Open-Label, Balanced, Randomized, Single-Dose, Three-Treatment, Three-Sequence, Three-Period, Three-Way Crossover Oral Bioequivalence Study of Desmopressin Acetate Oral Solution

Abstract

Desmopressin is first-line therapy for central diabetes insipidus, also known as arginine vasopressin deficiency, but presents dosing challenges due to its narrow therapeutic index. This open-label, randomized, three-way crossover study evaluated the bioequivalence of a new desmopressin acetate oral solution (50 mcg/mL) compared to desmopressin acetate tablets (200 mcg) in 75 healthy adults. In a balanced, three-sequence, three-period design with 14-day washout periods, participants received a single 600-mcg dose of test product and reference product under fasted conditions. Plasma desmopressin concentrations were measured using a validated liquid chromatography-electrospray ionization tandem mass spectrometry method, and primary pharmacokinetic parameters (maximum plasma concentration [C_max], area under the plasma concentration–time curve from time 0 to the last measurable concentration [AUC_0–t], AUC from time 0 extrapolated to infinity [AUC_0–∞]) were derived from resulting concentration–time profiles. Bioequivalence was assessed using analysis of variance on log-transformed parameters, with 90% confidence intervals (CIs) for geometric mean ratios 80%–125%. Results demonstrated bioequivalence between formulations, with geometric mean ratios of 101.9% (93.9%–110.5%) for C_max, 103.7% (94.8%–113.5%) for AUC_0–t, and 103.7% (94.9%–113.3%) for AUC_0–∞. Both formulations exhibited similar pharmacokinetic profiles with 1.0 h median time to maximum concentration, ∼3.6 h mean elimination half-life, and 30%–33% intrasubject variability. Five adverse events were reported by five participants (6.7%), including two cases of hyponatremia (reference group) and one case of vomiting (test group); all were mild to moderate and resolved completely. This study establishes bioequivalence between desmopressin acetate oral solution and tablets, supporting regulatory approval of the oral solution formulation.