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Population pharmacokinetics of doxorubicin and doxorubicinol in patients diagnosed with non-Hodgkin's lymphoma.
- Source :
-
British journal of clinical pharmacology [Br J Clin Pharmacol] 2016 Dec; Vol. 82 (6), pp. 1517-1527. Date of Electronic Publication: 2016 Sep 06. - Publication Year :
- 2016
-
Abstract
- 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.<br />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.<br />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 <subscript>m</subscript> ) clearance were 62 l h <superscript>-1</superscript> and 27 l h <superscript>-1</superscript> , respectively. The fraction metabolized to DOXol (F <subscript>m</subscript> ) was estimated at 0.22. While bilirubin and aspartate aminotransferase showed an influence on the CL and CL <subscript>m</subscript> , the objective function value decrease was not statistically significant. A trend towards an association between the total area under the concentration-time curve (AUC <subscript>total</subscript> ), the area under the concentration-time curve for DOX (AUC) plus the area under the concentration-time curve for DOXol (AUC <subscript>m</subscript> ), and the neutropenia grade (P = 0.068) and the neutrophil counts (P = 0.089) was observed, according to an exponential relationship.<br />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.<br /> (© 2016 The British Pharmacological Society.)
- Subjects :
- Antibiotics, Antineoplastic adverse effects
Antibiotics, Antineoplastic blood
Antibiotics, Antineoplastic therapeutic use
Area Under Curve
Clinical Trials, Phase II as Topic
Dose-Response Relationship, Drug
Doxorubicin adverse effects
Doxorubicin blood
Doxorubicin pharmacokinetics
Doxorubicin therapeutic use
Female
Humans
Male
Metabolic Clearance Rate
Randomized Controlled Trials as Topic
Antibiotics, Antineoplastic pharmacokinetics
Doxorubicin analogs & derivatives
Lymphoma, Non-Hodgkin drug therapy
Models, Biological
Subjects
Details
- Language :
- English
- ISSN :
- 1365-2125
- Volume :
- 82
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- British journal of clinical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 27447545
- Full Text :
- https://doi.org/10.1111/bcp.13070