Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

11.2 Pharmacodynamics
In a pharmacodynamic study following sublingual administration of 60 mcg desmopressin (1.2 and 2.4 times the maximum recommended dose in men and women, respectively) with suppression of the 
endogenous vasopressin release by continuous intake of water, the mean time to onset of antidiuretic action was observed within 30 minutes and lasted 6 hours after dosing.
In a study in patients with nocturia due to nocturnal polyuria, the weight-corrected NOQDIRNA dose that induced 50% maximum achievable drug effect on nocturnal urine volume (ED50) differed significantly between women and men. The ED50 value for men was 2.7-fold (95% CI 1.3-8.1) higher than the value for women, corresponding to higher desmopressin sensitivity among women [see Dosage and Administration (2.1)].

Dose, sex, age and renal impairment affect the risk of developing hyponatremia [see Warnings and Precautions (5.1)].

Pharmacokinetic Properties

11.3 Pharmacokinetics

The pharmacokinetics of desmopressin following sublingual administration of NOQDIRNA has not been characterized. The pharmacokinetic information provided below is from studies following sublingual administration of higher doses or intravenous injection of desmopressin.
Absorption
The overall mean absolute bioavailability of desmopressin administered sublingually (at doses of 200, 400 and 800 mcg, which represents 4, 8, and 16 times the maximum recommend dosage in men) was
0.25% (95% CI 0.21–0.31%).

Distribution
The volume of distribution of desmopressin after intravenous administration of 2 mcg is 26.5 L.

Elimination
The geometric mean terminal half-life is 2.8 hours.
Metabolism
In vitro studies in human liver microsome preparations have shown that desmopressin is not a substrate for the human CYP450 system.
Excretion
Desmopressin is mainly excreted in the urine. After intravenous administration of 2 mcg, 52% of the dose was recovered in the urine within 24 hours as unchanged desmopressin.
Drug Interaction Studies
In vitro studies in human liver microsome preparations have shown that desmopressin does not inhibit the human CYP450 system. No in vivo interaction studies have been performed with NOQDIRNA.


Patients with Renal Impairment
A pharmacokinetic study was conducted in subjects with normal renal function and patients with mild, moderate, and severe renal impairment (n=24, 6 subjects in each group) who received a single 2 mcg dose of desmopressin intravenous injection.

The geometric mean terminal half-life was 2.8 hours in subjects with normal renal function, and 4, 6.6, and 8.7 hours in patients with mild, moderate, and severe renal impairment, respectively. In patients with mild, moderate and severe renal impairment, mean desmopressin area under the plasma drug concentration time curve (AUC) was 1.5-fold, 2.4-fold and 3.7-fold higher, respectively, compared to that of subjects with normal renal function [see Contraindications (4), Use in Specific Populations (8.6)].