SAFETY, TOLERANCE, AND PRELIMINARY PHARMACOKINETICS OF NEFAZODONE AFTER ADMINISTRATION OF SINGLE AND MULTIPLE ORAL DOSES TO HEALTHY ADULT MALE-VOLUNTEERS - A DOUBLE-BLIND, PHASE-I STUDY

Safety, tolerance, and preliminary pharmacokinetics of nefazodone, a n ew antidepressant, were assessed in a randomized, double-blind, parall el group study carried out in two sequential segments: a single and a multiple daily dose segment. Nine subjects in the single daily dose se gment were divided into three treatment groups and received nefazodone doses in a leapfrog fashion. Each day of treatment with nefazodone wa s followed by 2 days of placebo treatment and then administration of t he next higher drug dose. Single doses ranged from 5-500 mg. 8 subject s enrolled in the multiple daily dose segment were divided into two tr eatment groups. In each group, 3 subjects received nefazodone and one received placebo 3 times a day. Each dosage level was administered for 2 days before proceeding to the next higher dose from 5 mg or 10 mg 3 times a day to a maximum of 500 mg 3 times a day. After the dose-esca lation period, the subjects in the multiple daily dose segment underwe nt a 3-day washout, after which they received a single dose of nefazod one at the maximum tolerated level. Safety and tolerance assessment in volved analyses of adverse events, laboratory tests, vital signs, opht halmic examinations, and ECGs. Blood and urine samples were obtained o nly in the multiple daily dose segment and analyzed for nefazodone and its two pharmacologically active metabolites, hydroxynefazodone and m CPP. A single blood sample was collected on 8 different days for asses sment of trough levels (C-min) and serial samples were obtained on day s 5, 9, and 22 of dosing for pharmacokinetic profiles. Additional seri al samples were also obtained after the last single dose of 500 mg aft er a 3-day washout. Nefazodone was found to be safe and well-tolerated in total daily doses as high as 1350 mg (450 mg 3 times a day). Nefaz odone was rapidly absorbed after oral administration and converted to hydroxynefazodone and mCPP. The pharmacokinetics of nefazodone, hydrox ynefazodone, and mCPP were found to be dose-dependent, as evidenced by dose normalized values of C-min, C-max, and AUC(0-8) that progressive ly increased with dose. Although exposure of normal subjects to nefazo done and its 2 pharmacologically active metabolites was disproportiona tely higher than the corresponding increase in dose, the safety and to lerance profiles did not show a parallel increase in adverse events. N efazodone may be well-tolerated by patients receiving expected therape utic doses from 200-600 mg per day when administered in divided doses every 8 to 12 hours.