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Randomized cross-over clinical trial to study potential pharmacokinetic interactions between cisplatin or carboplatin and etoposide

Lookup NU author(s): Huw Thomas, Mike Cole, Suzanne Elliott, Emeritus Professor Herbie Newell, Professor Alan Calvert, Dr Martin Highley, Professor Alan Boddy

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Abstract

Aims: Cisplatin and carboplatin are often used in combination with etoposide. In a randomized cross-over study, the potential interaction between the two platinum drugs and the metabolism of etoposide was explored. In vitro investigations using human liver microsomes were also performed. Methods: Etoposide was administered to 15 patients over 3 days, with the platinum drug administered on day 2. The alternate platinum drug was administered on the second course. The pharmacokinetics of etoposide were determined on all 3 days of each cycle. The effect of platinum drugs on etoposide metabolism by human liver enzymes was explored in vitro. Results: Neither cisplatin nor carboplatin coadministration affected the pharmacokinetics of etoposide during cycle 1. When carboplatin was administered on course 2, etoposide AUC was 8% higher on day 2 compared with day 1 or day 3 (for day 2 vs day 3, 95% CI: -0.72, -0.08 mg ml-1 min). In contrast, cisplatin on course 2 increased the AUC of etoposide (28%) on day 3 (day 3 vs day 1, 95% CI: 0.67, 2.09 mg ml-1 min), with no effect on day 2. In vitro carboplatin and cisplatin (10-100 μM) inhibited the metabolism of etoposide, if rat liver microsomes were preincubated (30 min) with NADPH and the platinum complexes. With human liver microsomes a small effect on etoposide metabolism, but not on catechol formation, was observed. Conclusions: The interaction between etoposide and platinum drugs is small and, given the pharmacokinetic variability seen with etoposide, the clinical impact is unlikely to be significant.


Publication metadata

Author(s): Thomas HD, Porter D, Bartelink I, Nobbs J, Cole M, Elliott S, Newell DR, Calvert AH, Highley M, Boddy AV

Publication type: Article

Publication status: Published

Journal: British Journal of Clinical Pharmacology

Year: 2002

Volume: 53

Issue: 1

Pages: 83-91

Print publication date: 01/01/2002

ISSN (print): 0306-5251

ISSN (electronic): 1365-2125

URL: http://dx.doi.org/10.1046/j.0306-5251.2001.01513.x

DOI: 10.1046/j.0306-5251.2001.01513.x

PubMed id: 11849199


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