Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 PHARMACODYNAMIC PROPERTIES
Pharmacotherapeutic group: vasopressin and analogues.
ATC code: HO1B A02
Minirin Melt contains 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.

Pharmacokinetic Properties

5.2 PHARMACOKINETIC PROPERTIES
Absorption
The overall mean absolute bioavailability of desmopressin administered sublingually as Melts at doses of 200, 400 and 800 micrograms is 0.25% with a 95% confidence interval of 0.21% - 0.31%. The Cmax was 14, 30 and
65pg/ml after administration of 200, 400 and 800 micrograms respectively. Tmax was observed at 0.5 – 2.0 hours after dosing. The geometric mean terminal half-life is 2.8 (CV = 24%) hours.

Correlation table between desmopressin in Tablet and Melt forms:
Tablet                  Tablet                   Melt                    Melt 
Desmopressin            Desmopressin             Desmopressin            Desmopressin acetate acetate                 free base                free base


0.1mg                   89 micrograms            60 micrograms           Approx. 67 micrograms* 
0.2mg                   178 micrograms           120 micrograms          Approx. 135 micrograms* 
0.4mg                   356 micrograms           240 micrograms          Approx. 270 micrograms* 
* calculated for comparative purposes
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.
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 metabolised in the liver by the cytochrome P450 system. Thus human liver metabolism in vivo by the cytochrome P450 system is unlikely to occur. The effect of desmopressin on the pharmacokinetics 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-live of desmopressin is estimated to 2.8 hours. In healthy subjects the fraction excreted unchanged was 52 % (44 % - 60 %).
Linearity/non-linearity
There are no indications of non-linearities in any of the pharmacokinetic parameters of desmopressin.
Characteristics in specific groups of patients
Renal impairment:
Depending on the degree of renal impairment the AUC and half-live increased with the severity of the renal impairment. Desmopressin is contraindicated in patients with moderate and severe renal impairment (creatinine clearance below 50 ml/min).

Hepatic impairment:
No studies have been performed.
Children:
The population pharmacokinetics of desmopressin tablets has been studied in children with PNE and no significant difference from adults were detected.