Optimized Trientine‐dihydrochloride Therapy in Pediatric Patients With Wilson Disease

Abstract

Objectives: The aim of the study was to investigate the efficacy and safety of trientine-dihydrochloride (TD) in pediatric patients with Wilson disease (WD) and the effect of different weight-based dosages on their clinical and biochemical outcome. Methods: We retrospectively reviewed the clinical data of 31 children with WD receiving TD therapy ages under 18 years at the time of diagnosis. Outcome measures included parameters of copper metabolism and liver function tests. To examine the impact of different weight-based dosages, 2 dosage subgroups were analyzed. Group 1 received less than 20 mg/kg TD per day, group 2 more than 20 mg · kg−1 · day−1. Results: Median follow-up was 60 (5–60) months in the total study group. During TD therapy, nonceruloplasmin-bound copper was reduced from mean 1.53 (0.01–6.95) at baseline to 0.62 (0.01–4.57) μmol/l. 24h-urinary copper excretion diminished to 1.85 (0.8–9.6) μmol/day approximating the therapeutic goal of 1.6 μmol/day. Seven of 31 patients (22.6%) required discontinuation of TD treatment, in 4 cases it was because of adverse events (ulcerative colitis, gingival and breast hypertrophy, hirsutism, elevation of transaminases). Investigations about weight-based dosage showed no significant difference of any laboratory parameter between the 2 cohorts. But in terms of clinical safety, adverse effects because of TD were only found in 6.7% of children in group 1 (<20 mg · kg−1 · day−1, median follow-up 60 [9–60] months), whereas in group 2 (>20 mg · kg−1 · day−1, median follow-up 60 [14–60] months), it was 63.6%. Conclusions: TD proves to be an efficacious alternative chelating agent for children with WD. Weight-based dosages above the recommended 20 mg · kg−1 · day−1 may increase the rate of adverse effects in pediatric patients.

Comparison of the Effectiveness and Safety of d-Penicillamine and Zinc Salt Treatment for Symptomatic Wilson Disease: A Systematic Review and Meta‐Analysis

“…We also analyzed the occurrence of adverse effects in WD patients treated with D-penicillamine and trientine. There were four studies (Couchonnal et al, 2021;Mayr et al, 2021;Weiss et al, 2011;Merle et al, 2007), including 608 patients treated with D-penicillamine and 286 patients treated with trientine, that compared the occurrence of adverse effects between the two treatment regimens. The result showed that the adverse effects of trientine is lower than that of D-penicillamine (RR: 5.19, 95% CI: 1.79%-15.05%; p = 0.002, Supplementary Figure S9), which is consistent with EASL guideline recommendations.…”

A multidisciplinary approach to the diagnosis and management of Wilson disease: Executive summary of the 2022 Practice Guidance on Wilson disease from the American Association for the Study of Liver Diseases

“…[290,291] Available data suggest that trientine is safe and effective in pediatric patients with WD. [292,293] The tetrahydrochloride form of trientine was approved in 2022 by the Food and Drug Administration (FDA) for previously treated D-penicillamine-tolerant patients with WD. Bioequivalence between trientine dihydrochloride and trientine tetrahydrochloride has not yet been established because of differences in pharmacokinetics and bioavailability.…”

“…Exceeding 20 mg/kg/day may be associated with increased adverse effects. [293] Maintenance treatment in children can be 10-15 mg/kg/day, but normal growth often compensates for actual dose modification. Trientine should be administered 1 h before or 2 h after meals.…”

“…Trientine was effective initial therapy for patients, even with decompensated liver disease at the outset. Available data suggest that trientine is safe and effective in pediatric patients with WD 45,46. The tetrahydrochloride form of trientine was approved in 2022 by the Food and Drug Administration (FDA) for previously treated, d ‐penicillamine‐tolerant patients with WD.…”

“…In children, the initial dose generally used is 20 mg/kg/day rounded off to the nearest 250 mg, given in two or three divided doses, started incrementally. Exceeding 20 mg/kg/day may be associated with increased adverse effects 46. Maintenance treatment can be 10–15 mg/kg/day, but normal growth often compensates for actual dose modification.…”