title: Pharmacokinetic and pharmacodynamic profile following oral administration of the phosphodiesterase (PDE)4 inhibitor V11294A in healthy volunteers.
abstract: OBJECTIVE
  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, infinity ) 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.
authors.affiliation: Purdue Frederick Inc., Norwalk, CT, USA.
authors.forename: Donna Donigi
authors.initials: DD
authors.lastname: Gale
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Landells
authors.forename: Domenico
authors.initials: D
authors.lastname: Spina
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Miller
authors.forename: Kate
authors.initials: K
authors.lastname: Smith
authors.forename: Terry
authors.initials: T
authors.lastname: Nichols
authors.forename: Yakov
authors.initials: Y
authors.lastname: Rotshteyn
authors.forename: Alfred
authors.initials: A
authors.lastname: Tonelli
authors.forename: Peter
authors.initials: P
authors.lastname: Lacouture
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Burch
authors.forename: Clive P
authors.initials: CP
authors.lastname: Page
authors.forename: Brian J
authors.initials: BJ
authors.lastname: O'Connor
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000328:Adult; D002455:Cell Division; D018592:Cross-Over Studies; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D011687:Purines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: C465284:3-(3-cyclopentyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H-purine; D010726:Phosphodiesterase Inhibitors; D011687:Purines; D014409:Tumor Necrosis Factor-alpha; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4