Pharmacokinetics of nefazodone following multiple escalating oral doses in the dog

Abstract

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) andp-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 (T_1/2) and area under the plasma concentration-time curve (AUC) extended to infinity were significantly smaller (P ≤ 0.05) than the multiple dose T_1/2 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 NEF exhibits nonlinear pharmacokinetics within 100–1000 mg/kg dose range in dogs.