Karl Heinz Weiss1, Catherine Thompson2, Peter Dogterom3, Yi-Jin Chiou4, Tim Morley5, Brinley Jackson5, Naseem Amin5, Camille Omar Farouk Kamlin6. 1. Department of Internal Medicine, Salem Medical Center, Heidelberg, Germany. 2. June Pharma Consulting Limited, London, UK. 3. QPS Netherlands B.V., Hanzeplein 1, 9713 GZ, Groningen, The Netherlands. 4. QPS Taiwan, 12F, No. 3, Park St, Nangang Dist, Taipei, 115, Taiwan. 5. Orphalan, 226 Boulevard Voltaire, 75011, Paris, France. 6. Orphalan, 226 Boulevard Voltaire, 75011, Paris, France. omar.kamlin@gmp-o.com.
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.
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.
Authors: Anna Członkowska; Tomasz Litwin; Petr Dusek; Peter Ferenci; Svetlana Lutsenko; Valentina Medici; Janusz K Rybakowski; Karl Heinz Weiss; Michael L Schilsky Journal: Nat Rev Dis Primers Date: 2018-09-06 Impact factor: 52.329
Authors: Peter Ferenci; Anna Członkowska; Uta Merle; Szalay Ferenc; Grazyna Gromadzka; Cihan Yurdaydin; Wolfgang Vogel; Radan Bruha; Hartmut T Schmidt; Wolfgang Stremmel Journal: Gastroenterology Date: 2007-02-25 Impact factor: 22.682