Intraperitoneal clearance as a potential biomarker of cisplatin after intraperitoneal perioperative chemotherapy: a population pharmacokinetic study

Abstract

Background: Intraperitoneal (IP) perioperative chemotherapy with cisplatin is an interesting option in ovarian cancer treatment. A combination of cisplatin with IP epinephrine (already shown to improve IP and decrease systemic platinum (Pt) exposure) was evaluated using a population pharmacokinetic analysis.

Methods: Data from 55 patients treated with cisplatin-based IP perioperative chemotherapy with (n=26) or without (n=29) epinephrine were analysed using NONMEM.

Results: Epinephrine halves clearance between peritoneum and serum (IPCL) and increases the Pt central volume of distribution, IP exposure and penetration in tissue. IPCL has a better predictive value than any other parameter with respect to renal toxicity.

Conclusion: This confirms that IPCL could be useful in assessing renal toxicity. As IPCL is also linked to tissue penetration and IP exposure, it may be proposed as biomarker. In addition to a Bayesian estimation, we propose a single-sample calculation-way to assess it. Prospective studies are needed to validate IPCL as a biomarker in this context.

Figure 1

Scheme of the compartmental final model used for the modelling of both Uf and bound Pt. Administration of PIPC was performed in the IP compartment and Uf Pt was transferred to the central (serum) compartment following IP clearance IPCL. Ultrafiltered Pt can change between the central and peripheral compartments and be eliminated following central clearance (CL). Ultrafiltered Pt can also bind to protein following a Michealis–Menten model (K_max, V_M) and thereafter be eliminated (k_B).

Figure 2

Scatterplots allowing us to assess the goodness-of-fit for the final models. Graphs represent model-Predicted (PRED) (A) and Individual Predicted (B – shrinkage ⩽11.0%) concentrations plotted vs Observed concentrations, as well as Conditional (C) and Individual (D) Weighted Residuals vs Time. These concentrations were observed for the concentrations obtained IP, in serum and for bound Pt. The scatterplots for each compartment are displayed in Supplementary Figure S2 of the Supplementary data.

Figure 3

Effect of epinephrine on Pt behaviour during PIPC. (A) The effect of epinephrine on individual rate of transfer of Uf Pt from peritoneum to bloodstream. (B) Assessment of the effect of epinephrine on the individual Pt penetration. 3x₀ (μm) is the distance in peritoneal tissue at which the concentration difference between tissue and blood perfusing this tissue decreased to 5% of its maximal value. (C) Time during which the IP Pt concentration is over 10 mg l^–1. The data were obtained for patients treated with cisplatin with (white box) or without (grey box) epinephrine. ‡ means P<10⁻⁴ (t-test) as compared with values observed without epinephrine.