Randomized cross-over clinical trial to study potential pharmacokinetic interactions between cisplatin or carboplatin and etoposide.
OBJECTIVE
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 microm) 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.
Thomas
Huw D
HD
Cancer Research Unit, Medical School, University of Newcastle, Newcastle General Hospital, Newcastle upon Tyne NE2 4HH, UK.
Porter
David J
DJ
Bartelink
Imke
I
Nobbs
Joy R
JR
Cole
Michael
M
Elliott
Suzie
S
Newell
David R
DR
Calvert
A Hilary
AH
Highley
Martin
M
Boddy
Alan V
AV
D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D016190:Carboplatin / Q000493:pharmacokinetics*; D002945:Cisplatin / Q000493:pharmacokinetics*; D016001:Confidence Intervals; D018592:Cross-Over Studies; D004347:Drug Interactions / Q000502:physiology; D004359:Drug Therapy, Combination; D005047:Etoposide / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D051381:Rats
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D005047:Etoposide; D016190:Carboplatin; D002945:Cisplatin