Pharmacokinetic and pharmacodynamic profile following oral administration of the phosphodiesterase (PDE)4 inhibitor V11294A in healthy volunteers

Aims  To assess the pharmacokinetic and pharmacodynamic profile of the novel PDE4 inhibitor V11294A (3‐(3‐cyclopentyloxy‐4‐methoxybenzyl)‐6‐ethylamino‐8‐isopropyl‐3H purine hydrochloride) in healthy male volunteers.

Methods  This was a double‐blind, single dose, randomized crossover study in eight healthy volunteers who received a single oral, fasting dose of V11294A (300 mg) or placebo. Blood samples were taken before and 0.5, 1, 2, 2.5, 3, 4, 6, 9, 12, 18 and 24 h after oral dosing for determination of plasma concentrations of V11294A. Blood samples were also taken before and 3 and 24 h after dosing for the assessment of the effect of V11294A on mononuclear cell proliferation and tumour necrosis factor (TNF) release in whole blood.

Results  Following a single oral dose of 300 mg V11294A, plasma concentrations of V11294A and its active metabolite V10332 reached C_max (ng ml⁻¹; mean ± s.d.; 1398 ± 298, 1000 ± 400, respectively) after 2.63 ± 0.79 and 5.9 ± 2.3 h, respectively. For V11294A and V10332, t_1/2 were 9.7 ± 3.9 and 9.5 ± 1.7 h, and AUC(0,∞) were 18100 ± 6100 and 18600 ± 8500 ng ml⁻¹ h, respectively. At 3 h dosing, plasma concentrations of V11294A and V10332 (3‐(3‐cyclopentyloxy‐4‐methoxy‐benzyl)‐8‐isopropyl‐3H‐purin‐6‐ylamine) were 1300 ± 330 and 860 ± 300 ng ml⁻¹, 7 and 3 times their in vitro IC₅₀s for inhibition of TNF release and proliferation, respectively. Treatment with V11294A resulted in a significant reduction of lipopolysaccharide (LPS)‐induced TNF release at 3 h (P < 0.001) and at 24 h (P < 0.05) post ingestion. The amount of TNF released (pmol ml⁻¹) in response to a submaximal concentration of LPS (4 ng ml⁻¹) was not significantly altered following placebo treatment (before 681 ± 68 vs 3 h postdose 773 ± 109, P = 0.27). In contrast, there was a significant reduction in the amount of TNF released following treatment with V11294A (before 778 ± 87 vs 3 h postdose 566 ± 72, P = 0.02). Phytohaemagluttinin (PHA) stimulated the incorporation of [³H]‐thymidine in whole blood prior to drug administration. V11294A inhibited the PHA‐induced proliferation at 3 h (P < 0.05). No adverse reactions were noted following single oral administration of V11294A.

Conclusions  A single oral 300 mg dose of V11294A administered to healthy volunteers results in plasma concentrations adequate to inhibit activation of inflammatory cells ex vivo, which persists for at least 24 h without any adverse reactions.

DOI: 10.1046/j.1365-2125.2002.01682.x

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