PKPD Modeling and Dosing Considerations in Advanced Ovarian Cancer Patients Treated with Cisplatin-Based Intraoperative Intraperitoneal Chemotherapy

Feifan Xie*, Jan Van Bocxlaer, Pieter Colin, Charlotte Carlier, Olivier Van Kerschaver, Joseph Weerts, Hannelore Denys, Philippe Tummers, Wouter Willaert, Wim Ceelen, An Vermeulen

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Intraperitoneal chemoperfusion (IPEC) of cisplatin is a popular treatment for advanced ovarian cancer, typically under hyperthermia (HIPEC). The use of cisplatin under (H)IPEC is off-label, and the role of hyperthermia is unknown. The aim of this study was to characterize the pharmacokinetic/pharmacodynamic (PKPD) properties of cisplatin under (H)IPEC and to predict the optimal treatment regimen. Using a randomized design, data on intact cisplatin perfusate and plasma concentrations, leukocyte counts—a hematotoxicity marker—and serum creatinine—a nephrotoxicity marker—were collected from 50 patients treated with a combination of cytoreductive surgery (CRS) and either normothermic or hyperthermic IPEC of cisplatin dosed at 75, 100, and 120 mg/m2. The non-linear mixed effects modeling technique was used to construct the PKPD models. The PK of intact cisplatin was characterized by a two-compartment model. A semi-physiological myelosuppression model for the leukopenia was modified to account for the CRS-induced leukocytosis and the residual myelosuppression effect of neoadjuvant chemotherapy. The incidence and severity of nephrotoxicity were described by a discrete-time Markov model. Hyperthermia increased the absorption rate of cisplatin by 16.3% but did not show a clinically relevant impact on the investigated toxicities compared with normothermia. Leukopenia was not severe, but nephrotoxicity can become severe or life-threatening and was affected by the dose and IPEC duration. The model predicted that nephrotoxicity is minimal at a cisplatin dose of 75 mg/m2 with an IPEC duration of 1–2 h and an 1-h duration is favored for doses between 100 and 120 mg/m2. [Figure not available: see fulltext.].

Original languageEnglish
Article number96
Number of pages12
JournalAaps journal
Volume22
Issue number5
DOIs
Publication statusPublished - 24-Jul-2020

Keywords

  • cisplatin
  • HIPEC
  • ovarian cancer
  • PKPD
  • NONMEM
  • POPULATION PHARMACOKINETICS
  • CYTOREDUCTIVE SURGERY
  • UNCHANGED CISPLATIN
  • PLATINUM
  • NEPHROTOXICITY
  • HYPERTHERMIA
  • PHARMACODYNAMICS
  • MYELOSUPPRESSION
  • CHEMOPERFUSION
  • CARBOPLATIN

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