Open-Label, Balanced, Randomized, Single-Dose, Three-Treatment, Three-Sequence, Three-Period, Three-Way Crossover Oral Bioequivalence Study of Desmopressin Acetate Oral Solution.
This study confirms that the new desmopressin acetate oral solution is bioequivalent to the tablet formulation, which may facilitate its regulatory approval.
Where it sits
this study against the rest of the desmopressin corpusSummary and findings
This 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. Participants received a single 600-mcg dose of each formulation under fasted conditions. Results indicated bioequivalence between the two formulations.
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<sub>max</sub>], area under the plasma concentration-time curve from time 0 to the last measurable concentration [AUC<sub>0-t</sub>], AUC from time 0 extrapolated to infinity [AUC<sub>0-∞</sub>]) 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<sub>max</sub>, 103.7% (94.8%-113.5%) for AUC<sub>0-t</sub>, and 103.7% (94.9%-113.3%) for AUC<sub>0-∞</sub>. 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.
Background
This paper addresses the bioequivalence of desmopressin formulations, which is important due to the drug's narrow therapeutic index and dosing challenges. Previous studies have established desmopressin as a first-line therapy for central diabetes insipidus, but the pharmacokinetic profiles of different formulations have not been thoroughly compared. Establishing bioequivalence is crucial for regulatory approval and clinical use.
Methods
This was an open-label, randomized, three-way crossover study involving 75 healthy adults. Participants received a single 600-mcg dose of either the oral solution or the tablet formulation, with 14-day washout periods between doses. Primary outcome measures included maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) metrics.
Results
The primary endpoint showed a geometric mean ratio of 101.9% (93.9%-110.5%) for Cmax, indicating bioequivalence. For AUC0-t, the geometric mean ratio was 103.7% (94.8%-113.5%), and for AUC0-∞, it was 103.7% (94.9%-113.3%). Both formulations exhibited similar pharmacokinetic profiles with a median time to maximum concentration of 1.0 h and a mean elimination half-life of ∼3.6 h.
Interpretation
The results align with prior literature indicating that different formulations of desmopressin can achieve similar pharmacokinetic profiles. While the findings are statistically significant, the clinical significance of the observed differences in bioavailability may be minimal. Limitations such as the open-label design and small sample size may affect the robustness of the conclusions drawn.
Key findings
- Geometric mean ratio of 101.9% (93.9%-110.5%) for Cmax.
- Geometric mean ratio of 103.7% (94.8%-113.5%) for AUC0-t.
- Geometric mean ratio of 103.7% (94.9%-113.3%) for AUC0-∞.
- 1.0 h median time to maximum concentration.
- ∼3.6 h mean elimination half-life.
- 5 adverse events reported by 5 participants (6.7%).
Limitations
- open-label design may introduce bias
- small sample size of n=75
- adverse events were mild to moderate
- short duration of study with single-dose administration