Article
Population pharmacokinetic model for cisplatin during intraoperative hyperthermic intraperitoneal chemoperfusion (HIPEC) in patients with platinum-sensitive recurrent epithelial ovarian cancer (EOC)
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Published: | September 25, 2014 |
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Aim: Epithelial ovarian cancer is the leading cause of death from a gynaecologic malignancy. Because the natural history of the disease is mostly confined to the peritoneal cavity, hyperthermic intraperitoneal chemoperfusion (HIPEC) has a strong rationale as treatment option. It was the aim of this study to characterize the pharmacokinetic disposition of cisplatin after intraperitoneal administration.
Method: Thirteen patients with operable, recurrent platinum-sensitive EOC and ECOG performance status 0–1 were included in the underlying phase I study. After surgical cytoreduction, a single dose of cisplatin (60, 80 or 100 mg/m²) was administered in normal saline via HIPEC for 90 minutes at 41–43°C. At 0, 15, 30, 45, 60, 75, 90 min and additionally at 3, 6, 12, 18, 24, 48, 72h blood was drawn. Plasma and ultrafiltrated plasma were obtained from each blood sample. Perfusate samples were drawn at 0, 5, 10, 15, 30, 45, 60, 75, 90 min. Platinum concentrations were measured by validated flameless atomic absorption spectrometry (AAS) methods.
A population model was built to simultaneously describe platinum concentration-time profiles in all three matrices by using NONMEM®. Furthermore, we pooled the data with fifteen patients who received an intravenous 1-hour infusion to estimate rate and extent of systemically absorbed platinum. Potential covariates (including age, body surface area (BSA), dose, Peritoneal Cancer Index and completeness of cytoreduction) were investigated on all pharmacokinetic parameters using the forward inclusion/backward elimination method. The model was internally validated by bootstrap analysis and visual predictive checks.
Results: Platinum concentration time-profiles during HIPEC were best described using a linear four-compartment model with perfusate as dose compartment and a biexponential disposition for ultrafiltrated platinum. Plasma protein binding was considered as an irreversible metabolite formation with a separate clearance. BSA was identified as a significant covariate on perfusate volume. Platinum absorption was fast and incomplete with a systemically available fraction (fa) of 0.8 (RSE 14%) and an absorption rate of 4.74 L/h (RSE 12%, CV 42.6%).
Conclusion: We developed a population pharmacokinetic model to simultaneously describe platinum concentration-time profiles in perfusate, ultrafiltrate and plasma. In addition, the combination with data of intravenously administered cisplatin allowed us to estimate rate and extent of platinum absorption during the HIPEC procedure.