INFLUENCE OF ITRACONAZOLE ON THE PHARMACOKINETICS AND ELECTROCARDIOGRAPHIC EFFECTS OF ASTEMIZOLE

Aims The aim of this study was to investigate the influence of chronic itraconazole treatment on the pharmacokinetics and cardiovascular eff ects of single dose astemizole in healthy subjects was studied. Method s Twelve male volunteers were taking orally 200 mg twice daily itracon azole or placebo for 14 days with a washout period of 4 weeks in betwe en. Approximately 2 h after the morning dose of itraconazole or placeb o on day 11, 10 mg astemizole was orally administered. The plasma conc entrations of astemizole and desmethylastemizole were measured by radi oimmunoassay up to 504 h after administration; electrocardiograms with analysis of the QT(c) interval were recorded up to 24 h post administ ration. Results Itraconazole treatment did not significantly change th e peak concentration of astemizole (0.74 vs 0.81 ng ml(-1)) but it inc reased the area under the curve from 0 to 24 h (5.46 to 9.95 ng ml(-1) h) and from 0 to infinity (17.4 to 48.2 ng ml(-1) h), and the elimina tion half-life (2.1 to 3.6 days). The systemic bioavailability of desm ethylastemizole was also increased. The QT(c) interval did not increas e after astemizole administration and there was no difference in the Q T(c) intervals between the itraconazole and placebo session. Conclusio ns Chronic administration of itraconazole influences the metabolism of single dose astemizole in normal volunteers without changes of cardia c repolarization during the first 24 h after astemizole administration . However, the reduction in astemizole clearance under concomitant adm inistration of itraconazole may result in a marked increase in astemiz ole plasma concentrations and QT(c) alterations during chronic combine d intake of astemizole with itraconazole.