Population pharmacokinetics of doxorubicin and doxorubicinol in patients diagnosed with non-Hodgkin's lymphoma.

Abstract

The aims of the study were: (i) to characterize the pharmacokinetics (PK) of doxorubicin (DOX) and doxorubicinol (DOXol) in patients diagnosed with non-Hodgkin's lymphoma (NHL) using a population approach; (ii) to evaluate the influence of various covariates on the PK of DOX; and (iii) to evaluate the role of DOX and DOXol exposure in haematological toxicity. Population PK modelling (using NONMEM) was performed using DOX and DOXol plasma concentration-time data from 45 NHL patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). The influence of drug exposure on haematological toxicity was analysed using the Mann-Whitney-Wilcoxon test. A five-compartment model, three for DOX and two for DOXol, with first-order distribution and elimination for both entities best described the data. Population estimates for parent drug (CL) and metabolite (CLm ) clearance were 62lh-1 and 27lh-1 , respectively. The fraction metabolized to DOXol (Fm ) was estimated at 0.22. While bilirubin and aspartate aminotransferase showed an influence on the CL and CLm , the objective function value decrease was not statistically significant. A trend towards an association between the total area under the concentration-time curve (AUCtotal ), the area under the concentration-time curve for DOX (AUC) plus the area under the concentration-time curve for DOXol (AUCm ), and the neutropenia grade (P = 0.068) and the neutrophil counts (P = 0.089) was observed, according to an exponential relationship. The PK of DOX and DOXol were well characterized by the model developed, which could be used as a helpful tool to optimize the dosage of this drug. The results suggest that the main active metabolite of DOX, DOXol, is involved in the haematological toxicity of the parent drug.