Pharmacokinetic study of omacetaxine mepesuccinate administered subcutaneously to patients with advanced solid and hematologic tumors

John Nemunaitis, Alain Mita, Joe Stephenson, Monica M. Mita, John Sarantopoulos, Swami Padmanabhan-Iyer, Nisha Nanda, Lyon Gleich, Annie Claude Benichou, Adam Craig

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Purpose: Omacetaxine mepesuccinate is a first-in-class cephalotaxine demonstrating clinical activity in chronic myeloid leukemia. A subcutaneous (SC) formulation demonstrated efficacy and safety in phase 1/2 trials in patients previously treated with ≥1 tyrosine kinase inhibitor. This study assessed pharmacokinetics and safety of SC omacetaxine in patients with advanced cancers. Methods: Omacetaxine 1.25 mg/m2 SC was administered BID, days 1-14 every 28 days for 2 cycles, until disease progression or unacceptable toxicity. Blood and urine were collected to measure omacetaxine concentrations and inactive metabolites. Adverse events, including QT interval prolongation, were recorded. Tumor response was assessed at cycle 2 completion. Results: Pharmacokinetic parameters were estimated from cycle 1, day 1 data in 21 patients with solid tumors or hematologic malignancies and cycle 1, day 11 data in 10 patients. Omacetaxine was rapidly absorbed, with mean peak plasma concentrations observed within 1 h, and widely distributed, as evidenced by an apparent volume of distribution of 126.8 L/m2. Plasma concentration versus time data demonstrated biexponential decay; mean steady-state terminal half-life was 7 h. Concentrations of inactive metabolites 4′-DMHHT and cephalotaxine were approximately 10 % of omacetaxine and undetectable in most patients, respectively. Urinary excretion of unchanged omacetaxine accounted for <15 % of the dose. Grade 3/4 drug-related adverse events included thrombocytopenia (48 %) and neutropenia (33 %). Two grade 2 increases in QTc interval (>470 ms) were observed and were not correlated with omacetaxine plasma concentration. No objective responses were observed. Conclusions: Omacetaxine is well absorbed after SC administration. Therapeutic plasma concentrations were achieved with 1.25 mg/m2 BID, supporting clinical development of this dose and schedule.

Original languageEnglish (US)
Pages (from-to)35-41
Number of pages7
JournalCancer chemotherapy and pharmacology
Volume71
Issue number1
DOIs
StatePublished - Jan 2013

Keywords

  • Cephalotaxine
  • Homoharringtonine
  • Omacetaxine mepesuccinate
  • Phase 1
  • Subcutaneous

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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    Nemunaitis, J., Mita, A., Stephenson, J., Mita, M. M., Sarantopoulos, J., Padmanabhan-Iyer, S., Nanda, N., Gleich, L., Benichou, A. C., & Craig, A. (2013). Pharmacokinetic study of omacetaxine mepesuccinate administered subcutaneously to patients with advanced solid and hematologic tumors. Cancer chemotherapy and pharmacology, 71(1), 35-41. https://doi.org/10.1007/s00280-012-1963-2