Pharmacokinetic and Pharmacodynamic Analysis of Hyperthermic Intraperitoneal Oxaliplatin-Induced Neutropenia in Subjects with Peritoneal Carcinomatosis

Abstract

Abstract. The objective of this study was to characterize the pharmacokinetics and the time course of the neutropenia-induced by hyperthermic intraperitoneal oxaliplatin (HIO) after cytoreductive surgery in cancer patients with peritoneal carcinomatosis. Data from 30 patients who received 360 mg/m 2 of HIO following cytoreductive surgery were used for pharmacokinetic-pharmacodynamic (PK/PD) analysis. The oxaliplatin plasma concentrations were characterized by an open two-compartment pharmacokinetic model after first-order absorption from peritoneum to plasma. An oxaliplatin-sensitive progenitor cell compartment was used to describe the absolute neutrophil counts in blood. The reduction of the proliferation rate of the progenitor cells was modeled by a linear function of the oxaliplatin plasma concentrations. The typical values of oxaliplatin absorption and terminal half-lives were estimated to be 2.2 and 40 h, with moderate interindividual variability. Oxaliplatin reduced the proliferation rate of the progenitor cells by 18.2% per mg/L. No patient's covariates were related to oxaliplatin PK/PD parameters. Bootstrap and visual predictive check evidenced the model was deemed appropriate to describe oxaliplatin pharmacokinetics and the incidence and severity of neutropenia. A peritoneum oxaliplatin exposure of 65 and 120 mg·L/h was associated with a 20% and 33% incidence of neutropenia grade 4. The time course of neutropenia following HIO administration was well described by the semiphysiological PK/PD model. The maximum tolerated peritoneum oxaliplatin exposure is 120 mg L/h and higher exposures should be avoided in future studies. We suggest the prophylactic use of granulocyte colony stimulating factor for patients treated with HIO exposure higher than 65 mg L/h.

Platelet Dynamics in Peritoneal Carcinomatosis Patients Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Oxaliplatin

“…Fortyone (51.2%) patients were treated with CRS followed by HIO diluted in isotonic 4% icodextrin (cohort A), 21 (26.3%) patients underwent CRS followed by HIO diluted in isotonic 5% dextrose (Cohort B), and 18 (22.5%) patients underwent CRS but did not receive HIO (cohort C). The details of the patient's eligibility criteria, CRS procedure, HIO treatment, study conduct, and descriptive statistics of the baseline patient characteristics have been extensively described elsewhere (15,19,26). The oxaliplatin pharmacokinetics following HIO administration have been characterized in patients from cohorts A and B as described elsewhere (15,19,27).…”

A case report of acute pulmonary hypertension after hyperthermic intraperitoneal chemotherapy (HIPEC) and review of the literature

“…Multivisceral surgery accompanied by HIPEC procedure generates a vast field of damaged tissue resulting in barrier disturbances and peritoneal leakage. These effects lead to significant variations of the peritoneal absorption and plasmatic Oxaliplatin concentrations as described in former studies [ [45] , [46] , [47] ]. In the presented case the operative procedure lasted over 10 hours with extensive surgical trauma, which might have led to relevant Oxaliplatin-absorption.…”

Hyperthermic intraperitoneal chemotherapy with oxaliplatin for peritoneal carcinomatosis: a clinical pharmacological perspective on a surgical procedure

“…Oxaliplatin is rapidly absorbed from the peritoneal compartment, with reported mean peritoneal half‐lives (t 1/2 s) of 29 min , 35 min and 40 min , indicating that approximately half of the dose is cleared from the peritoneal compartment during a 30‐min HIPEC procedure. Some studies have report much longer peritoneal t 1/2 s of up to 2.2 h . The rate constant for the absorption of oxaliplatin from the peritoneal perfusate to the plasma is independent of the administered dose and shows low interpatient variability (with a coefficient of variation of 22%) .…”

“…Few studies have investigated the PD of oxaliplatin during HIPEC [34,39,68,69]. These studies use PK/PD models to find associations between PK parameters and PD toxicities of the treatment.…”

“…Considering this, it is important to differentiate between the analytical techniques that are used for the detection of platinum derivatives when interpreting PK data. The majority of PK studies that have used the HIPEC procedure determined the platinum content by flameless atomic absorption spectrometry (AAS) , direct current plasma emission spectroscopy , inductively coupled plasma optical emission spectrometry or inductively coupled plasma mass spectrometry . These analytical techniques measure both the parent drug oxaliplatin and other active and inactive platinum‐containing complexes that are formed as a result of the high reactivity of oxaliplatin in vivo .…”