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

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: x0.72, x0.08 mg ml x1 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 x1 min), with no effect on day 2. In vitro carboplatin and cisplatin (10±100 mM) 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 signi®cant.

Effect of Aprepitant on Etoposide Pharmacokinetics in Patients with Testicular Cancer: A Pharmacokinetic Study to Determine the Absence of a Clinically Relevant Interaction

“…The systemic exposure to etoposide found in our study is comparable to earlier findings. Thomas and colleagues observed an AUC 0–24h of 85 mg/L*hour to etoposide after a dose of 100 mg/m 2 , which is in line with the AUC 0–24h of 83.7–86.2 mg/L*hour, as reported in our study after an equal dose 20 . Based on dose‐proportional pharmacokinetics of etoposide over a dose range of 100–600 mg/m 2 , it is not expected that a different effect will be observed at other dose levels 21 .…”

“…Geometric means and the geometric mean ratio (GMR) of exposure over time (AUC 0–24h ) of etoposide with and without aprepitant was calculated. When the 90% confidence interval (CI) of the GMR falls within the 0.8–1.25 limits, this interaction is considered non‐clinically relevant in line with the FDA guideline “Clinical Drug Interaction studies – Cytochrome P450 enzyme‐ and transporter‐mediated drug interactions guidance for industry” 20 . Pharmacokinetic parameters and descriptive statistics were performed by noncompartmental analysis using Phoenix WinNonlin 8.3.4.295.…”

Herbal Interactions with Anticancer Drugs: Mechanistic and Clinical Considerations

“…However, tamoxifen did not alter the pharmacokinetics of etoposide in patients with hepatocellular carcinoma [254]. Cisplatin or carboplatin only had a minor effect on the pharmacokinetics of etoposide in cancer patients [255].…”

Population pharmacokinetics of carboplatin, etoposide and melphalan in children: a re‐evaluation of paediatric dosing formulas for carboplatin in patients with normal or mild impairment of renal function

“…There are two studies that have reported no pharmacokinetic interaction between carboplatin and etoposide [33,34], and one study has reported an interaction between melphalan and carboplatin [35]. As these drugs were coadministered in all patients in the present study, potential drug-drug interactions could not be investigated directly.…”