Population PKPD of paclitaxel and carboplatin in ovarian cancer patients: A study by the EORTC-PAMM-NDDG

2529 Background: Paclitaxel (P) and carboplatin (C) are considered standard first-line treatment in advanced ovarian cancer following cytoreductive surgery. Threshold-models have been used to predict P PKPD, whereas the time above P plasma concentration of 0.05- 0.2 μmol/L (P tC>0.05–0.2) predicts neutropenia. The objectives of this study was to build a population PKPD-model of PC in ovarian cancer patients. Methods: 139 ovarian cancer patients received P 175 mg/m2 over three hours followed by C AUC 5 over 30 min. Plasma concentration-time data of PC were measured, and data processed using nonlinear mixed-effect modelling. Semiphysiological models with linear or sigmoidal maximum response, and threshold models were adapted to the data. Results: 105 patients had complete PK 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. Mean P tC>0.05 was 61.4 hrs. P tC>0.05 was significantly higher in patients with a complete (91.8 hrs) or partial response (76.3 hrs) compared to patients with progressive disease (31.5 hrs) (p=0.02 and 0.05, respectively). Patients with P tC>0.05 > 61.4 hrs had a longer time to disease- progression compared to patients with P tC>0.05 < 61.4 hours (89.0 vs 61.9 weeks, p=0.05). P tC>0.05 was a good predictor for severe neutropenia (p=0.01), while carboplatin exposure (Cmax and AUC) was the best predictor for thrombocytopenia (p<10-4). Conclusions: In this group of patients, P tC>0.05 is a good predictive marker for severe neutropenia and clinical outcome, while C exposure is a good predictive marker for thrombocytopenia. (Biomed grant PL96–2333, JHM Schellens coordinator) No significant financial relationships to disclose.