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Pharmacokinetic and biotransformation studies of ormaplatin in conjunction with a phase I clinical trial

  • Original Articles
  • Ormaplatin, Pharmacokinetics, Phase I
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Abstract

Ormaplatin is a second-generation platinum (Pt) analogue with in vitro activity against some cisplatin-resistant malignant cell lines. We have evaluated the pharmacokinetics and biotransformations of ormaplatin during a phase I trial in which ormaplatin was administered by daily 30-min infusions on 5 consecutive days every 28 days. Sixteen patients received 25 courses at doses ranging from 5.0 to 11.6 mg/m2 per day. Pharmacokinetic parameters determined for ultrafilterable Pt measured by atomic absorption spectrophotometry revealed a short half-life (t1/2 16 min), moderate volume of distribution (Vd 12 l/m2), and relatively fast systemic clearance (Cls 544 ml/min per m2). Cls and percentage of drug unbound decreased during the 5-day administration period. Average systemic exposure increased with dose; however, inter-individual variability in Cls produced overlap in systemic exposure between the dose levels. The major active biotransformation product [PtCl2(dach)] was evaluated at the highest dose level by HPLC. This product decayed monoexponentially with a mean t1/2 of 13 min and a higher degree of pharmacokinetic variability than that of ultrafilterable Pt at this dose. No uncreacted ormaplatin was detected; however, several inactive biotransformation products persisted for at least 120 min. Approximately 32% of the dose was excreted in the urine during the first day, one-third of this during the initial 1.5 h. The human pharmacokinetic characteristics of ormaplatin resemble those of cisplatin; however, additional study will be required to discern which analyte of ormaplatin correlates best with clinical effects.

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Author notes

  1. David C. Smith & Donald L. Trump

    Present address: Pittsburgh Cancer Institute, Montefiore University Hospital, Pittsburgh, Pennsylvania, USA

Authors and Affiliations

  1. Department of Medicine, Comprehensive Cancer Center, Duke University Medical Center, Box 3961, 27710, Durham, NC, USA

    William P. Petros, David C. Smith, James Fangmeier, Thomas D. Brown & Donald L. Trump

  2. Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA

    Stephen G. Chaney & Michael Sakata

Authors
  1. William P. Petros
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The biotransformation studies were supported by the Upjohn Company.

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Petros, W.P., Chaney, S.G., Smith, D.C. et al. Pharmacokinetic and biotransformation studies of ormaplatin in conjunction with a phase I clinical trial. Cancer Chemother. Pharmacol. 33, 347–354 (1994). https://doi.org/10.1007/BF00685911

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  • DOI: https://doi.org/10.1007/BF00685911

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