PHARMACOKINETICS, SAFETY AND TOLERABILITY OF THE ORALLY-ADMINISTERED RECEPTOR ANTAGONIST OF CYSTEINYL-LEUKOTRIENES BAY-X-7195 IN SINGLE-DOSE ESCALATION STUDIES
R. Heinig et al., PHARMACOKINETICS, SAFETY AND TOLERABILITY OF THE ORALLY-ADMINISTERED RECEPTOR ANTAGONIST OF CYSTEINYL-LEUKOTRIENES BAY-X-7195 IN SINGLE-DOSE ESCALATION STUDIES, International journal of clinical pharmacology and therapeutics, 33(10), 1995, pp. 573-579
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.