Abstract 3237: Evaluation of the pharmacokinetics and efficacy of a novel pro-drug of the HSP90 inhibitor, MPC-3100, designed with improved solubility
Authors: Papac Damon , Patton J. Scott , Reeves Leslie , DeMie Lynn , Bradford Chad , Hachey Brian , Clemetson Brian , Christensen Christin , Kim Se-Ho , Tangallapally Rajendra , Parker Daniel , Trovato Richard , Kim In Chul , Wettstein Daniel , Baichwal Vijay R. , Bajji Ashok 
Published: June 2012

MPC-3100 is a synthetic, orally bioavailable HSP90 inhibitor in clinical development. The low solubility of this compound requires a solubility enhancing agent to enable uniform oral bioavailability. A pro-drug of MPC-3100 with enhanced aqueous solubility was synthesized and evaluated for its physical-chemical and pharmacokinetic properties, and anti-tumor activity in mice.

The alanine ester of MPC-3100 was synthesized by esterifying a hydroxyl group on the active compound, MPC-3100. Solubility and permeability were determined over the pH range of 5 – 7.5 using the PIon solubility analyzer and the double sink PAMPA method. To investigate esterase-mediated activation of the pro-drug, the pro-drug was incubated with biological matrices known to contain esterases (mouse and human plasma and liver microsomes). The pharmacokinetics of the active component of the pro-drug was determined at 360 mg/kg in female CD-1 mice after administration as an oral suspension in 2% carboxymethylcellulose (CMC). Plasma concentrations of the active compound, MPC-3100, were quantified by LC-ESI-MS/MS. Five million NCI-N87 human gastric carcinoma cells were implanted subcutaneously into athymic mice (nu/nu) to produce a mouse xenograft model. Efficacy was determined in this model using once daily oral dosing in 2% CMC for 21 days.

The kinetic solubility of the alanine ester pro-drug of MPC-3100 at pH 6.5 was 536 µg/mL compared to 10.2 µg/mL for MPC-3100. The pro-drug had an apparent permeability of 2.7 × 10-6 cm/sec at pH 6.2; whereas, the apparent permeability of MPC-3100 was 420 × 10-6 cm/sec. The low permeability of the pro-drug suggests conversion to active would be required to occur in the lumen prior to MPC-3100 absorption. The pro-drug was converted to MPC-3100 (half-life &lt; 3 minutes) in mouse plasma and in mouse and human NADPH-deficient liver microsomes, but was converted slowly in human plasma with a half-life of 105 minutes, similar to the rate of non-enzymatic conversion in phosphate buffer (pH 7.4). An oral dose of 360 mg/kg of the pro-drug yielded a Cmax for MPC-3100 of 21.7 ug/mL and an AUC(0-inf) of 91.0 hr*ug/mL, which was comparable to exposures seen at efficacious doses of MPC-3100 formulated with solubility-enhancing agents. At this same dose, the pro-drug demonstrated a 42% tumor regression in the N-87 mouse xenograft model. This anti-tumor effect observed with the pro-drug was comparable to the 80% tumor regression observed with MPC-3100 at 200 mg/kg formulated with solubility-enhancing agents.

The alanine ester pro-drug of MPC-3100 had a &gt; 50-fold increase in aqueous solubility and was converted rapidly by mouse plasma and mouse and human liver microsomes into active MPC-3100 in vitro and in vivo. These improved properties resulted in pro-drug that was efficacious in a xenograft tumor model, when dosed without a solubility enhancing agent.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3237. doi:10.1158/1538-7445.AM2011-3237