Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: vasopressin and analogues.
ATC code: HO1B A02
Minirin Tablets 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.
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.
Clinical trials with desmopressin tablets in the treatment of nocturia showed the following: - A reduction of at least 50 % in the mean number of nocturnal voids was obtained in 39 % of patients with desmopressin compared to 5 % of patients with placebo (p<0.0001)
- The mean number of voids per night decreased by 44 % with desmopressin compared to 15 % with placebo (p<0.0001)
- The median duration of first undisturbed sleep period increased by 64% with desmopressin compared to 20 % with placebo (p<0.0001)
- The mean duration of first undisturbed sleep period increased by 2 hours with desmopressin compared to 31 minutes with placebo (p<0.0001)
Effect of treatment with individual oral dose of desmopressin between 0.1 and 0.4 mg during 3 weeks, compared with placebo (pooled data).

Desmopressin                               Placebo                Statistical significance vs.
placebo
Variable         Mean                    Mean value         Mean           Mean value baseline                during 3           baseline       during 3 value                   weeks of           value          weeks of treatment                         treatment
Number of        2.97 (0.84)             1.68(0.86)         3.03 (1.10)    2.54 (1.05)         p<0.0001 nocturnal voids
Nocturnal        1.51 (0.55)             0.87 (0.34)        1.55(0.57)     1.44 (0.57)         p<0.0001 diuresis rate (ml/min)
Duration of      152 (51)                270 (95)           147 (54)       178 (70)            p<0.0001 first undisturbed sleep period (min)

Eight percent of the patients interrupted in the desmopressin dose titration phase due to adverse effects, and 2 % in the subsequent double-blind phase (0.63 % on desmopressin and 1.45 % on placebo). 5.2 

Pharmacokinetic Properties

Pharmacokinetic properties
The absolute bioavailability of desmopressin 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%.
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 metabolized 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 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-life of desmopressin is estimated to be 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-life increased with the severity of the renal impairment. In patients with moderate and severe renal impairment (creatinine clearance below 50ml/min) desmopressin is contraindicated.
Hepatic Impairment: No studies performed.
Children: The population pharmacokinetics of desmopressin tablets has been studied in children with PNE and no significant differences from adults were detected.