MULTIPLE-DOSE PHASE-I STUDY OF TRANSNASAL BUTORPHANOL

The safety, tolerance, and pharmacokinetics of transnasal butorphanol were evaluated in a double-blind, multiple-dose phase I study. A total of 18 subjects received either placebo (n = 6) or a single transnasal dose of 2 mg butorphanol tartrate on the first day and 1, 2, and 4 mg doses of butorphanol tartrate every 6 hours on days 2 through 6, 7 th rough 11, and 12 through 16, respectively. Safety assessment was perfo rmed on days 7, 12, and 17. Serial blood samples were collected on day s 1, 6, 11, and 16, and the plasma was analyzed for unchanged butorpha nol by a validated and specific radioimmunoassay. Butorphanol was rapi dly absorbed and peak levels in plasma were generally attained within 1 hour after the nasal administration. The values of maximum concentra tion, minimum concentration, and area under the concentration versus t ime curve from time zero to the dosing interval AUC(0-tau)! increased as the administered dose increased in a dose-proportional manner. The values of AUC from time zero to infinity after a single dose of 2 mg butorphanol tartrate, 10.9 ng . hr/ml, were identical to the values of AUC(0-tau) after a multiple administration of 2 mg dose, 10.4 ng . hr /ml. Mean elimination half-life value was 5.45 hours. Steady state was reached in fewer than eight doses when given every 6 hours. Transnasa l butorphanol was well tolerated by all subjects. After repeated admin istration of transnasal butorphanol, no significant changes were obser ved in the nasal examination, which included evaluation of color, wetn ess, and thickness of nostril membrane, air flow, airway patency, and general nasal conditions. The findings of this phase I study indicate that transnasal butorphanol is well tolerated, locally as well as syst emically, and pharmacokinetics are linear within the expected therapeu tic dose range.