Oblimersen can be administered by subcutaneous (SC) and brief intravenous (IV) infusion: Clinical pharmacokinetics and pharmacodynamics (PK/PD) in patients with advanced cancer

Abstract

14083 Background: Oblimersen (OBL) is a phosphorothioate oligodeoxynucleotide that decreases Bcl-2 protein levels. OBL has been administered by continuous intravenous infusion (CIVI) in most clinical studies. However, recent preclinical data suggest that equivalent or superior antitumor efficacy can be achieved with intermittent administration. We conducted a dose-ranging PK/PD study of OBL given by bolus SC injection and brief IV infusion to evaluate the feasibility of intermittent dosing. Methods: In this within-subject dose-escalation study, OBL was administered subcutaneously (SC) at doses of 75, 150 and 225 mg. In part II of the study, OBL was administered by 2-hr IV infusion beginning at 150 mg on day 1, by single-dose SC injection on day 8, and 2-hr IV daily x 5 consecutive days. Pharmacokinetics were assessed by non-compartmental analysis. Pharmacodynamic measurements of Bcl-2 levels in peripheral blood mononuclear (PBM) cells were made using Western blot analysis. Results: OBL absorption after SC administration was rapid with a Tmax of ∼2 hours. Mean Cmax values were 0.76, 1.70 and 3.10 μg/ml for the 75, 150 and 225 mg SC doses, respectively. Mean AUC0- inf values were 7.78, 15.36 and 25.57 hr*μg/mL. Plots of dose-normalized Cmax and AUC vs. dose showed slopes close to zero, indicating approximate dose proportionality. AUC0–24 exposure with the 225 mg SC dose was similar to previously established 24-hr steady-state AUCs after 3 mg/kg CIVI. SC injection was associated with an inflammatory erythematous grade 1 rash at the injection site that resolved within 7 days. The 150 mg 2-hr IV infusion x 1 or daily x 5 has been well-tolerated. Conclusions: OBL exposure from a single SC injection is similar to a 24-hr 3 mg/kg CIVI, and the 2-hr IV infusion is currently being evaluated. Both schedules appear to be well- tolerated, may reduce requirements for CIVI, and could be incorporated into intermittent dosing regimens. No significant financial relationships to disclose.