2010 - Berlin - Germany

PAGE 2010: Applications- Oncology
Anne Keunecke

Pharmacokinetic/Pharmacodynamic Modeling of Platinum-DNA-Adduct Formation in Leukocytes after Oxaliplatin Infusion

Anne Drescher (1,2), Andreas Lindauer (1), Anne Christin Pieck (1), GŁnther Weber (3), Ralf A. Hilger (4), Dirk Strumberg (5), Max E. Scheulen (4), Ulrich Jaehde (1)

(1) Dept. of Clinical Pharmacy, Rheinische Friedrich-Wilhelms-Universitšt Bonn, Bonn, Germany, (2) Dept. of Clinical Pharmacy, Martin-Luther-Universitšt Halle-Wittenberg, Halle, Germany; (3) Leibniz-Institute of Analytical Sciences Ė ISAS, Dortmund, Germany, (4) West German Cancer Center, University Hospital Essen, Germany, (5) Marienhospital Herne, University Hospital Bochum

Objectives: The cytotoxic efficacy of platinum (Pt) complexes relies on their ability to bind to DNA, what in turn leads up to apoptosis [1]. Furthermore the unbound fraction of the Pt complexes is understood to be the active species [2]. The primary aim of this study was to describe the possible relationships between Pt pharmacokinetics and Pt-DNA adduct formation in leucocytes (WBC) in patients with solid tumours after administration of oxaliplatin.

Methods: Oxaliplatin was administered as a two hour infusion with doses of 50 mg/m≤ and 130 mg/m≤. Blood samples were drawn within the first two cycles of treatment. A total of 982 concentrations of ultrafiltrable Pt from 59 patients were measured using a validated GF-AAS method. Furthermore, Pt-DNA adducts were measured in 245 leukocyte samples from 37 patients by absorptive voltammetry. A sequential population PK/PD analysis was performed using NONMEM 6.2. Possible differences in the area under the adduct curve (AUA) between responders and non-responders were investigated by using the Mann-Whitney U-test. To proof selectivity and sensitivity of the chosen test scenario, a receiver-operating-characteristic (ROC) was generated.

Results: The PK of Pt in ultrafiltrated plasma after i.v. administration of oxaliplatin could be adequately described with a two-compartment model and resulted in parameter estimates similar to published data [1,2]. The significant covariate relationship of creatinine clearance to total Pt clearance only explained 6.7 % of inter-subject variability The relationship between the unbound platinum to platinum-DNA-adduct formation could be best described by a receptor-binding model. A former platinum-containing chemotherapy was found to be a significant covariate on the baseline Pt-DNA adduct. Using the model-predicted AUA a significant difference (p < 0.01) between responders and non-responders was found. Responders showed approximately three fold higher AUA values than non-responder.

Conclusions: Time course of the DNA platination could be successfully described with the developed PK/PD model. Exposure to oxaliplatin is, through DNA-adduct formation, the major determinant of tumour response in this population. Hence these results may contribute to therapy individualization and optimization with the aim to improve tumour response and reduce toxicity.

[1] Saris CP, van de Vaart PJM, Rietbroek RC, et al. Carcinogenesis 1996; 17(12): 2763-2769.
[2] Graham MA, Lockwood GF, Greenslade D, et al. Clin Cancer Res 2000; 6(4): 1205-1218.
[3] Bastian G, Barrail A, Urien S. Anticancer Drugs 2003; 14(10): 817-824.

Reference: PAGE 19 (2010) Abstr 1848 [www.page-meeting.org/?abstract=1848]
Poster: Applications- Oncology