Abstract
The absorption, distribution, metabolism, and excretion (ADME) and the pharmacokinetic characteristics of BMS-562086 [pexacerfont; 8-(6-methoxy-2-methyl-3-pyridinyl)-2,7-dimethyl-N-[(1R)-1-methylpropyl]pyrazolo(1,5-a)-1,3,5-triazin-4-amine (DPC-A69448)] were investigated in vitro and in animals to support its clinical development. BMS-562086 was orally bioavailable in rats, dogs, and chimpanzees, with an absolute oral bioavailability of 40.1, 58.8, and 58.5%, respectively. BMS-562086 was extensively metabolized in hepatocytes from all species and completely metabolized in rats. The primary biotransformation pathways found for BMS-562086 in both liver microsomal and hepatocyte preparations and in rats were similar. These included O-demethylation, hydroxylation at the N-alkyl side chain and N-dealkylation. Multiple cytochromes P450 including CYP3A4/5 were involved in the metabolic clearance of BMS-562086. Both renal and biliary excretion played a significant role in elimination of the metabolites of BMS-562086. The involvement of other metabolic enzymes in addition to CYP3A4/5 in elimination of BMS-562086 suggests a reduced potential for drug-drug interaction through modulation of CYP3A4/5. Chimpanzees proved to be a good animal model in predicting BMS-562086 human clearance. Virtual clinical trials performed with a population-based ADME simulator suggested that a minimal dose of 100 mg daily would provide sufficient drug exposure to achieve plasma concentrations above the projected human efficacious plasma concentration of BMS-562086 (>500 nM). In summary, BMS-562086 exhibited favorable ADME and pharmacokinetic properties for further development.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
ABBREVIATIONS:
- CRF
- corticotropin-releasing factor
- IBS
- irritable bowel syndrome
- BMS-562086
- 8-(6-methoxy-2-methyl-3-pyridinyl)-2,7-dimethyl-N-[(1R)-1-methylpropyl]pyrazolo(1,5-a)-1,3,5-triazin-4-amine
- ADME
- absorption, distribution, metabolism, and excretion
- BDC
- bile duct-cannulated
- DPH-123554
- O-demethylated metabolite of BMS-562086
- DPH-124921
- N-dealkylated metabolite of BMS-562086
- BMS-572273
- N-dealkylated and hydrolyzed metabolite of BMS-562086
- AP
- apical
- BL
- basolateral
- TEER
- transepithelial electrical resistance
- 7-EC
- 7-ethoxycoumarin
- 7-HC
- 7-hydroxycoumarin
- LC-MS/MS
- liquid chromatography-tandem mass spectrometry
- HPLC
- high-performance liquid chromatography
- QC
- quality control
- Cmax
- maximal observed concentration
- Tmax
- time of maximal observed concentration
- AUC(INF)
- area under the plasma concentration-time curve from time zero extrapolated to infinite time
- CLb
- blood clearance
- CLp
- plasma clearance
- dQ/dt
- appearance rate
- VZ
- terminal volume of distribution
- F
- oral bioavailability.
- Received October 29, 2011.
- Accepted March 1, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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