Pharmacokinetics of Doxorubicin In Normal Weight and Obese Lymphoma Patients
Authors: Hoffmann Martin , Bergner Raoul , Stützle Marion , Uppenkamp Michael J. , Foerster Rabea 
Published: October 2019

Abstract
Abstract 4935

Background
Doxorubicin (Dox) is the back bone of chemotherapy in the therapy of several types of carcinomas, lymphomas and acute leukemias. Obese patients (Body Mass Index > 30) have due to their body weight a relatively high Body Surface Area (BSA). Their calculated doxorubicin dose is therefore greater than for patients with normal weight. This could lead to overdosing in case of e.g. a reduced drug clearance. Otherwise a recent study demonstrated a worse outcome in women receiving adjuvant therapy with reduced chemotherapy dose.

Patients and methods
Eligible were patients above the age of 18 years and receiving the first or second cycle of a Doxorubicin-based chemotherapy. Patients were divided due to their BMI in three groups (group 1: BMI < 25; group 2: BMI ≥ 25 and < 30, group 3: BMI ≥ 30).
Dox was administered in a dose of 50 mg/m2 as infusion over 15 minutes. Blood samples were obtained at 0, 0.25, 0.5, 1, 2, 3, 4, 8, 12, 24 hours.
Dox and its metabolite Doxorubicinol were measured by High Performance Liquid Chromatography. Area under the curve (AUC), clearance (Cl), half life (T1/2), and volume of distribution in steady state (Vss) were calculated using a 2-compartment-model for Dox and a non-compartmental-model for Doxorubicinol with PK software (WinNonlin).

Results
31 Patients with untreated indolent or aggressive lymphomas were included in the study. Patients received CHOP-21 or CHOP-14 + G-CSF. 11 were in group 1, 10 in group 2 and 10 in group 3. 18 patients were male and 13 female. The mean age was 66 ± 10 years.
The mean BMI was 27.9 ± 4.9 (group 1: 22.5 ± 2.1 group 2: 28.0 ± 1.4; group 3: 33.9 ± 1.8). Patients received a mean dose of 95.5 mg Dox (87.3 ± 8.1, 99.1 ± 10.2, 100.8 ± 7.5).
We found a significant difference between the groups for the AUC by an analysis of variance. (p=0.014). This was also noticed for the differences between group 1 and 3 (p=0.029) and 2 and 3 (0.042) evaluated by a Scheffe test. The Cl showed no statistically significant difference (p=0.079). The BMI correlated (P=0.046) with the AUC.
The AUC of Doxorubicinol was significantly different between the three groups (p=0.009), as was the clearance (p=0.04). The BMI was correlated with the AUC (p=0.009), the Cl (p=0.003), and T1/2 (p=0.036).
We did not find any correlation between the pharmacokinetic parameters of Dox or Doxorubicinol and response to therapy. The evaluation of the hematological toxicity showed a non significant trend for higher WHO grade 3–4 leucopenia in patients with increased AUC of Dox.

Conclusion
The AUC in the patient group with BMI ≥ 30 was increased. This was caused by a reduced clearance as there was no relevant difference to the other groups in Vss. This suggested that Dox and Doxorubicinol penetrate only minimally into the fat tissue. However, the pharmacokinetic parameters of Dox and Doxorubicinol in non obese and obese patients showed considerable interindividual variability. The hematologic toxicity in obese patients was not significantly increased and therapy outcome did not correlate with any pharmacokinetic parameter. Thus, based on these data, we can not recommend a reduction of dose for Dox in patients up to a BMI of 35.

Disclosures:
No relevant conflicts of interest to declare.