The effect of a standard regimen of
dirithromycin, a
macrolide antibiotic, on the single-dose pharmacokinetics of the H (1) receptor blocker
astemizole was evaluated in a sample of 18 healthy young adults (nine males and nine females). The study was conducted in a two-way cross-over fashion after the subjects had been randomly given either
dirithromycin (two 250 mg
tablets) or placebo (two
tablets) every morning for 10 days. On the morning of the fourth dose of either
dirithromycin or placebo each subject ingested a single 30-mg oral dose (three 10-mg
tablets) of
astemizole. The disposition kinetics of both
astemizole and its major metabolite, N-
desmethylastemizole, were characterized after measuring the concentrations of both analytes in the serum fraction of serial blood samples collected for 14 days after the
astemizole dose. In addition, corrected QT (QT(c) ) intervals were estimated from electrocardiogram rhythm strips that were run 24 hours prior to the
astemizole dose, 12 hours after the
astemizole dose, and after the last treatment (
dirithromycin or placebo) dose in both study periods. Pharmacokinetic parameters that were measured for both
astemizole and N-
desmethylastemizole during each treatment were: C(max), t(max), AUC (0-infinity), CL(oral), half-life, and volume of distribution (V). None of the parameters for N-
desmethylastemizole was different when comparing data by ANOVA from the
dirithromycin treatment period with that of the placebo treatment period. On the other hand, during
dirithromycin treatment
astemizole CL(oral) was 34% slower, volume of distribution was 24% larger, and half-life was 84% longer. Generally, all QT ( c ) intervals did not appear to be affected by
dirithromycin treatment. The changes in
astemizole kinetics could not be attributed to its N-demethylation since the dispositional kinetics of N-
desmethylastemizole were unaffected by
dirithromycin. Therefore, it is difficult to ascertain the clinical significance of the changes in
astemizole kinetics. Since there were no significant differences for mean QT(c) intervals and no effect of
dirithromycin treatment on N-
desmethylastemizole kinetics, it is unlikely that a standard regimen of
dirithromycin would place a patient taking
astemizole at an increased risk of
torsade de pointes or related ventricular arrhythmias.