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Comparison of the Pharmacokinetic Profiles of Trientine Tetrahydrochloride and Trientine Dihydrochloride in Healthy Subjects

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objective

Wilson disease (WD) is an autosomal recessive inherited disorder of copper metabolism. Chelation of excessive copper is recommended but data on the pharmacokinetics of trientine are limited. The aim of this study was to compare the pharmacokinetics of a new trientine tetrahydrochloride formulation (TETA 4HCl) with those of an established trientine dihydrochloride (TETA 2HCl) salt.

Methods

A randomised single-centre crossover study to evaluate the pharmacokinetics, safety and tolerability of two different oral formulations of trientine (TETA 4HCl tablets vs TETA 2HCl capsules) in 23 healthy adult subjects receiving a single dose equivalent to 600 mg of trientine base was performed.

Results

Following oral administration, the median time to reach maximum plasma concentration (Tmax) was 2.00 h (TETA 4HCl) and 3.00 h (TETA 2HCl). The rate (maximum plasma concentration [Cmax]) and extent (area under the plasma concentration-time curve from time zero to infinity [AUC0–∞]) of absorption of the active moiety, trientine, were greater (by approximately 68% and 56%, respectively) for TETA 4HCl than for the TETA 2HCl formulation. The two formulations presented a similar terminal elimination rate (λz) and a similar terminal half-life (t½) for trientine. Differences between TETA 4HCl and TETA 2HCl in the levels of the two main mono- and diacetylated metabolites were less than seen for trientine. For both tested formulations, healthy male volunteers demonstrated higher trientine plasma levels but lower mono- and diacetylated metabolite levels compared with females, with no sex differences in terminal half-life (t½) observed. Single oral doses of both formulations were safe and well tolerated.

Conclusions

Compared with an identical dose of a TETA 2HCl formulation, the TETA 4HCl formulation provided more rapid absorption of trientine and greater systemic exposure in healthy subjects.

Clinical Trials Number EudraCT # 2015-002199-25.

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Acknowledgements

Medical writing support (initial draft) was provided by Debbie Jordan (Debbie Jordan Ltd, Hampshire, UK) and funded by Orphalan SA, France. Graphs were produced by Dr. Margreke Brill (QPS, Netherlands).

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Salem Medical Center, Heidelberg, Germany

    Karl Heinz Weiss

  2. June Pharma Consulting Limited, London, UK

    Catherine Thompson

  3. QPS Netherlands B.V., Hanzeplein 1, 9713 GZ, Groningen, The Netherlands

    Peter Dogterom

  4. Orphalan, 226 Boulevard Voltaire, 75011, Paris, France

    Tim Morley, Brinley Jackson, Naseem Amin & Camille Omar Farouk Kamlin

  5. QPS Taiwan, 12F, No. 3, Park St, Nangang Dist, Taipei, 115, Taiwan

    Yi-jin Chiou

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  1. Karl Heinz Weiss
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Corresponding author

Correspondence to Camille Omar Farouk Kamlin.

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Funding

This study was funded by Orphalan.

Conflict of interest

KHW advises for Alexion, Bayer, Chiesi, Eisai, Orphalan, Pfizer, Ultragenyx, Univar, Vivet Therapeutics; KHW received research funding (to the institution) from Alexion, Novartis, Orphalan, Univar; KHW received travel grants from Abbvie, Bayer and Gilead.

Ethics approval

The clinical trial protocol (version 2), as well as the subject information and consent form, version 2, both dated 4 June 2015, were approved by the Independent Ethics Committee (IEC) on 9 June 2015. There were no amendments to the protocol. The competent authority of the Netherlands [Centrale Commissie Mensgebonden Onderzoek (CCMO)] was notified by the IEC according to the Dutch regulations on 4 June 2015.

Consent to participate

Informed written consent was provided by all participating subjects.

Consent to publish

Not applicable.

Availability of data and material

The clinical study report for this pharmacokinetics study, the TRIUMPH study, can be accessed on request from Orphalan.

Code availability

Not applicable.

Author contributions

KHW provided expert consultation on the study findings, presented the study at EASL, and edited and approved the final manuscript. PD designed the study, conducted the study at the study centre, analysed the data, and edited and approved the final manuscript. YC analysed data and approved final manuscript. CT designed the study, analysed the data, and edited and approved the final manuscript. TM provided scientific input into the study outcomes, analysed the data, and edited and approved the final manuscript. BJ provided scientific input into the study outcomes, analysed the data, and edited and approved the final manuscript. NA provided scientific input into the study outcomes, analysed the data, and edited and approved the final manuscript. COFK provided scientific input into the study outcomes, analysed the data, and edited and approved the final manuscript.

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Weiss, K.H., Thompson, C., Dogterom, P. et al. Comparison of the Pharmacokinetic Profiles of Trientine Tetrahydrochloride and Trientine Dihydrochloride in Healthy Subjects. Eur J Drug Metab Pharmacokinet 46, 665–675 (2021). https://doi.org/10.1007/s13318-021-00704-1

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