Comparative Pharmacokinetics of Trientine Dihydrochloride Capsules: A Randomized, Open-Label, Reference-Controlled, Two-Period Crossover Study in Healthy Volunteers

Abstract

Trientine dihydrochloride (TETA-2HCl) is an oral copper chelator used for Wilson disease. Because available formulations differ in marketed strength and may have formulation-specific pharmacokinetic properties, this study compared a 250 mg test capsule and a 300 mg reference capsule administered under fasting conditions. This randomized, open-label, balanced, two-treatment, two-period, two-sequence crossover study enrolled 36 healthy adults. Plasma samples collected over 48 h after single-dose administration were analyzed for parent trientine and N1-acetyltriethylenetetramine using validated liquid chromatography (LC)-tandem mass spectrometry (MS/MS). The primary comparative pharmacokinetic evaluation was based on parent trientine C max and AUC 0–t at the administered strengths. Dose-normalized and metabolite analyses were supportive. Thirty-five participants were included in the pharmacokinetic and statistical analyses. Parent trientine was absorbed more rapidly after the test formulation, with median T max values of 1.25 versus 2.25 h. At the administered strengths, test/reference geometric least-squares mean ratios (90% confidence intervals) were 114.96% (104.40–126.60) for C max and 109.36% (98.40–121.55) for AUC 0–t . Dose-normalized ratios were 137.95% (125.28–151.92) and 131.24% (118.08–145.86), respectively, indicating higher exposure per milligram for the test formulation. Metabolite findings were supportive and did not determine the primary comparative conclusion. No serious adverse events occurred; five mild adverse events were reported during post-study safety assessment. At the administered strengths, AUC 0–t was similar between the formulations, whereas the upper confidence limit for C max slightly exceeded 125.00%. Faster absorption and higher dose-normalized exposure with the test formulation indicate formulation-dependent pharmacokinetic differences and support cautious use of bioequivalence terminology outside the specific regulatory assessment context.