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Pharmacology: Pharmacodynamics: MINIRIN contain desmopressin, a structural analogue of the natural pituitary hormone arginine vasopressin. The difference lies in the desamination of cysteine and substitution of L-arginine by D-arginine. This results in a considerably longer duration of action and a complete lack of pressor effect in the dosages clinically used.
Tablet: Desmopressin is a potent compound with an EC50 value of 1.6 pg/mL, for the antidiuretic effect. After oral administration, an effect lasting from 6 to 14 hours or more, can be expected.
Injection: Desmopressin at high dosage, 0.3 μg/kg body weight intravenously, leads to a two- to fourfold increase in plasma of factor VIII coagulant activity (VIII:C). Also the content of von Willebrand factor-antigen (vWF:Ag) increases, but to a lesser extent. At the same time there is a release of the plasminogen activator (t-PA).
Administration of desmopressin at a high dosage has also been shown to lead to a shortening or normalisation of the bleeding time in patients with prolonged bleeding time as in uremia, liver cirrhosis, congenital or drug-induced thrombocyte dysfunction and in patients with prolonged bleeding time of unknown etiology.
By administration of desmopressin instead of factor VIII concentrates, the risk of transmission of HIV-infection and hepatitis virus is avoided.
Pharmacokinetics: Absorption: Tablet & Oral lyophilisate: The absolute bioavailability of MINIRIN tablets is 0.16% with an SD of 0.17%. Mean maximum plasma concentration is reached within 2 hours.
Concomitant use of food decreases the rate and extent of absorption by 40%.
Correlation table between MINIRIN tablet and MINIRIN oral lyophilisate: (See Table 1.)
Click on icon to see table/diagram/imageOral lyophilisate: The overall mean absolute bioavailability of desmopressin administered sublingually as Minirin oral lyophilisate at doses of 200, 400 and 800 mcg is 0.25% with a 95% confidence interval of 0.21-0.31%. The Cmax was 14, 30 and 65 pg/mL after administration of 200, 400 and 800 mcg, respectively. Tmax was observed at 0.5-2 hrs after dosing.
Injection: The bioavailability following subcutaneous injection compared with intravenous administration is about 85%. Maximal plasma concentration after 0.3 μg/kg given as a subcutaneous injection is achieved after approximately 60 minutes and it amounts to 600 pg/ml in average.
Nasal spray: Bioavailability is approx. 3-5%. The maximum plasma concentration is reached after approx. one hour and does not increase in proportion to the administered dose. One intranasal dose of 10-20 μg produces an antidiuretic effect for 8-12 hours.
Distribution: The distribution of desmopressin is best described by a two-compartment distribution model with a volume of distribution during the elimination phase of 0.3-0.5 L/kg.
Nasal spray: The distribution volume during the elimination phase is 38 L. Desmopressin does not cross the blood-brain barrier.
Biotransformation: The in-vivo metabolism of desmopressin has not been studied. In vitro human liver microsome metabolism studies of desmopressin have shown that no significant amount is metabolized in the liver by cytochrome P450 system. Thus human liver metabolism in vivo by the cytochrome P450 system is unlikely to occur. The effect of desmopressin on the PK of other drugs is likely to be minimal due to its lack of inhibition of the cytochrome P450 drug metabolizing system.
Elimination: The total clearance of desmopressin has been calculated to 7.6 L/hr. The terminal half-lives of desmopressin is estimated to 2.8 hours. In healthy subjects the fraction excreted unchanged was 52% (44%-60%).
Injection: The duration of the haemostatic effect depends of the half-life for VIII:C which is about 8-12 hours.
Linearity/Nonlinearity: Oral lyophilisate: Linearity (dose-proportional pharmacokinetics) was established for Minirin oral lyophilisate for dose levels from 60-240 mcg.
Characteristics in specific group of patients: Renal Impairment: Depending on the degree of renal impairment the AUC and half-live increased with the severity of the renal impairment in patients with moderate and severe renal impairment (creatinine clearance below 50 ml/min) desmopressin is contraindicated.
Hepatic Impairment: No studies performed.
Children: Tablet & Oral lyophilisate: The population pharmacokinetics of MINIRIN tablets has been studied in children with PNE and no significant difference from adults were detected.
Nasal spray: Metabolism: In vitro studies with human liver microsomes have shown that an insignificant amount of desmopressin is metabolised in the liver microsomes. It is therefore unlikely that desmopressin is metabolised in the liver in humans. Desmopressin does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4 in vitro and thus should desmopressin not affect the pharmacokinetics of other drugs metabolized by CYP enzymes.
Elimination: The total clearance of desmopressin has been calculated to 7.6 L/h. The half-life for desmopressin in the elimination phase is 2.8 hours in average. In healthy subjects the fraction excreted unchanged in urine is 52%.
Toxicology: PRECLINICAL SAFETY DATA: Tablet: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, toxicity to reproduction; and development (injection).
Tablet: Carcinogenicity studies have not been performed with desmopressin, because it is very closely related to the naturally-occurring peptide hormone.
Injection: No studies of the carcinogenic potential have been performed.
