Continuous infusion prochlorperazine: Pharmacokinetics, antiemetic efficacy, and feasibility of high-dose therapy

Jr Morgan R.J., T. Synold, B. I. Carr, J. H. Doroshow, E. P. Womack, S. Shibata, G. Somlo, J. Raschko, L. Leong, M. McNamara, W. Chow, M. Tetef, K. Margolin, S. Akman, J. Longmate

Research output: Contribution to journalArticle

Abstract

Purpose: The purpose of these sequential phase I studies was to evaluate the antiemetic efficacy and pharmacokinetics of high-dose continuous infusion prochlorperazine. Methods: A total of 52 patients with advanced cancer were treated in two sequential phase I studies utilizing high-dose prochlorperazine. In study 1, designed to investigate the antiemetic effects of dose-intensive prochlorperazine, various cisplatin-based multi-agent chemotherapeutic regimens were administered in combination with escalating doses of prochlorperazine. In study 2, a fixed dose of cisplatin (60 mg/m2) was administered over 24 h as a continuous intravenous infusion in combination with infusional high-dose prochlorperazine. Antiemetic efficacy in the first trial was assessed in terms of the number of episodes of nausea, retching, and/or emesis during the 24 h following cisplatin administration. The pharmacokinetics of high-dose prochlorperazine were evaluated in eight patients treated in study 2 at the two dose levels below those at which dose-limiting toxicity was noted. Results: The maximally tolerated dose of prochlorperazine in combination with cisplatin (60 mg/m2 administered as a continuous infusion over 24 h) was 24 mg/h. The dose-limiting toxicity was grade 4 agitation and confusion noted in one patient treated at 26 mg/h. This patient died 3 days following cessation of chemotherapy due to the toxicity of the regimen in combination with the debilitating pulmonary effects of the disease. The mean end of infusion prochlorperazine level at the 24 mg/h dose level was 1.1 μM, a concentration previously reported to be consistent with the reversal of the multidrug resistance phenotype. Two partial responses were observed in study 2. Conclusions: We conclude that the antiemetic efficacy of high-dose infusional prochlorperazine does not appear to be improved over more convenient bolus administration. However, prochlorperazine levels consistent with those required in vitro for drug resistance reversal are attainable within the dose range having a tolerable toxicity profile.

Original languageEnglish
Pages (from-to)327-332
Number of pages6
JournalCancer Chemotherapy and Pharmacology
Volume47
Issue number4
DOIs
Publication statusPublished - 2001

Keywords

  • Continuous infusion
  • Prochlorperazine

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

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    Morgan R.J., J., Synold, T., Carr, B. I., Doroshow, J. H., Womack, E. P., Shibata, S., Somlo, G., Raschko, J., Leong, L., McNamara, M., Chow, W., Tetef, M., Margolin, K., Akman, S., & Longmate, J. (2001). Continuous infusion prochlorperazine: Pharmacokinetics, antiemetic efficacy, and feasibility of high-dose therapy. Cancer Chemotherapy and Pharmacology, 47(4), 327-332. https://doi.org/10.1007/s002800000232