

    Article  PubMed  CAS  Google Scholar 

  32. Schneider BJ, Kalemkerian GP, Bradley D, Smith DC, Egorin MJ, Daignault S, Dunn R, Hussain M (2012) Phase I study of vorinostat (suberoylanilide hydroxamic acid, NSC 701852) in combination with docetaxel in patients with advanced and relapsed solid malignancies. Invest New Drugs 30:249–257. doi:10.1007/s10637-101-9503-6

    Article  PubMed  CAS  Google Scholar 

  33. Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, Yoshida M, Wang XF, Yao TP (2002) HDAC6 is a microtubule-associated deacetylase. Nature 417:455–458

    Article  PubMed  CAS  Google Scholar 

  34. Taxotere (docetaxel) [package insert] (2010) sanofi-aventis U.S. LLC, Bridgewater, NJ

  35. Munster P, Marchion D, Bicaku E, Schmitt M, Lee JH, DeConti R, Simon G, Fishman M, Minton S, Garrett C, Chiappori A, Lush R, Sullivan D, Daud A (2007) Phase I trial of histone deacetylase inhibition by valproic acid followed by the topoisomerase II inhibitor epirubicin in advanced solid tumors: a clinical and translation study. J Clin Oncol 25:1979–1985. doi:10.1200/JCO.2006.08.6165

    Article  PubMed  CAS  Google Scholar 

  36. Munster PN, Marchion D, Thomas S, Egorin M, Minton S, Springett G, Lee JH, Simon G, Chiappori A, Sullivan D, Daud A (2009) Phase I trial of vorinostat and doxorubicin in solid tumours: histone deacetylase 2 expression as a predictive marker. Br J Cancer 101:1044–1050. doi:10.1038/sj.bjc.6605293

    Article  PubMed  CAS  Google Scholar 

  37. Rubex (doxorubicin) [package insert] (2001) Bristol-Myers Squibb Company, Princeton, NJ

  38. Dickson MA, Rathkopf DE, Carvajal RD, Grant S, Roberts JD, Reid JM, Ames MM, McGovern RM, Lefkowitz RA, Gonen M, Cane LM, Dials JF, Schwartz GK (2011) A phase I pharmacokinetic study of pulse-dose vorinostat with flavopiridol in solid tumors. Invest New Drugs 29:1004–1012. doi:10.1007/s10637-010-9447-x

    Article  PubMed  CAS  Google Scholar 

  39. Hagenauer B, Salamon A, Thalhammer T, Kunert O, Haslinger E, Klinger P, Senderowicz AM, Sausville EA, Jager W (2001) In vitro glucuronidation of the cyclin-dependent kinase inhibitor flavopiridol by rat and human liver microsomes: involvement of UDP-glucuronosyltransferases 1A1 and 1A9. Drug Metab Dispos 29:407–414

    PubMed  CAS  Google Scholar 

  40. Grem JL (2006) 5-Fluoropyrimidines. In: Chabner BA, Longo DL (eds) Cancer chemotherapy and biotherapy, 4th edn. Lippincott Williams & Wilkins, Philadelphia

    Google Scholar 

  41. Leucovorin calcium [package insert] (2003) Mayne Pharma (USA) Inc., Paramus, NJ

  42. Yamasaki D, Tsujimoto M, Ohdo S, Ohtani H, Sawada Y (2007) Possible mechanisms for the pharmacokinetic interaction between phenytoin and folinate in rats. Ther Drug Monit 29:404–411

    Article  PubMed  CAS  Google Scholar 

  43. Eloxatin (oxaliplatin) [package insert] (2009) sanofi-aventis U.S. LLC, Bridgewater, NJ

  44. Fakih MG, Fetterly G, Egorin MJ, Muindi JR, Espinoza-Delgado I, Zwiebel JA, Litwin A, Holleran JL, Wang K, Diasio RB (2010) A phase I, pharmacokinetic, and pharmacodynamic study of two schedules of vorinostat in combination with 5-fluorouracil and leucovorin in patients with refractory solid tumors. Clin Cancer Res 16:3786–3794. doi:10.1158/1078-0432.CCR-10-0547

    Article  PubMed  CAS  Google Scholar 

  45. Garcia-Manero G, Yang H, Bueso-Ramos C, Ferrajoli A, Cortes J, Wierda WG, Faderl S, Koller C, Morris G, Rosmer G, Loboda A, Fantin VR, Randolph SS, Hardwick JS, Reilly JF, Chen C, Ricker JL, Secrist JP, Richon VM, Frankel SR, Kantarjian HM (2008) Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. Blood 111:1060–1066. doi:10.1182/blood-2007-06-098061

    Article  PubMed  CAS  Google Scholar 

  46. Sanchez-Gonzalez B, Yang H, Bueso-Ramos C, Hoshino K, Quintas-Cardama A, Richon VM, Garcia-Manero G (2006) Antileukemia activity of the combination of an anthracycline with a histone deacetylase inhibitor. Blood 108(4):1174–1182. doi:10.1182/blood-2005-09-008086

    Article  PubMed  CAS  Google Scholar 

  47. Kadia TM, Yang H, Ferrajoli A, Maddipotti S, Schroeder C, Madden TL, Holleran JL, Egorin MJ, Ravandi F, Thomas DA, Newsome W, Sanchez-Gonzalez B, Zweibel JA, Espinoza-Delgado I, Kantarjian HM, Garcia-Manero G (2010) A phase I study of vorinostat in combination with idarubicin in relapsed or refractory leukaemia. Br J Hematol 150:72–82. doi:10.1111/j.1365-2141.2010.08211.x

    CAS  Google Scholar 

  48. Idamycin (idarubicin) [package insert] (2006) Pfizer Inc., New York, NY

  49. Doroshow JH (2006) Anthracyclines and Anthracenediones. In: Chabner BA, Longo DL (eds) Cancer chemotherapy and biotherapy, 4th edn. Lippincott Williams & Wilkins, Philadelphia

    Google Scholar 

  50. Nadin L, Murray M (1999) Participation of CYP2C8 in retinoic acid 4-hydroxylation in human hepatic microsomes. Biochem Pharmacol 58:1201–1208

    Article  PubMed  CAS  Google Scholar 

  51. Allen JG, Bloxham DP (1989) The pharmacology and pharmacokinetics of the retinoids. Pharmacol Ther 40:1–27

    Article  PubMed  CAS  Google Scholar 

  52. Perucca E (2005) Clinically relevant drug interactions with antiepileptic drugs. Br J Clin Pharmacol 61:246–255. doi:10.1111/j.1365-2125.2005.02529.x

    Article  Google Scholar 

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Acknowledgments

Deepest appreciation and thanks go to all of the patients who participated in the clinical studies referenced above.

Conflict of interest

M. Iwamoto, E. Friedman, N. Agrawal, P. Sandhu, E. Rubin, and J. Wagner are all current employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, and may own stock or hold stock options in the company.

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Authors and Affiliations

  1. Department of Project Leadership and Management, Merck Sharp & Dohme Corp. a Subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA

    Marian Iwamoto & John A. Wagner

  2. Department of Clinical Pharmacology, Merck Sharp & Dohme Corp. a Subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA

    Evan J. Friedman

  3. Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Sharp & Dohme Corp. a Subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA

    Punam Sandhu & Nancy G. B. Agrawal

  4. Department of Clinical Oncology, Merck Sharp & Dohme Corp. a Subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA

    Eric H. Rubin

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  1. Marian Iwamoto
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  2. Evan J. Friedman
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  3. Punam Sandhu
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  4. Nancy G. B. Agrawal
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Correspondence to Marian Iwamoto.

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Iwamoto, M., Friedman, E.J., Sandhu, P. et al. Clinical pharmacology profile of vorinostat, a histone deacetylase inhibitor. Cancer Chemother Pharmacol 72, 493–508 (2013). https://doi.org/10.1007/s00280-013-2220-z

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