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Purpose <p>Trientine dihydrochloride (TETA-2HCl) is an established treatment for Wilson disease. We assessed different dissolution profiles of TETA-2HCl capsules on the pharmacokinetics (PK) of trientine (TETA) and on direct copper (Cu) parameters.</p> Methods <p>In this open-label, randomized, two way cross-over study, 24 healthy subjects received two single oral doses of 600&#xa0;mg TETA-2HCl with a washout of at least one week; one dose with a fast and one dose with a slow dissolution profile. Blood and urine samples were collected up to 48&#xa0;h for analysis of plasma TETA and its metabolites, N1-acetyltriethylenetetramine (MAT) and N1-N10-diacetyltriethylenetetramine (DAT), serum Cu, ceruloplasmin (Cp) and urinary Cu excretion (UCE). The effect of dissolution profile on the PK was assessed through the ratio of geometric mean ratios (GMRs) and two-sided 90%-confidence intervals (CI) of the fast vs. slow dissolution profile.</p> Results <p>The C<sub>max</sub> of TETA was comparable for the two products (GMR 95.81%; CI 83.87-109.46%) while AUC<sub>0 − inf</sub> was slightly lower for the capsules with fast dissolution profile (GMR 90.65; 90% CI 78.32-104.91%). PK parameters were similar for the metabolites of TETA. Additionally, serum Cu and Cp concentrations remained stable over the 12&#xa0;h period after dosing and were comparable between the two products, as was UCE.</p> Conclusion <p>The pharmacokinetic profiles of TETA after administration of TETA-2HCl capsules with fast and slow dissolution characteristics were similar. Though the lower 90%-CI for AUC<sub>0-inf</sub> was outside the formal bioequivalence ranges, differences were small (9%) and not considered clinically relevant. A difference in dissolution profile did not affect copper parameters and tolerability.</p>

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New insights into the effects of dissolution profiles on the pharmacokinetics of trientine dihydrochloride

  • 期刊论文

  • 发表日期：

    2025年12月22日

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  • Karl Heinz Weiss,
  • Carlot Kruse,
  • Khalid Abd-Elaziz,
  • Eric van der Horst,
  • ChauHwei Fu,
  • Verena Aliane,
  • Jan-Jaap Scherpbier,
  • Mireille Gerrits,
  • Peter Dogterom

摘要

Purpose

Trientine dihydrochloride (TETA-2HCl) is an established treatment for Wilson disease. We assessed different dissolution profiles of TETA-2HCl capsules on the pharmacokinetics (PK) of trientine (TETA) and on direct copper (Cu) parameters.

Methods

In this open-label, randomized, two way cross-over study, 24 healthy subjects received two single oral doses of 600 mg TETA-2HCl with a washout of at least one week; one dose with a fast and one dose with a slow dissolution profile. Blood and urine samples were collected up to 48 h for analysis of plasma TETA and its metabolites, N1-acetyltriethylenetetramine (MAT) and N1-N10-diacetyltriethylenetetramine (DAT), serum Cu, ceruloplasmin (Cp) and urinary Cu excretion (UCE). The effect of dissolution profile on the PK was assessed through the ratio of geometric mean ratios (GMRs) and two-sided 90%-confidence intervals (CI) of the fast vs. slow dissolution profile.

Results

The Cmax of TETA was comparable for the two products (GMR 95.81%; CI 83.87-109.46%) while AUC0 − inf was slightly lower for the capsules with fast dissolution profile (GMR 90.65; 90% CI 78.32-104.91%). PK parameters were similar for the metabolites of TETA. Additionally, serum Cu and Cp concentrations remained stable over the 12 h period after dosing and were comparable between the two products, as was UCE.

Conclusion

The pharmacokinetic profiles of TETA after administration of TETA-2HCl capsules with fast and slow dissolution characteristics were similar. Though the lower 90%-CI for AUC0-inf was outside the formal bioequivalence ranges, differences were small (9%) and not considered clinically relevant. A difference in dissolution profile did not affect copper parameters and tolerability.