PKPD Modeling and Dosing Considerations in Advanced Ovarian Cancer Patients Treated with Cisplatin-Based Intraoperative
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Research Article PKPD Modeling and Dosing Considerations in Advanced Ovarian Cancer Patients Treated with Cisplatin-Based Intraoperative Intraperitoneal Chemotherapy Feifan Xie,1,2,10 Jan Van Bocxlaer,2 Pieter Colin,2,3 Charlotte Carlier,4,5 Olivier Van Kerschaver,6 Joseph Weerts,7 Hannelore Denys,5,8 Philippe Tummers,9 Wouter Willaert,4 Wim Ceelen,4,5 and An Vermeulen2
Received 11 June 2020; accepted 16 July 2020 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. KEY WORDS: cisplatin; HIPEC; ovarian cancer; PKPD; NONMEM.
INTRODUCTION Ovarian cancer ranks eighth in cancer deaths among women and is the deadliest gynecologic cancer (1). More than two-thirds of the patients receive a diagnosis of advanced
Electronic supplementary material The online version of this article (https://doi.org/10.1208/s12248-020-00489-2) contains supplementary material, which is available to authorized users. 1
Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Tongzipo Road 172, Changsha, 410013, China. 2 Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium. 3 Department of Anesthesiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
FIGO (International Federation of Gynecology and Obst
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