Pharmacokinetics Of Sarizotan After Oral Administration Of Single And Repeat Doses In Healthy Subjects

Obiective: Sarizotan is a 5-HT1 A receptor agonist with high affinity for D-3 and D-4 receptors. Here we report the pharmacokinetic and tolerability results from four Phase I studies. Materials: Two single-dose (5-25 mg, n = 25, 0.5 - 5 mg, n = 16) and two multiple-dose (10 and 20 mg b.i.d., n = 30, 5 mg b.i.d., n = 12) studies with orally administered sarizotan HC1 were carried out in healthy subjects. Methods: Plasma sarizotan HC1 concentrations were measured using a validated HPLC method and fluorescence or MS/MS detection. Pharmacokinetic parameters were obtained using standard non-compartmental methods. Results: Sarizotan was rapidly absorbed, group-median times to reach maximum concentration ranged from 0.5-2.25 h after single doses and during steady state. Maximum plasma concentration (C-max) and t(max) were slightly dependent on formulation and food intake, whereas area under the curve (AUC) was unaffected by these factors. AUC and C-max increased dose-proportionally over the tested dose range. Independently of dose and time, sarizotan HCI plasma concentrations declined polyexponenti ally with a terminal elimination half-life (t(1/2)) of 5-7 In. Accumulation factors corresponded to t(1/2) values, and steady state was reached within 24 h. Plasma metabolite concentrations were considerably lower than those of the parent drug. The ratio metabolite AUC : parent drug AUC was time- and dose-independent for all three metabolites suggesting that the metabolism of sarizotan is non-saturable in the tested dose range. Conclusions: The pharmacokinetics of sarizotan were dose-proportional and time-independent for the dose range 0.5-25 mg). The drug was well-tolerated by healthy subjects up to a single dose of 20 mg.