Metabolism and disposition of [14C]BMS-690514, an ErbB/vascular endothelial growth factor receptor inhibitor, after oral administration to humans.

(3R,4R)-4-Amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)-3-piperidinol (BMS-690514), an oral selective inhibitor of human epidermal growth factor receptors 1 (or epidermal growth factor receptor), 2, and 4, and vascular endothelial growth factor receptors 1, 2, and 3, is being developed as a treatment for patients with non-small-cell lung cancer and metastatic breast cancer. The disposition of [(14)C]BMS-690514 was investigated in nine healthy male subjects (group 1, n = 6; group 2, n = 3) after oral administration of a 200-mg dose. Urine, feces, and plasma were collected from all subjects for up to 12 days postdose. In group 2 subjects, bile was collected from 3 to 8 h postdose. Across groups, approximately 50 and 34% of administered radioactivity was recovered in the feces and urine, respectively. An additional 16% was recovered in the bile of group 2 subjects. Less than 28% of the dose was recovered as parent drug in the combined excreta, suggesting that BMS-690514 was highly metabolized. BMS-690514 was rapidly absorbed (median time of maximum observed concentration 0.5 h) with the absorbed fraction estimated to be approximately 50 to 68%. BMS-690514 represented ≤7.9% of the area under the concentration-time curve from time 0 extrapolated to infinite time of plasma radioactivity, indicating that the majority of the circulating radioactivity was from metabolites. BMS-690514 was metabolized via multiple oxidation reactions and direct glucuronidation. Circulating metabolites included a hydroxylated rearrangement product (M1), a direct ether glucuronide (M6), and multiple secondary glucuronide conjugates. None of these metabolites is expected to contribute to the pharmacology of BMS-690514. In summary, BMS-690514 was well absorbed and extensively metabolized via multiple metabolic pathways in humans, with excretion of drug-related radioactivity in both bile and urine.

Phase I dose-escalation study of the novel antiandrogen BMS-641988 in patients with castration-resistant prostate cancer.

PURPOSE: BMS-641988 is an androgen receptor antagonist with increased potency relative to bicalutamide in both in vitro and in vivo prostate cancer models. A first-in-man phase I study was conducted to define the safety and tolerability of oral BMS-641988 in patients with castration-resistant prostate cancer (CRPC). EXPERIMENTAL DESIGN: Doses were escalated from 5 to 150 mg based on discrete pharmacokinetic parameters in cohorts of three to six subjects. After establishing safety with 20 mg of BMS-641988 in the United States, a companion study was opened in Japan to assess differences in drug metabolism between populations. RESULTS: Sixty-one men with CRPC were treated with daily BMS-641988. The pharmacokinetics (PK) of BMS-641988 and its active metabolites were proportional to dose. One patient experienced an epileptic seizure at a dose of 60 mg administered twice. Despite achieving target drug exposures, antitumor activity was limited to one partial response. Seventeen of 23 evaluable patients (74%) exhibited stable disease on imaging (median 15 weeks; range 8-32), and 10 of 61 patients (16%) achieved a ≥ 30% decline in levels of prostate-specific antigen (PSA). Partial agonism was seen within the context of this study upon removal of the drug as evidenced by a decrease in PSA. CONCLUSIONS: Although the clinical outcomes of predominantly stable disease and partial agonism were similar to what was observed in the preclinical evaluation of the compound, the limited antitumor activity of BMS-641988 at therapeutic dose levels coupled with an episode of seizure activity led to study closure.

Enhancement of oral bioavailability of an HIV-attachment inhibitor by nanosizing and amorphous formulation approaches.

BMS-488043 is an HIV-attachment inhibitor that exhibited suboptimal oral bioavailability upon using conventional dosage forms prepared utilizing micronized crystalline drug substance. BMS-488043 is classified as a Biopharmaceutics Classification System (BCS) Class-II compound with a poor aqueous solubility of 0.04mg/mL and an acceptable permeability of 178nm/s in the Caco2 cell-line model. Two strategies were evaluated to potentially enhance the oral bioavailability of BMS-488043. The first strategy targeted particle size reduction through nanosizing the crystalline drug substance. The second strategy aimed at altering the drug's physical form by producing an amorphous drug. Both strategies provided an enhancement in oral bioavailability in dogs as compared to a conventional formulation containing the micronized crystalline drug substance. BMS-488043 oral bioavailability enhancement was approximately 5- and 9-folds for nanosizing and amorphous formulation approaches, respectively. The stability of the amorphous coprecipitated drug prepared at different compositions of BMS-488043/polyvinylpyrrolidone (PVP) was evaluated upon exposure to stressed stability conditions of temperature and humidity. The drastic effect of exposure to humidity on conversion of the amorphous drug to crystalline form was observed. Additionally, the dissolution behavior of coprecipitated drug was evaluated under discriminatory conditions of different pH values to optimize the BMS-488043/PVP composition and produce a stabilized, amorphous BMS-488043/PVP (40/60, w/w) spray-dried intermediate (SDI), which was formulated into an oral dosage form for further development and evaluation.