Warfarin pharmacodynamics unaffected by cilomilast.
OBJECTIVE
To demonstrate a lack of effect of steady-state concentrations of cilomilast, a new oral phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease, on warfarin-induced anticoagulation.


METHODS
This 28-day, randomized, double-blind, placebo-controlled, parallel-group study involved 36 healthy men. All volunteers received warfarin once daily on days 1 through 24 of the study. After a standard 5-mg loading dose on days 1 and 2, the warfarin dose was titrated between days 3 and 10 to achieve a stable prothrombin time, expressed as international normalized ratio (INR). Volunteers received either cilomilast 15 mg twice daily or placebo on days 18 through 24. The primary end point was the INR on day 24.


RESULTS
On day 24, the mean +/- SEM INR in subjects receiving concurrent warfarin and cilomilast was 1.35 +/- 0.05, compared with 1.38 +/- 0.07 in those receiving concurrent warfarin and placebo. The point estimate (90% CI) for the difference in day 24 INR values between cilomilast and placebo (adjusted for baseline) was 0.02 (90% CI-0.13 to 0.17), which translates to an INR ratio of 1.02 (90% CI 0.91 to 0.13). The 90% confidence interval for the ratio of mean INR (cilomilast:placebo) on day 24 was completely contained within the 25% equivalence range, indicating a lack of interaction between warfarin and cilomilast. The adverse event profiles of warfarin/placebo and warfarin/cilomilast were similar and favorable.


CONCLUSIONS
The pharmacodynamics of warfarin are unaffected by coadministration of cilomilast at steady-state concentrations in healthy volunteers.
Kelly
J
J
GlaxoSmithKline, New Frontiers Science Park, Third Ave., Harlow, CM19 5AW Essex, UK. John_A_Kelly@sbphrd.com
Murdoch
R D
RD
Clark
D J
DJ
Webber
D M
DM
Fuder
H
H
D000328:Adult; D000925:Anticoagulants / Q000494:pharmacology*; D001993:Bronchodilator Agents / Q000009:adverse effects / Q000494:pharmacology*; D002264:Carboxylic Acids; D003509:Cyclohexanecarboxylic Acids; D004311:Double-Blind Method; D004347:Drug Interactions; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D014859:Warfarin / Q000494:pharmacology*
D000925:Anticoagulants; D001993:Bronchodilator Agents; D002264:Carboxylic Acids; D003509:Cyclohexanecarboxylic Acids; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors; D014859:Warfarin; C433247:Cilomilast