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

Abstract

AIMSThe 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. METHODSPopulation 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. RESULTSA 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 À1 and 27 l h À1 , 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. CONCLUSIONSThe 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.

In vitro to Clinical Translation of Combinatorial Effects of Doxorubicin and Abemaciclib in Rb-Positive Triple Negative Breast Cancer: A Systems-Based Pharmacokinetic/Pharmacodynamic Modeling Approach

“…The estimated plasma and inter-compartment clearances for DOX such as: CL, Q2, Q3 (62.4 L/hr, 50.7 L/hr, 28.4 L/hr) as well as the volumes of distribution such as: Vc, Vp2, Vp3 (0.17 L, 1699 L, 121.3 L) are similar to the published parameter estimates obtained using a similar NONMEM approach. 42 Further, VL and k Rel were 3.93 L and 0.013 hr −1 , and are comparable to L_DOX parameters from previously reported values. 9 , 10 , 43 Collectively, the final DOX model parameter estimates are consistent with values from the literature.…”

Evaluation for pharmacokinetic exposure of cytotoxic anticancer drugs in elderly patients receiving (R-)CHOP therapy

“…The Bayesian estimation method provides a simple technique with good performance for estimating AUC of various drugs. Population pharmacokinetic parameters for DXR 21 , 31 and CPA 21 , 32 used in the Bayesian estimation method have already been reported. The plasma concentrations at 9–9.5 h after the start of administration are considered the best single sampling point for estimating AUCs of these cytotoxic anticancer drugs according to this Bayesian estimation method.…”

Prior information for population pharmacokinetic and pharmacokinetic/pharmacodynamic analysis: overview and guidance with a focus on the NONMEM PRIOR subroutine

“…However, implementation of the PRIOR subroutine raises some issues. One article mentioned the PRIOR subroutine but did not retain the prior approach, arguing that the sensitivity to prior information and the assumption of reliability of prior parameterization and structural model may affect the identifiability of the parameters [36].…”