Impact of obesity on doxorubicin pharmacokinetics in women with breast cancer

Abstract

Introduction

Experts suggest doxorubicin clearance is decreased in women with a body mass index (BMI) of ≥35 kg/m². However, few data support this recommendation.

Methods

Women receiving doxorubicin for breast cancer in three BMI groups were recruited (n = 15). Doxorubicin dosing was determined by body surface area and was administered by 30-min intravenous infusion. Blood samples were obtained at 0 h (pre-dose) and 0.5, 1, 1.5, 2, 3, 4, 5, 12–24, and 24–72 h following the beginning of infusion. Concentrations of doxorubicin and its metabolite, doxorubicinol, were assayed by LC-MS/MS. Non-compartment analysis was done using PKanalix2021R2 for pharmacokinetic (PK) analyses.

Results

The median [range] BMI and age were 30.3 [23.5–57] kg/m² and 53 [31–69] years. Thirteen of the 15 women had samples available for analysis. Four of the 13 had a BMI ≥ 35.0 kg/m². PK parameters ranged from 37.8% (AUC_0−inf) to 91.0% (Vd). Doxorubicinol PK parameters ranged from 37.8% (C_max) to 67.6% (AUC_0−inf). The average doxorubicinol:doxorubicin AUC_lasts ratio was 0.26 (range: 0.04–0.88). A t-test didn’t suggest a significant difference in individual PK parameters (BMI < 35 kg/m² vs. ≥35.0 kg/m²). The two highest clearances (380 L/h and 250 L/h) had a BMI ≥ 35.0 kg/m²; also, the highest clearance (1114 L/h) for doxorubicinol was ≥35.0 kg/m².

Conclusions

Large interindividual variabilities in doxorubicin PK were observed in women up to a BMI of 57 kg/m² and a total body weight of 141.5 kg. Women with a BMI ≥ 35.0 kg/m² and breast cancer did not appear to have lower clearances of doxorubicin.

ClinicalTrials.gov ID

NCT01537029.