Pharmacokinetics and pharmacodynamics of desmopressin administered orally versus intravenously at daytime versus night-time in healthy men aged 55-70 years

Objective: To investigate (1) the pharmacokinetic and pharmacodynamic profiles of desmopressin in men from an age group with a high incidence of nocturia; and (2) circadian variation in the pharmacokinetic parameters. Methods: The study had an open, randomised, four-way cross-over design. Desmopressin was administered orally (0.2 mg) and intravenously (2 mug), daytime and night-time, yielding four in-hospital sessions, separated by at least 2 days. Blood samples were taken before and at predetermined time points up to 12 h after dosing. Pharmacokinetic parameters were derived using a two-compartmental model except for AUC(0-->t), which was derived using non-compartmental analysis. Bioavailability was estimated using AUC(0-->t) for the oral and the intravenous periods. Urine, for measurements of volume and osmolality, was collected in predetermined intervals before and until 12 h after dosing. Results: Fifteen healthy men aged 55-70 years were included in the analysis. The concentration-time curve after 2 mug intravenous desmopressin was best described using a biexponential term. The mean (95% CI) AUC at night was 302 (272-335) pg x h/ml and in the day was 281 (253-312) pg x h/ml. No statistically significant differences were detected between night and day except for terminal half-life, which was 3.1 h at night and 2.8 h in the daytime (P=0.02). After oral desmopressin, concentrations above the limit of quantification (2.5 pg/ml) were only detected in 51% of the samples. Peak plasma concentration (C-max) was 6.2 (5.1-7.5) pg/ml at night and 6.6 (5.5-7.9) pg/ml in the daytime. Median time to reach C-max (t(max)) was 1.5 (range 1.0-4.1) It at night and 1.5 (range 0.5-3.0) h in the day. The bioavailability was 0.08%. The pharmacodynamic effects of oral and intravenous desmopressin given in the daytime were similar during the first 6 h after dosing. The night-time dosing and daytime intravenous dose resulted in anti-diuresis throughout the measuring period, while the effect of the daytime peroral dose receded after 6 h. Conclusion: The pharmacokinetic profile of desmopressin is biexponential. Terminal half-life was longer at night than in the daytime, but the difference is considered too small to be of clinical importance. The plasma levels given by the intravenous dose resulted in a duration of action of 12 h or more. Despite low bioavailability, the pharmacodynamic effects of oral desmopressin were similar in magnitude to those after intravenous dose at night and during the first 6 h after daytime administration.