Abstract 2664: Pharmacokinetics of a novel fumagillol conjugate XMT-1107 in the rat and the dog

Abstract

Abstract XMT-1107 is a novel polymer fumagillol derivative, comprised of the small molecule XMT-1191 conjugated to a 70 kDa biodegradable, hydrophilic polyacetal, poly(1-hydroxymethylethylene hydroxymethylformal) (PHF). The conjugated drug XMT-1107 is a prodrug that improves the pharmacokinetics (PK) of the active compound XMT-1191 and demonstrates significant antitumor activity in multiple rodent xenograft models providing a compelling rationale for clinical development. We evaluated the metabolism and PK of XMT-1107 in the rat and the dog and expect that the preclinical dog toxicokinetic (TK) data provide better guidance than the rat data for the assessment of XMT-1107 safety/PK in humans. XMT-1107 metabolism was studied in rodent, dog and human plasma as well as in liver microsomes. The PK of XMT-1107 was studied in rat and dog at a variety of doses and schedules. The extent and duration of the exposure was monitored over 120 hours post dosing. The analytical determinations of XMT-1107 and small molecule metabolites were carried out by LC/MS/MS. XMT-1107 was metabolized in rodent, dog and human plasma producing XMT-1191 and XMT-1201 (via conjugated XMT-1201) as major and minor metabolites, respectively. Considering that XMT-1201 does not bind to or inhibit MetAP2, the molecular target of XMT-1107, conjugated and free XMT-1191 are of most interest since conjugated XMT-1191 is a prodrug and XMT-1191 is its active release product. In both species the PK of conjugated and free XMT-1191 was approximately dose proportional with no marked gender differences. Consistent 2,000-4,000 fold differences between conjugated XMT-1191 and free XMT-1191 plasma exposure (AUC0–120) and Cmax suggest that observed pharmacological effects may result from extravascular distribution of conjugated XMT-1191 and local release of XMT-1191 rather than from systemic exposure to free XMT-1191. Conjugated XMT-1191 has a low volume of distribution, slow systemic clearance and is characterized by a t1/2 ranging from 27-35 hours in rat and 47-68 hours in dog. The 1.8-2.0-fold increase in conjugated XMT-1191 plasma t1/2 observed in dog relative to rat was accompanied by an approximately proportional increase in dose normalized exposure (AUC0–120) to conjugated XMT-1191 and conjugated XMT-1201. The rates for in vitro release of XMT-1191 and XMT-1201 from XMT-1107 in dog and human plasma were similar and at least 2 times lower than the release rates for corresponding compounds in rat plasma, suggesting that dog TK may be more predictive of human XMT-1107 PK compared to rat TK. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2664.