Impact of Class II/III Obesity on Doxorubicin Pharmacokinetics in Women with Breast Cancer
Introduction
Obesity is a common comorbid condition of patients with cancer and may alter drug pharmacokinetics. Few studies have evaluated the pharmacokinetics (PK) of doxorubicin, an anti-cancer agent, in patients with a body mass index (BMI) ≥ 35 kg/m2. This study was performed to address this limitation and determine whether a BMI ≥ 35 kg/m2 is associated with doxorubicin’s pharmacokinetics in women with breast cancer.
Methods
Women with a wide range of BMI receiving doxorubicin and cyclophosphamide as standard of care for breast cancer were consented and recruited into the study at the University of Texas Southwestern (UTSW) Simmons Cancer Center. Doses of doxorubicin were determined with patients’ body surface area (BSA) and the drug was administered by 30-minute IV infusion. Blood samples were obtained at 0 h (pre-dose) and 0.5, 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 to characterize the PK of the drug in the following BMI groups: underweight to class I obesity (BMI < 35 kg/m2), and class II/III obesity (BMI ≥ 35.0 kg/m2). Non-compartment analysis (NCA) was done using PKanalix2021R2 to analyze the PK data.
Results
Fifteen patients with a median [min, max] BMI and age of 30.3 [23.5, 57] kg/m2 and 53 [31, 69] years, respectively, have enrolled. Two patients opted out and PK data from 13 patients were analyzed. Among these 13 patients, 4 of them had a BMI ≥ 35.0 kg/m2. The NCA results show considerable variations in interindividual PK. The coefficients of variation (CV) for doxorubicin PK parameters ranged from 37.8% (for AUC0-inf) to 91.0% (for Vd) and for doxorubicinol PK parameters ranged from 37.8% (for Cmax) to 67.6% (for AUC0-inf). The ratio of the AUClasts for doxorubicinol: doxorubicin averaged 0.26 and ranged from 0.04 to 0.88. Although T-test did not suggest significant difference in individual PK parameters between patients with a BMI < 35 kg/m2 and ≥ 35.0 kg/m2, the top two highest CL among all patients (380 L/h and 250 L/h) were observed in patients whose BMI were ≥ 35.0 kg/m2. One patient with a BMI ≥ 35.0 kg/m2 also had the highest observed CL (1114 L/h) for doxorubicinol.
Conclusion
Large interindividual variabilities in doxorubicin PK were observed. Although the differences in CL of doxorubicin and doxorubicinol were not statistically significant between patients with a BMI < 35 kg/m2 and ≥ 35.0 kg/m2, high CL values were observed in the latter.