Development of a PBPK model of doxorubicin
Anna Pieper(1), Georg Hempel(1), Joachim Boos(2)
(1) Department of Pharmaceutical and Medical Chemistry - Clinical Pharmacy, University of Münster, (2)Department of Paediatric Haematology and Oncology, University Children’s Hospital Muenster, Germany
Objectives: The anthracycline antibiotic doxorubicin (DOX) is one of the most potent cytostatic agents and is used in both solid tumors and leukemia. Although DOX was developed in the 1960's its mechanism of action and its metabolism are not known in detail. The only partially active metabolite results from enzymatic degradation via an Aldo-keto reductase (AKR) and a Carbonylreductase. In addition, inactive 7-deoxy-aglyca are formed via biotransformation by a glycosidase (G). The aim of this work is to asses if the pharmacokinetics of DOX in children can be predicted from a PBPK model developed using data from adults. First of all, a PBPK model for adults has to be developed and it has to be transferred to children in the next step.
Methods: By entering several parameters of DOX pharmacokinetics such as Km or Vmax for drug transporters into PK-Sim®, simulations were computed and compared to data from a study from Callies et al. [1]. Our model implicates an AKR, a G and biliary transport in liver, an AKR, a G and active secretion in kidney, a G in heart, gut transport in small intestine and solute like carriers for liver, gonads, bone, and kidney [2, 3, 4]. The known rapid distribution into blood cells is also considered in the model. Data from 29 individuals could be used. Individual body surface area, but only the mean weight, height and age were available. Therefore, we estimated weight and height by using a nomogram.
Results: The simulation in PK-Sim® showed a mean doxorubicin clearance of 86.1 l/h (SD ± 12.7 l/h) for a female population vs. 62.3 ± 20.5 % in the study from Callies et al.. Thus, doxorubicin clearance is 19 % higher than the clearance reported in the study. In 25 patients, clearance resulting from PK-Sim® was higher than those calculated by Callies et al..
Conclusions: To evaluate the influence of age and gender further investigations will be necessary and the comparison with data from other studies is essential. Furthermore it is important to show if a less complex model could come to the same results. The transferability of this model to the younger population has to be proved in future studies as well.
Supported by Bayer Technologies
References:
[1] Callies S. et al. - A population pharmacokinetic model for doxorubicin and doxorubicinol in the presence of a novel MDR modulator, zosuquidar trihydrochloride (LY335979); Cancer Chemother Pharmacol 2003; 51: 107-118
[2] Jacobsson J. A. et al. - Identification of six putative human transporters with structural similarity to the drug transporter SLC22 family; Genomics 90 (2007) 595-609
[3] Guastafson D. L.et al.- Doxorubicin Pharmacokinetics: Macromolecule Binding, Metabolism, and Excretion in the Context of a Physiologic Model; Journal of Pharmaceutical Sciences, Vol. 91, 1488-1501 (2002)
[4] Loveless H. et al. - Comparative Mammalian Metabolism of Adriamycin and Daunorubicin; Cancer Res. 1978; 38:593-598
