Abstract C214: WP769, an orally bioavailable blood-brain barrier penetrating anthracycline

Abstract

Abstract In our quest to design topoisomerase II targeting drugs having high CNS uptake we have developed a unique subclass of anthracyclines typified by berubicin (WP744, RTA 744) now in clinical trials. Our subsequent efforts were directed at identifying orally bioavailable inhibitors of this class such as WP769, a novel anthracycline with unique properties. In addition to its ability to circumvent P-gp and MRP1-mediated efflux and cross the blood-brain barrier (BBB), WP769 has been synthesized to have enhanced oral bioavailability. To determine the bioavailability, pharmacokinetics and tissue distribution of different WP769 formulations, CD1 mice (M, 50 gm) were administered WP769 as an IV bolus via the tail vein (0.1 ml; vehicle, DMSO:D5W, 5:95, v/v) and by oral gavage (0.2 ml; vehicles cyclodextrin (C) or microemulsion (ME)). Blood samples were collected in heparinized tubes (5 animal per time point) prior to and at selected time points between 5 min and 48 hrs after drug administration. Tissue samples were harvested, washed and weighed using the identical collection schedule. WP769 was extracted from solid tissue samples using a liquid-liquid extraction method, while solid phase extraction was used for blood samples. All samples were analyzed by LC/MS/MS using electrospray ionization operating in positive ion mode. This method has an LLQ of 0.5 ng/ml and is linear throughout a dynamic range of 0.5 ng/ml to 1.5 g/ml. PK parameters describing WP769 disposition were determined by fitting non-compartmental models to the mean plasma/brain concentration-time data. Bioavailability was determined by direct comparison between the AUCs achieved with oral and intravenous administration. Tissue concentration is expressed as ng/g. Mean peak plasma concentrations for IV was 510 ± 83.7 ng/ml vs. 225 ± 124.8 ng/ml (ME) and 96 ng/ml (C). Oral absorption was rapid with peak concentration occurring within 2 hrs of oral administration. Mean distribution volume (Vd), half-life (t1/2), and drug clearance (Cl) for intravenous WP769 were 87 L/kg, 6.4 hrs, and 8.4 L/hr/kg. Apparent oral PK parameters were as follows (ME vs C): Vd (237 vs 174), t1/2 (8.6 vs 6.9), Cl (19.2 vs 17.6)WP769 rapidly distributed to all tissues examined, regardless of administration route. Oral bioavailability (ME vs C) was 44% vs 48%, with the ratio of iv:oral peak and terminal plasma concentration for the ME for was 3.4:1 and 1.2:1, respectively. Of extreme interest was the ability of WP769 to penetrate the BBB and maintain high concentrations for an extended period of time. Mean peak concentrations in the CNS were 220.6 ± 11.3 ng/g and 221.6 ± 40.3 ng/g for intravenous and oral administration (ME). Drug persisted in the CNS with WP769 being measurable 48 hours after a single oral dose, where the CNS concentration was > 20-fold higher in the ME treated group. WP769 is an anthracycline with exceptional characteristics including enhanced cytotoxicity, the ability to avoid cellular resistance mechanisms, oral bioavailability, and the capacity to penetrate the CNS suggesting unique roles for this agent in the treatment of CNS leukemias, solid tumors, and metastases. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C214.