PHARMACOKINETICS, SAFETY AND TOLERABILITY OF THE ORALLY-ADMINISTERED RECEPTOR ANTAGONIST OF CYSTEINYL-LEUKOTRIENES BAY-X-7195 IN SINGLE-DOSE ESCALATION STUDIES

BAY x 7195 is a novel receptor antagonist of cysteinyl-leukotrienes cu rrently under development for the treatment of asthma. It is effective in antagonizing the leukotriene-D-4 induced bronchoconstriction in he althy volunteers following oral administration. The pharmacokinetics, safety and tolerability of the drug were investigated in six partially placebo-controlled studies in healthy volunteers with single oral adm inistration of a 50, 100, 250, 500 and 1000 mg dose as a tablet. The d rug was well tolerated. The only remarkable adverse event was diarrhea in one volunteer receiving the highest dose of 1000 mg. There were no additional clinically relevant changes in any safety parameter includ ing laboratory values. Concentrations of BAY x 7195 were determined in plasma and urine by high performance liquid chromatography with fluor escence detection and plasma-concentrations were further evaluated by compartmental and non-compartmental methods. The concentration vs time profiles of the drug were biphasic with a dominant tin of 0.5 - 2 h a nd a terminal t(1/2) of 5 - 10 h. Pharmacokinetics were linear in the investigated range of doses. In spite of substantial inter-subject var iability intra-individual variability in AUC and C-max was reasonable. In general, the concentration vs time profiles could be described wit h a 2-compartment body model. However, in some cases the occurrence of second and third concentration maxima necessitated the use of a multi ple segment absorption model to accomplish a good fit to the data. Ent erohepatic recirculation following glucuronidation of the drug is the likely reason for the multiple peaks. Urinary excretion of BAY x 7195 and its glucuronide metabolite was negligible the amount excreted into urine from 0 to 48 h being < 0.1% of the dose. The low renal clearanc e of BAY x 7195 (less than or equal to 0.07 ml/min) is suggestive of s ignificant reabsorption in the renal tubuli taking into account that t he expected renal clearance for a drug with 99.5% protein binding is a bout 0.6 ml/min.