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.