SEARCH

SEARCH BY CITATION

Keywords:

  • lymphocyte proliferation;
  • monocytes;
  • PDE4;
  • pharmacokinetics;
  • thymidine;
  • TNFα;
  • V11294A;
  • whole blood

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 Cmax (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, t1/2 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.