Hauke Rühs, Susanna Hausmann, Anne Drescher, Ulrich Jaehde
Department of Clinical Pharmacy, University of Bonn, Germany
Objectives: Oxaliplatin is rapidly transformed after infusion and binds irreversibly to plasma proteins, erythrocytes and DNA, where long half-lives of platinum have been observed.Erythrocytes are loaded with large amounts of platinum. Moreover, DNA adduct levels showed a characteristic time course and may serve as pharmacodynamic (PD) endpoint in clinical trials [1]. The aim of this investigation was to build a model describing the platinum concentration-time profiles in plasma, ultrafiltrated plasma, erythrocytes and leukocyte DNA simultaneously and explain the influence of covariates on the PK/PD of oxaliplatin.
Methods: Platinum concentrations were measured in ultrafiltrate and plasma using a validated flameless atomic absorption spectrometry method. Oxaliplatin-DNA adduct levels were measured using adsorptive stripping voltammetry. Concentration-time profiles were available from 56 cancer patients with different regimes and sampling strategies [1,2]. The model was built using NONMEM® 7.1.2. The forward inclusion, backward deletion procedure was applied to identify covariates.
Results: The unbound platinum, represented by the ultrafiltrated fraction, was best described by a two-compartment model. Protein-bound, intra-erythrocyte platinum and DNA platination were described by one compartment each, linked by first-order kinetics to the central compartment of the unbound fraction. Creatinine clearance was identified as a covariate for the elimination rate from the central unbound compartment.
Conclusions: Our PK/PD model simultaneously describes concentration-time courses of platinum in whole blood, plasma, ultrafiltrate as well as DNA-adduct formation after oxaliplatin administration and can be used for simulations.
References:
[1] Pieck et al. Br. J. Cancer 2008, 98(12):1959-65.
[2] Junker et al. Int. J. Clin. Pharmacol. Ther. 2002, 40(12):569-70.
Reference: PAGE 21 () Abstr 2385 [www.page-meeting.org/?abstract=2385]
Poster: Oncology