Abstract 3768: Evaluating the effects of bortezomib (Velcade®) on the pharmacokinetics (PK) of pegylated liposomal doxorubicin (Doxil®, PLD)

Abstract

Abstract Background: PLD is a pegylated liposomal formulation of doxorubicin approved for the treatment of ovarian cancer, Kaposi's sarcoma, and multiple myeloma. We have reported that age, gender, and monocyte count may affect the clearance (CL) of PLD. In multiple myeloma, PLD is used with bortezomib, a proteosome inhibitor which can affect monocyte count. The purpose of this cross study comparison was to assess the effects of bortezomib on the CL of PLD. Methods: This was a cross trial comparison of patients with solid tumors who received PLD alone and PLD + bortezomib. The PLD alone group (n = 34) received PLD at 10 to 60 mg/m2 IV every 28 days. The PLD + bortezomib group (n = 25) received bortezomib at 0.90 to 1.50 mg/m2 IV on days 1, 4, 8, and 11, and PLD at 30 mg/m2 IV on day 4, every 21 days. PK studies of PLD were performed for cycle 1, after administration of PLD alone and PLD + bortezomib. Serial blood samples were obtained from 0 to 96 h and from 7 to 28 days after administration of PLD. Plasma samples were processed to measure sum total (encapsulated + released) doxorubicin via HPLC and the clearance (CL) was calculated with WinNonlin using noncompartmental methods. Results: In patients < 60 years old, the mean (± standard deviation) PLD CL after administration of PLD alone and in combination with bortezomib was 63.4 (± 46.1) and 23.3 (± 7.6) mL/h, respectively (P=0.017). In patients >= 60 years old, the PLD CL after administration of PLD alone and in combination with bortezomib was 39.1 (± 18.5) and 38.0 (± 15.5) mL/h, respectively (P>0.05). In male patients, the PLD CL after administration of PLD alone and in combination with bortezomib was 65.4 (± 33.4) and 38.4 (± 9.7) mL/h respectively (p>0.05). In female patients, the PLD CL after administration of PLD alone and in combination with bortezomib was 40.1 (± 33.4) and 24.6 (± 11.2) mL/h respectively (P>0.05). Conclusion: This cross study comparison suggests that bortezomib decreases PLD CL in younger patients and in male patients. Although the underlying mechanism for this effect on PLD CL is not known, it may be related to bortezomib inhibition of mononuclear phagocyte activity in certain patient populations, which is responsible for the CL of PLD. There is a need to further investigate this in a prospective drug interaction study. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3768. doi:1538-7445.AM2012-3768