Population pharmacokinetic of doxorubicin and doxorubicinol in hematological patients
JS Pérez-Blanco (1,2), MJ García Sánchez (1,2), MM Fernández de Gatta (1,2), JM Hernández-Rivas (2,3), D Santos Buelga (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, (3) Hematology Service, University Hospital of Salamanca and IBMCC, Cancer Research Center, Salamanca, Spain
Objective: To develop a population pharmacokinetic (PK) model for doxorubicin (DX) and doxorubicinol (DXol) in hematological patients.
Methods: The study has been conducted in 29 patients diagnosed of hematological malignancies and treated with 30 min intravenous infusion (25-71 mg/m2 range doses) of DX included in different treatment schedules. From 80 plasma samples, DX and DXol concentrations were measured and fitted to a PK model using non-linear mixed-effects modeling implemented in NONMEM V7.2 (FOCEI). The analyzed covariates were: age, gender, weight, height, BSA, LBM, BMI, AST, ALT, creatinine, serum albumin, bilirubin and hemoglobin. A preliminary screening of covariates with influence on PK parameters, using GAM implemented in Xpose4 (R v.3.0.3), was conducted. S-Plus applications were used to represent the goodness of fit plot of the tested models. The stepwise covariate procedure was applied to select those ones in the final model. The evaluation of the model, using non-parametric bootstrap, was performed with the PSN program.
Results: A four compartment model, two for DX and the other two for DXol[1], both showing linear elimination, has been selected as the best structural model. The values of the distribution volumes to the different compartments were initially fixed to those proposed by Wilde et al[2]. In the final model only LBM was included on the CLDX which explained a 10% of its variability[3]. The relative standard error for all fixed effect parameters was lower than 20%. Residual variabilities for DX and DXol, estimated from a proportional error model, were 15% (shr = 41%) and 42% (shr = 15%), respectively.
Gender, age, hemoglobin levels and ALT showed in the preliminary analysis some influence on the CLDX, but they did not fulfill statistical criteria to be included in the final model. A larger set of data should be considered to evaluate the possible contribution of these covariates on the variability of this parameter. The proposed model showed a reasonable suitability to describe the evolution of the plasma concentrations of DX and DXol in hematological patients.
Conclusions: A suitable population PK model of DX and DXol in hematological patients has been developed. Although the model only included LBM on CLDX, additional studies with a larger set of data should be performed to know if the other covariates selected in the preliminary analysis might be included in a future PK model.
References:
[1] Jacquet JM, Bressolle F, Galtier M, Bourrier M, Donadio D, Jourdan J, et al. Doxorubicin and doxorubicinol: intra- and inter-individual variations of pharmacokinetic parameters. Cancer Chemoth Pharm (1990) 27(3): 219–225
[2] Wilde S, Jetter A, Rietbrock S, Kasel D, Engert A, Josting A, et al. Population pharmacokinetics of the BEACOPP polychemotherapy regimen in Hodgkin's lymphoma and its effect on myelotoxicity. Clin Pharmacokinet (2007) 46(4): 319–333
[3] Rudek MA, Sparreboom A, Garrett-Mayer ES, Armstrong DK, Wolff AC, Verweij J, et al. Factors affecting pharmacokinetic variability following doxorubicin and docetaxel-based therapy. Eur J Cancer (2004) 40(8): 1170–1178
