The effects of concentration and dose volume on the nasal bioavailability and biological response to desmopressin [DDAVP; 1-(3-mercaptoproprionic acid)-8-D-arginine vasopressin] were investigated in humans. A nasal formulation of 300 micrograms of desmopressin was administered using a premetered spray device in doses of either 1 x 50-, 2 x 50-, or 1 x 100- microL actuations to both nostrils. Intravenous administration of 0.2 micrograms/kg was also given as a reference for bioavailability calculations. Plasma levels of desmopressin were measured by radioimmunoassay. The biological response was determined by measuring circulating levels of Factor VIII (F VIII), the antihemophilia factor. Peak plasma levels of desmopressin were greatest after the 2 x 50-microL dose, followed by the 1 x 50- and 1 x 100-microL doses. The bioavailability of desmopressin from the 2 x 50-microL dose was 20%, which was significantly greater than the 11% after the 1 x 50-microL (p less than 0.01) and 9% after the 1 x 100-microL (p less than 0.001) doses. The biological response was clearly enhanced after the 2 x 50-microL dose compared with the 1 x 50- and 1 x 100-microL doses. The interindividual response in F VIII levels to nasal desmopressin ranged from 20 (CV) to 30%, which compared favorably with the 36% variation after intravenous administration. This study confirms the premetered spray device as the preferred intranasal drug delivery system, and shows that by optimizing concentration, volume, and technique of administration, a significant enhancement can be obtained in bioavailability and clinical efficacy.