Feifan Xie (1), Charlotte Carlier (2), Wim Ceelen (2,3), Jan Van Bocxlaer (1), An Vermeulen (1), and Pieter Colin (1,4)
(1) Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium, (2) Laboratory of Experimental Surgery, Department of Surgery, Ghent University, B-9000 Ghent, Belgium, (3) Cancer Research Institute Ghent, Ghent University, Belgium, (4) Department of Anesthesiology, University Medical Center Groningen, University of Groningen, The Netherlands
Objectives: One of the well-known side effects of cisplatin, a chemotherapeutic agent used since the 1970s, is haematological toxicity[1]. However, little is known on the quantitative relationship between the pharmacokinetics and the haematological toxicity. The goal of this study is to develop a pharmacokinetic-pharmacodynamic (PKPD) model that explains the time course of leukocytes in stage III ovarian cancer patients. Ideally, this model should account for the residual myelosuppressive effects of prior doses of neo-adjuvant systemic chemotherapy (carboplatin and paclitaxel), the transient leucocytosis induced by cytoreductive surgery (CRS), and the myelosuppressive effect of cisplatin-based intraperitoneal chemoperfusion.
Methods: In a randomized design, 24 patients received CRS followed by a normothermic (37°C) or hyperthermic (41°C) intraperitoneal chemoperfusion ((H)IPEC) with a cisplatin dose of 75 or 120 mg/m2. 19 out of 24 patients had extensive tumor dissemination and received 3-4 courses of systemic carboplatin and paclitaxel based neo-adjuvant chemotherapy before CRS and (H)IPEC. A minimal waiting period of at least 1.5 weeks was respected between the last dose of neo-adjuvant chemotherapy and the date of CRS and (H)IPEC. Peritoneal perfusate (n=70; range: 2–3 per patient) and venous blood samples (n=144; range: 5–8 per patient) were collected up to 1.5 h and 24 h respectively after the start of 90 min cisplatin-based (H)IPEC. The intact cisplatin was measured using a validated UHPLC-MS/MS method[2]. Leukocytes (n=236; range: 5–15 per patient) were measured before CRS and up to 14 days post (H)IPEC. The data were analysed using the first-order conditional estimation (FOCE) method with interaction implemented in NONMEM®(version 7.3; Icon Development Solutions, Hanover, MD, USA). A sequential approach was followed where first a population pharmacokinetic model was constructed for intact cisplatin. Subsequently, the resulting individual predicted concentrations were used as a driving force for the leukocyte counts.
Results: A two-compartment model with first-order absorption and elimination was shown to adequately describe intact cisplatin pharmacokinetics. The PKPD model was based on a previously described semi-physiological chemotherapy-induced myelosuppression model[3]. The reported myelosuppression model was extended by adding a deposit compartment representing the stored mature leukocytes within the bone marrow sinusoids. A linear cisplatin concentration-effect on the proliferation rate of the leukocytes best described their counts. A feedback loop on the proliferation from the circulating leukocytes was incorporated in order to describe the rebound of leukocytes compared with the baseline value. CRS was assumed to initialize the mobilization of leukocytes from the deposit compartment to the circulating compartment[4] and increased the mitosis rate of proliferative cells[5]. The mobilization of leukocytes was modelled as a first-order release from the estimated initial amount of cells in the deposit compartment. The CRS effect on the proliferation rate was modelled by a stimulatory function resulting from the surgery and exponentially declining over time. The residual myelosuppressive effect of the neo-adjuvant chemotherapy was added to ascertain a physiologically reasonable model prediction of baseline leukocyte counts once all treatment effects had worn out. Diagnostic plots and visual predictive checks demonstrated a good agreement of model predictions with the observed data. The model also allows for reasonable extrapolations outside the range of data measured.
Conclusions: A leukocyte model was developed to simultaneously account for the residual myelosuppressive effect of neo-adjuvant chemotherapy, the transient leucocytosis response induced by CRS, and the myelosuppressive effect of cisplatin-based (H)IPEC. The PKPD model demonstrates that leucocytosis and leucopenia were reversible and short-lasting following CRS and cisplatin based (H)IPEC. In the absence of other cisplatin-induced side effects, higher cisplatin (H)IPEC doses could be considered without significantly raising the risk of major haematological toxicities.
References:
[1] R.Y. Tsang, T. Al-Fayea, H.-J. Au, Cisplatin overdose, Drug safety 32(12) (2009) 1109-1122.
[2] F. Xie, P. Colin, J. Van Bocxlaer, Zwitterionic hydrophilic interaction liquid chromatography-tandem mass spectrometry with HybridSPE-precipitation for the determination of intact cisplatin in human plasma, Talanta 174 (2017) 171-178.
[3] L.E. Friberg, A. Henningsson, H. Maas, L. Nguyen, M.O. Karlsson, Model of chemotherapy-induced myelosuppression with parameter consistency across drugs, J Clin Oncol 20(24) (2002) 4713-21.
[4] C. Summers, S.M. Rankin, A.M. Condliffe, N. Singh, A.M. Peters, E.R. Chilvers, Neutrophil kinetics in health and disease, Trends in immunology 31(8) (2010) 318-324.
[5] C. Pérez-Ruixo, B. Valenzuela, J.E. Peris, P. Bretcha-Boix, V. Escudero-Ortiz, J. Farré-Alegre, J.J. Pérez-Ruixo, Neutrophil dynamics in peritoneal carcinomatosis patients treated with cytoreductive surgery and hyperthermic intraperitoneal oxaliplatin, Clinical Pharmacokinetics 52(12) (2013) 1111-1125.
Reference: PAGE 27 (2018) Abstr 8421 [www.page-meeting.org/?abstract=8421]
Poster: Drug/Disease Modelling - Oncology