DETERMINATION OF THE INTERACTION OF 3S-HYDROXY-10,11-DIHYDROQUINIDINEON THE PHARMACOKINETICS AND PHARMACODYNAMICS OF WARFARIN

The investigational antiarrhythmic drug LNC-834 ((9S)-10,11-didhydro-6 '-methoxy-cinchonan-3,9-diol hydrogen sulfate pentahydrate, CAS 85405- 59-0) is structurally related to quinidine. It was investigated, if co ncurrent administration of LNC-834 affects the single dose pharmacokin etics and pharmacodynamics of warfarin (CAS 81-81-2). The study was pe rformed as an open, randomized two-way cross-over, controlled investig ation in 10 healthy volunteers. In treatment A, 2 tablets of LNC-834 ( 350 mg of hydrated salt corresponding to 226 mg anhydrous free base ea ch) were ingested twice daily for a period of 9 days in total. On the 4th study day, 2 h after the application of LNC-834 in the morning, th e volunteers received a mean dose of 0.36 +/- 0.03 mg/kg warfarin oral ly. In treatment B only warfarin was administered. Pharmacokinetics of warfarin and anticoagulant effect (prothrombin complex activity) were determined from plasma samples withdrawn up to 144 h after administra tion; LNC-409 (free base of LNC-834) and the metabolite LNC-253 (2'-ox o-analog) were monitored for check of compliance over the same time pe riod. Concurrent administration of LNC-834 decreased significantly the area under the plasma concentration-time curve of warfarin (117,889 /- 25,010 (A) vs. 125,294 +/- 22,314 ng/ml . h (B); p = 0. 0488). Thus , a significant increase in apparent oral clearance (CL/f) of warfarin in the presence of LNC-834 was determined (3.98 +/- 0.63 vs. 3.71 +/- 0.50 ml/min; p = 0.0488). All other pharmacokinetic parameters determ ined (apparent volume of distribution (V/f), C(max), t(max), terminal half-life of elimination) were not altered by concurrent treatment wit h LNC-834. Concurrent administration of LNC-834 had no effect either o n the maximum anticoagulant effect nor on the total anticoagulant effe ct per dose. However, administration of LNC-834 at a dose of 700 mg tw ice daily over a period of three days increased significantly the prot hrombin complex activity before administration of warfarin (PCA: 95.81 +/- 10.83 vs. 85.02 +/- 12.47% of normal; p = 0.0195). Thus, the anti coagulant effect of a single oral dose of warfarin was not affected by LNC-834. The observed ''pro-coagulatory'' effect of LNC-834 itself as well as the effects on the pharmacokinetics of warfarin were small. A t the present point of view, the therapeutic relevance seems to be que stionable and has to be investigated further.