Abstract
PurposeAntidiuretic therapy with desmopressin for nocturia has been hampered by formulations with high doses, low bioavailability and variable pharmacokinetics. AV002 (SER120), a novel, emulsified, microdose desmopressin nasal spray, with a permeation enhancer (cylcopentadecanolide), was developed to have pharmacokinetic characteristics suitable for nocturia treatment.MethodsTwelve healthy subjects participated in an open-label, dose-escalating study. Water-loaded subjects were sequentially dosed every 48 h with AV002 0.5, 1.0, 2.0 μg and 0.12 μg desmopressin subcutaneous (SC) bolus injection.ResultsAV002 intranasal administration produced a time-to-maximum concentration (Tmax) between 15 and 30 min and a maximum concentration (Cmax) <10 pg/mL. Cmax and area under the curve showed dose proportionality. Coefficient of variation for AV002 was similar to that observed for the SC dose. Bioavailability of AV002 was approximately 8% compared to SC injection. AV002 demonstrated pharmacodynamic effects within 20 min of dosing and showed increasing magnitude and duration with escalating doses. AV002 2.0 μg had maximum median urine osmolality of 629 mOsm/kg and median urine output ≤2 mL/min for 5–6 h.ConclusionsAV002 demonstrated rapid absorption, high bioavailability, limited duration of action, and low coefficient of variation, suggesting it may be a suitable formulation for nocturia treatment.Trial registration not required (single-center, phase 1).
Highlights
The vasopressin analogue, desmopressin, is a synthetic nonapeptide originally introduced for treatment of central diabetes insipidus [1,2,3] and later in patients with primary nocturnal enuresis [4,5] and nocturia caused by nocturnal polyuria [6,7,8]
The subjects enrolled in the study had a mean age of 22.3 years and 91.7% were Caucasian
Pharmacokinetic samples were collected at pre-dose and 0.083, 0.167, 0.25, 0.50, 0.75, 1.05, 1.50, 2.05, 3.05, 4.05, and 6.05 h post dose each dosing day
Summary
The vasopressin analogue, desmopressin, is a synthetic nonapeptide originally introduced for treatment of central diabetes insipidus [1,2,3] and later in patients with primary nocturnal enuresis [4,5] and nocturia caused by nocturnal polyuria [6,7,8]. Similar to natural antidiuretic hormone (arginine vasopressin), the antidiuretic activity of desmopressin is mediated by binding to the vasopressin receptor 2 on principal cells of renal collecting tubules, thereby stimulating a cascade of biochemical events that increases urine concentration and decreases urine production [9]. These changes are mediated by passive reabsorption of solute-free water down the osmotic gradient created by the hypertonicity in the renal medulla [9].
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