Modeling of sertindole pharmacokinetic disposition in healthy volunteers in short term dose-escalation studies

The pharmacokinetics of sertindole were studied in young, healthy volunteer s after single and multiple oral dose administered under an escalating mann er. In a low-dose study (study 1), subjects received 4-8 mg with a maintena nce dose period of 7 days. Ina high-dose study (study 2), subjects received 4 mg daily for 2 days, and the dose was increased by 4 mg increments every third day until reaching 20 mg daily. The mean terminal t(1/2) was 73 h af ter the final 8 mg dose in study 1 and 60 h after the 20 mg dose in study 2 . The terminal elimination phase appeared to be monophasic in all the study subjects, suggesting that Michaelis-Menten saturable metabolism was not in volved in the elimination of sertindole. Compartmental analyses suggested t hat the disproportional increase of the C-max and AUC values from 4 mg to 2 0 mg during multiple dosing may be explained by saturable presystemic elimi nation of sertindole, leading to a higher fraction of sertindole available for-absorption at higher doses.