Abstract
The thiouracil derivative 2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide (PF-06282999) is an irreversible inactivator of myeloperoxidase, and currently in clinical trials for the potential treatment of cardiovascular diseases. Concerns over idiosyncratic toxicity arising from bioactivation of the thiouracil motif to reactive species in the liver have been largely mitigated through the physicochemical (molecular weight, lipophilicity, and topological polar surface area) characteristics of PF-06282999, which generally favor elimination via non-metabolic routes. In order to test this hypothesis, pharmacokinetics and disposition studies were initiated with PF-06282999 using animals and in vitro assays with the ultimate goal of predicting human pharmacokinetics and elimination mechanism(s). Consistent with its physicochemical properties, PF-06282999 was resistant to metabolic turnover from liver microsomes and hepatocytes from animals and human, and was devoid of CYP inhibition. In vitro transport studies suggested moderate intestinal permeability and minimal transporter-mediated hepatobiliary disposition. PF-06282999 demonstrated moderate plasma protein binding across all the species. Pharmacokinetics in preclinical species were characterized by low to moderate plasma clearances, good oral bioavailability at 3-5 mg/kg doses, and renal clearance as the projected major clearance mechanism in humans. Human pharmacokinetic predictions using single species scaling of dog and/or monkey pharmacokinetics were consistent with the parameters observed in the first-in-human study, conducted in healthy volunteers at a dose range of 20-200 mg PF-06282999. In summary, disposition characteristics of PF-06282999 were relatively similar across preclinical species and human with renal excretion of unchanged parent emerging as the principal clearance mechanism in humans, which was anticipated based on its physicochemical properties and supported by preclinical studies.
- anti-inflammatory drugs
- drug design
- drug development/discovery
- glutathione conjugates
- idiosyncratic drug reactions
- metabolite identification
- pharmacokinetics
- The American Society for Pharmacology and Experimental Therapeutics