PK-PD model compared with K-PD model to predict haematotoxicity induced by anticancer drugs.
Diane Testart(1), Pascal GIRARD(1,4), Jean-Pierre Droz(2), Emilie Henin(1), Claude Ardiet(2), Sylvie Zanetta(3), Brigitte Tranchand(1,2)
(1) EA 3738, Faculty of Medecine Lyon-Sud , Oullins, France; (2) Centre Léon-Bérard, Lyon, France; (3) Centre GF Leclerc, Dijon, France ; (4) INSERM
Introduction: Pharmacokinetic-pharmacodynamic (PK-PD) models are available to predict haematological toxicity induced by anticancer chemotherapy, but they need pharmacokinetic knowledge. The aim of this work is to determine the feasibility of predicting haematological toxicity and to adapt dosage without pharmacokinetic information. This would be valuable in clinical practice.
Patients and methods: 28 patients treated for solid tumour received from 1 to 9 cycles of chemotherapy. Each cycle consists of a 15-min infusion of 40 mg/ m2 of methotrexate (MTX) on day 1, and on day 8 of a 15-min infusion of 40 mg/m2 of MTX followed by a 1-h infusion of docetaxel (TXT) given using a dose escalation scheme: TXT doses ranged from 60 and 100 mg/ m2. Population pharmacokinetic was studied for both drugs on cycle 1 and 3, at days 1 and 8. HPLC was used to determine drug levels of both drugs. Blood counts were followed during the overall courses for PD analysis. The time course of blood counts could be analysed using a K-PD model based on an adapted indirect response model without drug concentrations (Jacqmin et al 2001). The performance of the K-PD model was compared with the classical approach using PK-PD model. Data analyses were performed using NONMEM version V.
Results: 22 patients out of 28 could be followed for pharmacokinetic determination of MTX and TXT (72 administrations of MTX and 38 of TXT). For both drugs, a 3-compartment model described adequately the data. No influence of TXT on MTX pharmacokinetic was showed (t-test, p<0.05). Creatinine clearance and body surface area improved the model for MTX, and AAG and proteinemia improved the model for TXT. AUC of TXT grew regularly from 60 to 80 mg/m², and then no further increase with doses was observed. The only significant PK-PD relationship was found between the AUC of MTX and blood counts nadir including all courses. Regarding the K-PD model, the best fit was obtained with a sigmoid Emax equation, and is in accordance with the PK-PD model.
Conclusion: In conclusion, we have shown that this mechanism-based approach allows an accurate prediction of the haematological toxicity after cancer chemotherapy. Validation of the model has to be performed in a prospective study.