Desmopressin pharmacokinetics

Renal and Biliary Excretion, and Sex Differences in Desmopressin Pharmacokinetics Desmopressin Formulation... 

The pharmacokinetics of one dose of desmopressin 400 micrograms have been investigated in 15 men and nine women with nocturia aged over 65 years (40). They then entered a placebo-controlled crossover evaluation period. Peak concentrations occurred at 1-2 hours after administration and gradually fell over 6-7 hours. The women had significantly higher concentrations than the men, even after adjustment for body weight. Four women were withdrawn from the crossover period because of hyponatremia. 

Hvistendahl GM, Riis A, Nprgaard JP, Djurhuus JC. The pharmacokinetics of 400 pg of oral desmopressin in elderly patients with nocturia, and the correlation between the absorption of desmopressin and clinical effect. BJU Int 2005 95 804-9. 

PHARMACOKINETICS When vasopressin and desmopressin are given orally, they are rapidly inactivated by trypsin, which cleaves the peptide bond between amino acids 8 and 9. Inactivation by peptidases in various tissues (particularly the Uver and kidneys) results in a plasma tj of vasopressin of 17-35 minutes. Following intramuscular or subcutaneous injection, the antidiuretic effects of vasopressin last 2-8 hours. The plasma t of desmopressin has a fast component of 6.5-9 minutes and a slow component of 30-117 minutes. Only 3% and 0.15%, respectively, of intranasaUy and orally administered desmopressin is absorbed. 

In this section, the pharmacokinetics of clinically important peptide/protein drugs, such as insulin, EPO, G-CSF, interferon, growth hormone, leuprolide, desmopressin, and antibodies, are described in relation to their administration routes and formulations (i.e., dosage forms). 

As another parameter to alter the pharmacodynamic prohle of desmopressin, a sex difference is most important. In 2004, Odeberg et al. demonstrated that there was a sex difference in a human pharmacokinetic (PK) and pharmacodynamic (PD) study [214], where desmopressin was administered intravenously as a single dose (for the PK study, a 2-pg dose for the PD study, a 0.2-pg dose), and parameters for urine flow and urine osmolality were estimated. The pharmacokinetics of desmopressin after a fixed bofus injection were influenced neither by piroxicam nor by sex of subjects. However, the pharmacodynamics of desmopressin showed a sex difference where females exhibited a more pronounced antidiuretic effect than males, which was statistically signihcant when the effects were submaximal (>4.5h after dose). The sex differences were diminished after pretreatment with an NSAID, piroxicam, indicating a prostaglandin PGE2-mediated mechanism. 

Usually, desmopressin is administered intranasally by use of sprays or drops. This administration route of desmopressin was considered to be more efficacious than the oral route, because bypassing the gastrointestinal tract increases the absolute bioavailability from less than 1% to approximately 5%. However, nasal application of desmopressin is accompanied by high intersubject and intrasubject variability in plasma pharmacokinetics [215]. Therefore, there have been several pharmaceutical research efforts to improve nasal delivery of desmopressin. 

Rembratt A, Grangaard-Jensen C, Senderovitz T, et al. (2004). Pharmacokinetics and pharmacodynamics of desmopressin administred orally versus intravenously at daytime versus night-time in healthy men aged 55-70 years. Eur. J. Clin. Pharmacol. 60 397-402. 

Odeberg J M, Callreus T, Lundin S, et al. (2004). A pharmacokinetics and pharmacodynamics study of desmopressin Evaluationg sex differences and the effect of pretreatment with piroxicam, and further validation of an indirect response model. J. Pharm. Pharmacol. 56 1389-1398. 

Lethagen S, Harris A S, Sjorin E, et al. (1987). Intranasal and intravenous administration of desmopressin Effect on F VIII/vW, pharmacokinetics and reproducibility. Thromb. Haematost. 58 1033-1036. 

Nervous system The safety of desmopressin in children with primary monosjmiptomatic nocturnal enuresis has been reviewed [86 ]. After 61 cases of seizures, including two deaths, the FDA asked that the prescribing information be changed in 2007 to state that desmopressin spray is no longer indicated for monosymptomatic nocturnal enuresis or in patients at risk of hyponatremia. The authors of the review concluded that hyponatremia often resulted from inappropriately high doses of desmopressin and usually occurs in the elderly people they supported continuing the use of desmopressin to treat monosymptomatic nocturnal enuresis imder appropriate medical supervision. Hyponatremia has been reported more commonly with the spray than with the oral formulation this may reflect differences in pharmacokinetics or more extensive evaluation of the spray. 

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