The effects of pazopanib on doxorubicin pharmacokinetics in children and adults with non-rhabdomyosarcoma soft tissue sarcoma: a report from Children's Oncology Group and NRG Oncology study ARST1321

Abstract

Purpose: The use of tyrosine kinase inhibitors for the treatment for soft tissue sarcomas is increasing given promising signals of activity in a variety of tumor types. The recently completed study in non-rhabdomyosarcoma soft tissue sarcomas, ARST1321, demonstrated that the addition of pazopanib to neoadjuvant ifosfamide, doxorubicin, and radiation improved the pathological near complete response rate compared with chemoradiotherapy alone. Pharmacokinetic (PK) evaluation of doxorubicin with pazopanib has not been previously reported. As an exploratory aim, doxorubicin PK data were collected during the dose-finding phase of the study in patients receiving chemotherapy and pazopanib to assess the effect of pazopanib on doxorubicin PK parameters.

Methods: Blood samples were collected during cycle 2 (week 4) of chemotherapy at the following time points from doxorubicin administration: predose, 5, 30, and 60 min, and 2, 4, 8, 24 ± 3, and 48 ± 3 h after dosing. The population pharmacokinetic and individual post hoc estimates of doxorubicin and doxorubicinol were determined by nonlinear mixed-effects modeling.

Results: There were 52 doxorubicin and doxorubicinol samples from 7 individuals in this study (median age: 17 years; range 14-23). The doxorubicin clearance was 26.9 (16.1, 36.4, and 33.9) L/h/m² (post hoc median and range) and 25.8 (23.3%) L/h/m² [population estimate and IIV (CV%)]. The doxorubicinol apparent clearance was 67.5 (18.2, 1701) L/h/m² (post hoc median and range) and 58.7 (63.7%) L/h/m² [population estimate and IIV (CV%)].

Conclusion: The PK data of seven patients treated on ARST1321 is consistent with previously reported population and post hoc doxorubicin clearance and doxorubicinol apparent clearance estimates, showing that the addition of pazopanib does not significantly alter doxorubicin pharmacokinetics. These data support the safety of administration of pazopanib with doxorubicin-containing chemotherapy.

Keywords: Doxorubicin; Non-rhabdomyosarcoma soft tissue sarcoma; Pazopanib; Pharmacokinetics.