Disposition of CP-671, 305, a selective phosphodiesterase 4 inhibitor in preclinical species

Abstract

1. The disposition of (+)-2-[4-({[2-(benzo[1,3] dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic acid (CP-671,305), a potent and selective inhibitor of phosphodiesterase 4 (subtype D), was characterized in several animal species in support of its selection for preclinical safety studies and potential clinical development.

2. CP-671,305 demonstrates generally favourable pharmacokinetic properties in all species examined. Systemic plasma clearance after intravenous administration was low in Sprague–Dawley rats (9.60 ± 1.16 ml min⁻¹ kg⁻¹), beagle dogs (2.90 ± 0.81 ml min⁻¹ kg⁻¹) and cynomolgus monkeys (2.94 ± 0.87 ml min⁻¹ kg⁻¹) resulting in plasma half-lives > 5 h. Moderate to high bioavailability in rats (43–80%), dogs (45%) and monkeys (26%) was observed after oral dosing. In rats, oral pharmacokinetics were dose dependent over the dose range studied (10 and 25 mg kg⁻¹).

3. CP-671,305 was > 97% bound to plasma proteins in rat, dog, monkey and human.

4. The principal route of clearance of CP-671,305 in rats and dogs was by renal and biliary excretion of unchanged drug. This finding was consistent with CP-671,305 resistance towards metabolism in hepatocytes and NADPH-supplemented liver microsomes from preclinical species and human.

5. CP-671,305 did not exhibit competitive inhibition of the five major cytochrome P450 enzymes, namely CYP1A2, 2C9, 2C19, 2D6 and 3A4 (IC₅₀'s > 50 μM). Likewise, no time-dependent inactivation of the five major cytochrome P450 enzymes was discernible with CP-671,305.

6. Overall, the results indicate that the absorption, distribution, metabolism and excretion (ADME) profile of CP-671,305 is relatively consistent across preclinical species and predict potentially favourable pharmacokinetic properties in humans, supporting its selection for toxicity/safety assessment studies and possible investigations in humans.