Clinical pharmacokinetics of mizolastine

Mizolastine is a new histamine H-1 receptor antagonist. Mizolastine 10 mg/d ay is effective in allergic rhinitis and chronic idiopathic urticaria. In young healthy volunteers, absorption of mizolastine is rapid with time ( t(max)) to peak concentration (C-max) of about 1 hour. The absolute bioavai lability of mizolastine 10mg tablets is about 65%. Distribution is rapid wi th a mean distribution half-life of 1.5 to 1.9 hours, Mizolastine is > 98% bound to serum albumin and the apparent volume of distribution is between 1 and 1.4 L/kg. Mizolastine is extensively metabolised by hepatic glucuronid ation and sulphation, with no major active metabolite, and excreted in faec es. The terminal elimination half-life (t1/2 beta) is 7.3 to 17.1 hours. Th e apparent oral clearance after a repeated oral dose of 10mg is 6.02 L/h, w ith steady state reached from day 3 and no accumulation between days 1 and 7. C-max and area under the concentration-time curve (AUC) are linearly rel ated to dose. Mizolastine appears in vivo to be a relatively weak inhibitor of cytochrome P450 2E1, 2C9, 2D6 and 3A4. In vivo, no interactions were observed between mizolastine and lorazepam or ethanol. A significant increase in C-max and trough plasma concentration (C-min) of digoxin occurred after coadministrat ion with mizolastine, without change in AUC, t(max) or clinical parameters. Significant increases in theophylline Cmin and AUC were observed after coa dministration with mizolastine. Mizolastine C-max, and AUC were increased w hen coadministered with erythromycin, with no change in t1/2 beta. Concomit ant administration of mizolastine and ketoconazole increased mizolastine AU C values with no change in t1/2 beta. In a population analysis of the pharmacokinetics of mizolastine in patients with allergies, parameter values were close to those in healthy volunteers , except for duration of absorption, which was almost doubled in the patien ts. Bodyweight and creatinine clearance were found to have little influence on oral clearance, and no influence of liver transaminases was found on cl earance and distribution. Pharmacokinetic parameters of mizolastine in elderly individuals were simil ar to those observed in healthy young volunteers. In patients with chronic renal insufficiency, t1/2 beta was prolonged by 47% compared with young hea lthy volunteers. In patients with cirrhosis, t(max) was longer, C-max was l ower, distribution half-life was prolonged and AUC was 50% higher than in h ealthy volunteers. In pharmacodynamic-pharmacokinetic trials, the percentage of wheal and flar e inhibition was found to correlate with mizolastine C-min values. No direc t relationship was found between drug concentrations in skin blister fluid and antihistamine activity.