Trientine Capsule Comparison Reveals Faster Absorption and Higher Dose-Normalized Exposure in Healthy Volunteers

A single-dose crossover study in 36 healthy adults has found that two marketed trientine dihydrochloride capsule formulations, a 250 mg test product and a 300 mg reference product, produce broadly similar overall drug exposure when given at their commercial strengths, but differ in ways that matter for how the results should be read. The test capsule was absorbed faster, and when exposure figures were adjusted for the dose difference, the test formulation delivered more drug per milligram. The work, published in Drugs in R&D, was carried out in a regulatory development context and offers a detailed look at the pharmacokinetic behavior of a chelator that patients with Wilson disease may take for life.

Trientine dihydrochloride, or triethylenetetramine dihydrochloride, is an oral copper chelator used in Wilson disease, a rare autosomal-recessive disorder in which impaired biliary copper excretion leads to progressive copper accumulation in the liver, brain and other organs. Lifelong pharmacological reduction of systemic copper is central to management, and chelating agents such as d-penicillamine and trientine promote urinary copper excretion while zinc salts reduce intestinal copper absorption. Trientine has been used for several decades, particularly in patients who do not tolerate d-penicillamine, but its pharmacokinetics are challenging: oral absorption is limited and variable, food has a clinically relevant effect, and inter-individual variability is substantial.

Because Wilson disease requires continuous therapy, the availability of alternative trientine formulations is clinically important. Yet formulations can differ in salt form, capsule composition, dissolution behavior and marketed strength, and such differences can alter absorption rate and systemic exposure. The new study, protocol BE/18/204, compared a 250 mg test capsule from Emcure Pharmaceuticals Ltd. in India with a 300 mg reference capsule from Univar B.V. in the Netherlands under fasting conditions. Notably, the investigators did not administer the same molar dose, which is the conventional setting for formal bioequivalence assessment, and they therefore framed the work as a comparative pharmacokinetic evaluation at marketed strengths.

The design was a randomized, open-label, balanced, two-treatment, two-period, two-sequence, single-dose crossover study. Thirty-six healthy adults were enrolled, including seven women, with a mean age of 30.3 years and a mean body mass index of 23.4 kg/m2. Eligible volunteers were aged 18 to 45 years with a body mass index between 18.50 and 30.00 kg/m2. After an overnight fast of at least 10 hours, each participant received a single capsule with 240 ± 2 mL of water while sitting upright, and food was withheld for 4 hours after dosing. The two treatment sequences were separated by a 7-day washout. One subject withdrew for personal reasons unrelated to the investigational products, leaving 35 participants in the pharmacokinetic and statistical analyses.

Blood sampling was intensive. Venous samples were drawn before dosing and at 27 time points spanning 0.17 to 48.00 hours after each dose, collected into K3EDTA tubes, kept on wet ice and centrifuged within 45 minutes. Plasma concentrations of parent trientine and its metabolite N1-acetyltriethylenetetramine were quantified by Raptim Research Limited in Navi Mumbai using a validated liquid chromatography-tandem mass spectrometry method with deuterated internal standards, protein precipitation, and derivatization with fluorenylmethyloxycarbonyl chloride. The validated analytical range was 10.01 to 2000.56 ng/mL for trientine and 7.63 to 1524.28 ng/mL for the metabolite. Incurred sample reanalysis of 213 samples met acceptance criteria for 85.51% of trientine measurements and 95.77% of metabolite measurements.

The results showed that both formulations produced quantifiable parent trientine concentrations, but absorption was faster with the test product. Median time to peak concentration was 1.25 hours for the test formulation versus 2.25 hours for the reference, a difference that was statistically significant by the Wilcoxon signed-rank test with p < 0.0001. Mean peak concentration was 933.99 ± 345.99 ng/mL for the test capsule and 832.31 ± 370.89 ng/mL for the reference. Mean area under the concentration-time curve to the last quantifiable point was 3771.15 ± 1962.20 h·ng/mL for the test product and 3503.65 ± 1897.99 h·ng/mL for the reference, and the concentration-time profiles were generally similar in shape, with earlier peaks for the test formulation.

The primary statistical comparison used log-transformed peak concentration and AUC0–t analyzed by analysis of variance, yielding test/reference geometric least-squares mean ratios with 90% confidence intervals. At the administered strengths, the ratio was 114.96% (90% CI 104.40–126.60) for peak concentration, with an intra-subject coefficient of variation of 24.16%, and 109.36% (90% CI 98.40–121.55) for AUC0–t, with an intra-subject CV of 26.55%. The conventional acceptance interval is 80.00 to 125.00%. Overall exposure as measured by AUC0–t fell within that interval, but the upper confidence limit for peak concentration slightly exceeded 125.00%.

Because the two products differed in nominal strength, the researchers also performed a supportive dose-normalized analysis in which plasma concentrations from the 250 mg test product were multiplied by a factor of 1.2 to align with the 300 mg reference strength. Under this normalization, the ratio for peak concentration rose to 137.95% (90% CI 125.28–151.92) and for AUC0–t to 131.24% (90% CI 118.08–145.86), both exceeding the conventional interval. This indicates higher exposure per milligram for the test formulation and points to formulation-dependent pharmacokinetic differences, potentially related to absorption efficiency, disintegration, dissolution, excipients or other galenic characteristics. Metabolite data were treated as supportive only: dose-unadjusted metabolite ratios were 95.17% (88.00–102.92) for peak concentration and 95.58% (89.34–102.26) for AUC0–t, rising to 114.20% and 114.69% after dose normalization, and median metabolite Tmax was 5.00 hours for both formulations.

Safety findings were reassuring within the limits of the design. No serious adverse events occurred, and no adverse events were reported during either treatment period. Five mild adverse events were reported during post-study safety assessment, and the authors concluded that both formulations were safe and well tolerated under fasting conditions, with no outstanding safety concerns for either product. This profile is consistent with the tolerability previously reported for trientine, although a single-dose study in healthy volunteers cannot capture the safety experience of long-term chelation therapy in patients.

The authors are explicit about the limits of interpretation. Formal bioequivalence is generally assessed after administration of the same molar dose and interpreted against predefined acceptance limits, whereas this study compared the marketed strengths actually administered, so the term bioequivalence is reserved for the specific regulatory assessment context. The study also did not assess clinical outcomes, steady-state exposure, urinary copper excretion or pharmacodynamic endpoints in patients with Wilson disease, meaning direct conclusions about therapeutic equivalence cannot be drawn. The shorter Tmax reflects the rate rather than the extent of absorption and, because trientine is used as chronic therapy, onset of action is not expected to be the clinically decisive driver of therapeutic effect. The investigators argue that the crossover design, intensive sampling, validated assay and transparent presentation of both administered-strength and dose-normalized analyses provide a robust basis for comparative pharmacokinetic characterization, while clinical monitoring and formulation-specific dosing recommendations remain important, particularly when switching between trientine products in long-term care.

Subject of Research: Comparative pharmacokinetics of two marketed trientine dihydrochloride capsule strengths in healthy volunteers

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

Article References: Hartmann, C. J., Tacke, F., Mohr, I., Praktiknjo, M., Jankofsky, M., Wahler, S., & Weiss, K. H. (2026). Comparative Pharmacokinetics of Trientine Dihydrochloride Capsules: A Randomized, Open-Label, Reference-Controlled, Two-Period Crossover Study in Healthy Volunteers. Drugs in R&D. https://doi.org/10.1007/s40268-026-00553-w

Image Credits: AI Generated

DOI: 10.1007/s40268-026-00553-w

Keywords: trientine dihydrochloride, Wilson disease, pharmacokinetics, bioequivalence, crossover study, healthy volunteers, copper chelator, dose normalization, LC-MS/MS, drug formulations, absorption rate, Drugs in R&D