Assessment of Pharmacokinetics and Safety with Bioequivalence of the Nitroglycerin Sublingual Tablets of Two Formulations in Chinese Healthy Subjects: A Bioequivalence Study.

Abstract

Background and objective: Nitroglycerin, a cornerstone therapy for acute angina pectoris, achieves rapid symptom relief through sublingual administration by bypassing hepatic first-pass metabolism. This study aimed to investigate the pharmacokinetics (PK), bioequivalence, and safety profiles between a test (T) formulation and a reference (R) formulation of nitroglycerin sublingual tablets in healthy volunteers (HVs).

Methods: In this single-center, randomized, open, single-dose, two-part formulations, four-cycle, two-sequence complete repeat crossover design, fasting-dose bioequivalence study, HVs (n = 36) were 1:1 divided into two groups (T-R-T-R and R-T-R-T) and received 0.6 mg of nitroglycerin sublingual with a 3 d washout. Venous blood was collected 3 h after each administration. Plasma levels of nitroglycerin were analyzed using a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) technique, and PK parameters were calculated using noncompartmental methods.

Results: For nitroglycerin, the bioequivalence between the test and reference formulations was assessed using the Reference-Scaled Average Bioequivalence (RSABE) method for the maximum plasma concentration (C_max), area under the curve (AUC) from t = 0 to infinity (AUC_0-∞) and AUC from t = 0 to the final measurable concentration (AUC_0-t). Results showed that the least squares geometric mean ratios (T/R) of C_max, AUC_0-t, and AUC_0-∞ for nitroglycerin (94.62%, 89.92%, and 89.44%, respectively) were in the range of 80.00-125.00%, and the upper limit of unilateral 95% confidence interval (CI) of C_max, AUC_0-t, and AUC_0-∞ for nitroglycerin (-0.06, -0.03, and -0.03, respectively) were less than 0. Safety profiles were comparable between formulations, with no serious adverse events (AE) reported.

Conclusions: The study confirmed bioequivalence between the test and reference formulations, demonstrating equivalent absorption rates (C_max) and extents (AUC). Rapid therapeutic plasma levels were achieved via sublingual administration, aligning with nitroglycerin's clinical need for prompt angina relief. These findings, combined with favorable safety data, support the test formulation as a therapeutically equivalent alternative.