Population Pharmacokinetics and Pharmacodynamics of Paclitaxel and Carboplatin in Ovarian Cancer Patients: A Study by the European Organization for Research and Treatment of Cancer-Pharmacology and Molecular Mechanisms Group and New Drug Development Group

Abstract

Purpose: Paclitaxel and carboplatin are frequently used in advanced ovarian cancer following cytoreductive surgery. Threshold models have been used to predict paclitaxel pharmacokineticpharmacodynamics, whereas the time above paclitaxel plasma concentration of 0.05 to 0.2 Amol/L (t C > 0.05-0.2 ) predicts neutropenia.The objective of this study was to build a population pharmacokinetic-pharmacodynamic model of paclitaxel/carboplatin in ovarian cancer patients. Experimental Design: One hundred thirty-nine ovarian cancer patients received paclitaxel (175 mg/m 2 ) over 3 h followed by carboplatin area under the concentration-time curve 5 mg/mL*min over 30 min. Plasma concentration-time data were measured, and data were processed using nonlinear mixed-effect modeling. Semiphysiologic models with linear or sigmoidal maximum response and threshold models were adapted to the data. Results: One hundred five patients had complete pharmacokinetic and toxicity data. In 34 patients with measurable disease, objective response rate was 76%. Neutrophil and thrombocyte counts were adequately described by an inhibitory linear response model. Paclitaxel t C > 0.05 was significantly higher in patients with a complete (91.8 h) or partial (76.3 h) response compared with patients with progressive disease (31.5 h; P = 0.02 and 0.05, respectively).Patients with paclitaxel t C > 0.05 > 61.4 h (mean value) had a longer time to disease progression compared with patients with paclitaxel t C > 0.05 < 61.4 h (89.0 versus 61.9 weeks; P = 0.05).Paclitaxel t C > 0.05 was a good predictor for severe neutropenia (P = 0.01), whereas carboplatin exposure (C max and area under the concentration-time curve) was the best predictor for thrombocytopenia (P < 10 -4 ). Conclusions: In this group of patients, paclitaxel t C > 0.05 is a good predictive marker for severe neutropenia and clinical outcome, whereas carboplatin exposure is a good predictive marker for thrombocytopenia.

Pharmacokinetically based dosing of weekly paclitaxel to reduce drug-related neurotoxicity based on a single sample strategy

“…This can be explained due to missing concentration-time data at the beginning of the paclitaxel infusion. Paclitaxel maximum elimination capacity (VM EL ) and plasma concentration at half VM EL (KM EL ) were lower for the weekly regimen compared to the 3-weekly regimen (14.5 vs 29.6 µmol/h and 0.174 vs 3.12 µmol/L, respectively) [24]. For VM EL , this may be due to the elimination pathway not being saturated to full capacity with the lower weekly dose of paclitaxel.…”

“…Therefore, the predictive performance of the limited sampling model might be worse, when using real patient data. The strengths of this study include the availability of a population model that had been validated in several patient populations [24,25,30] and the integration of PK and (neuro)-toxicity data into an integrated PK-PD model. Therefore, our findings could result in a clinically relevant reduction of paclitaxel-associated CIPN, further supporting the use of weekly paclitaxel treatment regimens, which usually are preferred by patients and physicians due to its relative ease of administration, convenient monitoring and favorable clinical activity [1-6, 13, 14].…”

“…(2) the range of the central target category should include at least the residual (unexplained) PK variability to the upside and downside (roughly 2 h each); and (3) The smallest dose adaptation should be in the approximate range of residual (unexplained) PK variability, i.e., between 15 and 20 % for paclitaxel [18,24,25]. With respect to point 3, we have chosen 15 % based on the experience with the 3-weekly paclitaxel dosing algorithm [18] and the fact that repeated up-and down-dosing should be avoided.…”

Paclitaxel-carboplatin chemotherapy induced hematologic toxicities among epithelial ovarian cancer patients

“…(16) Carboplatin used in this regimen has a myelosuppressive effect via the mechanism of DNA-protein damage in bone marrow by means of crosslinking between them, thus resulting in decreased numbers of erythrocytes, leukocytes, and platelets, as well as other toxic effects (neurotoxicity, ototoxicity, and nephrotoxicity). (17,18) It also seems that carboplatin may increase serum TNF-α, suppressing the development of hematologic progenitor cells. (19) Currently, genetic polymorphisms are being investigated to determine their association with paclitaxel-carboplatin hematologic toxicity, depending on race and ethnicity.…”

PKPD and Disease Modeling: Concepts and Applications to Oncology

“…Joerger et al have developed a population pharmacokinetics and pharmacodynamics for the prediction of neutropenia and thrombocytopenia induced by paclitaxel and carboplatin. They have shown that in this group of patients, paclitaxel concentrations greater than 0.05 mmol/L is a good predictive marker for severe neutropenia and clinical outcome, whereas carboplatin exposure is a good predictive marker for thrombocytopenia (Joerger et al 2007a).…”