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Population pharmacokinetics of doxorubicin and doxorubicinol in patients diagnosed with non‐Hodgkin's lymphoma
Author(s) -
PérezBlanco Jonás Samuel,
SantosBuelga Dolores,
Fernández de Gatta María del Mar,
HernándezRivas Jesús María,
Martín Alejandro,
García María José
Publication year - 2016
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.13070
Subject(s) - pharmacokinetics , nonmem , pharmacology , medicine , population , area under the curve , doxorubicin , vincristine , neutropenia , gastroenterology , toxicity , prednisone , cyclophosphamide , chemotherapy , environmental health
Aims 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. Methods 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. Results 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 (CL m ) clearance were 62 l h −1 and 27 l h −1 , respectively. The fraction metabolized to DOXol (F m ) was estimated at 0.22. While bilirubin and aspartate aminotransferase showed an influence on the CL and CL m , the objective function value decrease was not statistically significant. A trend towards an association between the total area under the concentration–time curve (AUC total ), the area under the concentration–time curve for DOX (AUC) plus the area under the concentration–time curve for DOXol (AUC m ), and the neutropenia grade ( P = 0.068) and the neutrophil counts ( P = 0.089) was observed, according to an exponential relationship. Conclusions 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.