PHARMACOKINETICS OF NEFAZODONE FOLLOWING MULTIPLE ESCALATING ORAL DOSES IN THE DOG

The single and multiple dose pharmacokinetics of nefazodone (NEF) were, investigated in a dose-escalating study in which 4 beagle dogs (weighing approximately 10 kg) were orally administered 100 mg nefazodone hydrochloride on days 1-7, 500 mg on days 8-14 and 1000 mg on days 15-20 once daily. Serial blood samples were collected over a 24 h period following administration of the first (day 1) and last (day 7) doses for the 100 mg/day dose and the last dose for the 500 (day 14) and 1000 mg/day (day 20) doses. Blood samples were also collected for trough level (C(min)) determination on the morning of the 5th, 6th and 7th day of 100 and 500 mg/day dosing regimens and the 3rd, 5th and 6th day of 1000 mg/day regimen. Plasma was analyzed for NEF and 3 metabolites [hydroxynefazodone (HO-NEF), m-chlorophenylpiperazine (mCPP) and p-hydroxynefazodone (p-HO-NEF)] by a validated HPLC assay. There were no significant differences between the 100 mg single and 100 mg/day multiple dose pharmacokinetic parameters for NEF, HO-NEF and mCPP. However, for p-HO-NEF, single dose elimination half life (T1/2) and area under the plasma concentration-time curve (AUC) extended to infinity were significantly smaller (P less-than-or-equal-to 0.05) than the multiple dose T1/2 and AUC(TAU), respectively. Based on C(min) data, steady state was reached by the 5th day of 500 mg/day and 1000 mg/day multiple dosing. Mean multiple dose AUC(TAU) values for NEF increased in a 1:9:26 ratio for a 1:5:10 increase in dose. Due to extensive variability and small number of animals used in the study, the statistical analysis indicated that AUC(TAU) values were dose-proportional. However, metabolite formation decreased significantly with increasing dose as indicated by AUC(TAU) ratios for metabolite:NEF. These data suggest that NTEF exhibits nonlinear pharmacokinetics within 100-1000 mg/kg dose range in dogs.