title: Pharmacokinetics, safety and tolerability of the orally administered receptor antagonist of cysteinyl-leukotrienes BAY x 7195 in single-dose escalation studies.
abstract: BAY x 7195 is a novel receptor antagonist of cysteinyl-leukotrienes currently under development for the treatment of asthma. It is effective in antagonizing the leukotriene-D4 induced bronchoconstriction in healthy 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 administration of a 50, 100, 250, 500 and 1000 mg dose as a tablet. The drug 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 including laboratory values. Concentrations of BAY x 7195 were determined in plasma and urine by high performance liquid chromatography with fluorescence 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 t1/2 of 0.5-2 h and a terminal t1/2 of 5-10 h. Pharmacokinetics were linear in the investigated range of doses. In spite of substantial inter-subject variability intra-individual variability in AUC and Cmax was reasonable. In general, the concentration vs time profiles could be described with a 2-compartment body model. However, in some cases the occurrence of second and third concentration maxima necessitated the use of a multiple segment absorption model to accomplish a good fit to the data. Enterohepatic 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 clearance of BAY x 7195 (< or = 0.07 ml/min) is suggestive of significant reabsorption in the renal tubuli taking into account that the expected renal clearance for a drug with 99.5% protein binding is about 0.6 ml/min.
authors.affiliation: Institute of Clinical Pharmacology, Bayer AG, Wuppertal, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Heinig
authors.forename: H G
authors.initials: HG
authors.lastname: Schaefer
authors.forename: G
authors.initials: G
authors.lastname: Wensing
authors.forename: J
authors.initials: J
authors.lastname: Kuhlmann
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D003545:Cysteine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005965:Glucuronates / Q000652:urine; D006801:Humans; D006880:Hydroxy Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D020024:Leukotriene Antagonists; D008099:Liver / Q000378:metabolism; D008297:Male; D015588:Observer Variation
chemical_list: D001993:Bronchodilator Agents; D005965:Glucuronates; D006880:Hydroxy Acids; D020024:Leukotriene Antagonists; D003545:Cysteine; C092294:BAY x 7195