2014 - Alicante - Spain

PAGE 2014: Drug/Disease modeling - Absorption & PBPK
María José García Sánchez

PBPK analysis of doxorrubicin tissue uptake by Simcyp® simulator: influence of gender related variables

MJ García Sánchez (1,2), JS Pérez-Blanco (1,2), MJ de Jesús Valle (1,2), A Sánchez Navarro (1,2).

(1) Department of Pharmacy and Pharmaceutical Technology, University of Salamanca, Salamanca, Spain, (2) Salamanca Institute for Biomedical Research (IBSAL), University Hospital of Salamanca, Salamanca, Spain.

Objectives: to evaluate the influence of gender related biological differences on pharmacokinetics (PK) and tissue uptake of doxorubicin (DX) using the physiological based PK model implemented in Simcyp® simulator.

Methods: literature information about physicochemical characteristics [1] and PK parameters of DX was collected in order to include this drug as a new compound of Simcyp®. Simulation of plasma and tissue profiles of DX was performed selecting the full PBPK model. Virtual assays were performed in 100 healthy volunteers fixing the gender to 100 % and 0 % females, respectively [1]. A standard intravenous dosage of 50 mg/m2 perfused for fixed 15, 30 and 60 min was simulated and comparison of plasma and tissues profiles for both sex was performed.

Results: literature review of drug PK data reveal that information on tissue uptake and partition coefficient (R) values are very scarce, although all studies agree on DNA relevance and extremely high R values for all tissues, being kidney the one reaching the highest value [3]. Simulated profiles in plasma reveal narrow confidence intervals in the female population compared to male population due to a wider dispersion of heights values into the male population considered in Simcyp®. This fact leads to relevant differences in perfusion rates among individual showing extreme height values when drug is administered at a fixed perfusion time. Interesting differences were also found when comparing heart tissues profiles between males and females. Despite the higher cardiac output in males compared to females the total blood flow to heart tissue is lower; accordingly the simulated curves in this tissue show that the maximum concentrations reached are about 30 % higher in the female population than those reached in males.

Conclusions: results from PBPK model applied to DX using Simcyp® simulator reveals that gender related differences affect doxorubicin PK in adult population, with higher values of maximum concentrations in heart tissue predicted for woman than those predicted for men. This fact could be of clinical relevance taking in account the high cardiotoxicity of DX.

Acknowledgements: this work is part of a project (BIO/SA88/13 ) founded by the Consejeria de Salud y Bienestar Social de la Junta de Castilla y León.



References:
[1] DrugBank [Internet], available from: www.drugbank.ca, accessed 03/04/14.
[2] Boecker BB. Reference values for basic human anatomical and physiological characteristics for use in radiation protection. Radiat Prot Dosim (2003) 105(1-4): 571-574.
[3] Terasaki T, Iga T, Sugiyama Y and Hanano M. Pharmacokinetic study on the mechanism of tissue distribution of doxorubicin: Interorgan and interspecies variation of tissue-to-plasma partition coefficients in rats, rabbits and guinea pigs. J Pharm Sci (1984) 73(10): 1359-1363.


Reference: PAGE 23 (2014) Abstr 3297 [www.page-meeting.org/?abstract=3297]
Poster: Drug/Disease modeling - Absorption & PBPK
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