Effect of continuous subcutaneous treprostinil therapy on the pharmacodynamics and pharmacokinetics of warfarin.
Treprostinil sodium was recently approved in the United States for continuous subcutaneous infusion in the treatment of pulmonary arterial hypertension (PAH). Anticoagulation with warfarin is recommended in PAH therapy. Given the likelihood for treprostinil and warfarin coadministration, a single-blind, controlled, crossover study was conducted to evaluate the effect of treprostinil infusion on the pharmacodynamics and pharmacokinetics of a single dose of warfarin. Area under the effect-time curve (AUEC(0-1)) and maximum effect over the entire sampling phase (E(max)) for warfarin INR were 219.58 and 2.071 with treprostinil and 218.93 and 2.041 with vehicle, respectively. Mean time to attain the peak concentration of R-enantiomer of warfarin (T(max)), half-life, and elimination rate constant (k(el)) were 1.9 hours, 51.688 hours, and 0.0137 per hour, respectively, in the presence of treprostinil and 1.5 hours, 52.579 hours, and 0.0137 per hour, respectively, in the presence of vehicle (control). Results were similar for the S-enantiomer. The 90% confidence intervals for warfarin INR and warfarin R- and S-enantiomer pharmacokinetic parameter (C(max) and AUC( infinity )) ratios were within 0.80-1.25, which was established as the no-effect criterion for treprostinil coadministration. No serious or severe adverse events, anticoagulation-related events, or clinically significant physical or laboratory findings were reported. These findings suggest that a clinically important interaction between treprostinil and warfarin during therapy is unlikely.
Wade
Michael
M
United Therapeutics Corporation, Research Triangle Park, North Carolina 27709, U.S.A. mwade@unither.com
Hunt
Thomas L
TL
Lai
Allen A
AA
D000284:Administration, Oral; D000328:Adult; D000925:Anticoagulants / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D004347:Drug Interactions; D011464:Epoprostenol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D006207:Half-Life; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D013237:Stereoisomerism; D013997:Time Factors; D014859:Warfarin / Q000009:adverse effects / Q000493:pharmacokinetics*
D000925:Anticoagulants; D010975:Platelet Aggregation Inhibitors; D014859:Warfarin; D011464:Epoprostenol; C427248:treprostinil