The steady state pharmacokinetics of trientine in Wilson disease patients

被引:9
作者
Pfeiffenberger, Jan [1 ]
Kruse, Carlot [2 ]
Mutch, Peter [3 ]
Harker, Andrew [3 ]
Weiss, Karl Heinz [1 ]
机构
[1] Univ Hosp Heidelberg, Heidelberg, Germany
[2] Univ BV, Rotterdam, Netherlands
[3] ICON Consulting Serv, Marlow, Bucks, England
关键词
Wilson disease; Trientine dihydrochloride; Pharmacokinetics; GENE; TRIETHYLENETETRAMINE; ABSORPTION; MUTATIONS; DIAGNOSIS; ATPASE; SITE;
D O I
10.1007/s00228-018-2424-6
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Purpose To determine the steady state pharmacokinetics of trientine in children (>= 12 years of age) and adult patients who had been receiving trientine dihydrochloride therapy prior to the study. Methods Twenty patients were exposed to trientine (trientine dihydrochloride capsules supplied by Univar) after standard oral dosing as part of ongoing therapy. Plasma trientine concentration was determined pre-dose and at 30 min, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 h post-dose. Concentrations of trientine in plasma were determined by LC-MS/MS using a validated bioanalytical method with stable labelled trientine as the internal standard. Results Trientine was generally absorbed fairly rapidly with a median T-max of 1.49 h (range, 0.48-4.08 h). There was some variability in exposure, with a 10-fold range in C-max, and a 13.8-fold range in AUC0-t. This variability was slightly lower when PK parameters were dose-normalised (6.7-fold range in C-max/D and an 11.6-fold range in AUC0-t/D). The terminal half-life, which could be defined in 14 of the 20 patients, was broadly consistent between patients (range of 2.33 to 6.99 h). There was no marked difference in pharmacokinetics between adult patients (n = 16) and children (n = 4). The C-max range was 506 to 3100 ng/mL in adults and 309 to 1940 ng/mL in children-the equivalent ranges for AUC0-t were 1240 to 17,100 ng/mL h and 1500 to 8060 ng/mL h. When PK parameters were normalised for administered dose, the C-max/D and AUC0-t/D for children were contained within the ranges for the adult patients. Conclusions The steady state pharmacokinetics of trientine in Wilson disease patients were broadly similar to that reported in healthy subjects.
引用
收藏
页码:731 / 736
页数:6
相关论文
共 22 条
[1]   Wilson's disease [J].
Ala, Aftab ;
Walker, Ann P. ;
Ashkan, Keyoumars ;
Dooley, James S. ;
Schilsky, Michael L. .
LANCET, 2007, 369 (9559) :397-408
[2]   Wilson's disease and other neurological copper disorders [J].
Bandmann, Oliver ;
Weiss, Karl Heinz ;
Kaler, Stephen G. .
LANCET NEUROLOGY, 2015, 14 (01) :103-113
[3]   THE WILSON DISEASE GENE IS A PUTATIVE COPPER TRANSPORTING P-TYPE ATPASE SIMILAR TO THE MENKES GENE [J].
BULL, PC ;
THOMAS, GR ;
ROMMENS, JM ;
FORBES, JR ;
COX, DW .
NATURE GENETICS, 1993, 5 (04) :327-337
[4]   Pharmacokinetic and Pharmacodynamic Modeling of a Copper-Selective Chelator (TETA) in Healthy Adults [J].
Cho, Hea-Young ;
Blum, Robert A. ;
Sunderland, Tracey ;
Cooper, Garth J. S. ;
Jusko, William J. .
JOURNAL OF CLINICAL PHARMACOLOGY, 2009, 49 (08) :916-928
[5]   A genetic study of Wilson's disease in the United Kingdom [J].
Coffey, Alison J. ;
Durkie, Miranda ;
Hague, Stephen ;
McLay, Kirsten ;
Emmerson, Jennifer ;
Lo, Christine ;
Klaffke, Stefanie ;
Joyce, Christopher J. ;
Dhawan, Anil ;
Hadzic, Nedim ;
Mieli-Vergani, Giorgina ;
Kirk, Richard ;
Allen, K. Elizabeth ;
Nicholl, David ;
Wong, Siew ;
Griffiths, William ;
Smithson, Sarah ;
Giffin, Nicola ;
Taha, Ali ;
Connolly, Sally ;
Gillett, Godfrey T. ;
Tanner, Stuart ;
Bonham, Jim ;
Sharrack, Basil ;
Palotie, Aarno ;
Rattray, Magnus ;
Dalton, Ann ;
Bandmann, Oliver .
BRAIN, 2013, 136 :1476-1487
[6]   Late-onset Wilson's disease [J].
Ferenci, Peter ;
Czlonkowska, Anna ;
Merle, Uta ;
Ferenc, Szalay ;
Gromadzka, Grazyna ;
Yurdaydin, Chan ;
Vogel, Wolfgang ;
Bruha, Radan ;
Schmidt, Hartmut T. ;
Stremmel, Wolfgang .
GASTROENTEROLOGY, 2007, 132 (04) :1294-1298
[7]   Phenotype-genotype correlations in patients with Wilson's disease [J].
Ferenci, Peter .
HUMAN DISORDERS OF COPPER METABOLISM II, 2014, 1315 :1-5
[8]  
Ferenci P, 2012, J HEPATOL, V56, P671, DOI 10.1016/j.jhep.2011.11.007
[9]   INTESTINAL-ABSORPTION AND URINARY-EXCRETION OF TRIETHYLENETETRAMINE FOR WILSONS-DISEASE IN RAT [J].
KOBAYASHI, M ;
SUGAWARA, M ;
SAITOH, H ;
ISEKI, K ;
MIYAZAKI, K .
YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, 1990, 110 (10) :759-763
[10]   Pharmacokinetics, Pharmacodynamics, and Metabolism of Triethylenetetramine in Healthy Human Participants: An Open-Label Trial [J].
Lu, Jun ;
Poppitt, Sally D. ;
Othman, Asma A. ;
Sunderland, Tracey ;
Ruggiero, Katya ;
Willett, Michael S. ;
Diamond, Lisa E. ;
Garcia, Wilfredo D. ;
Roesch, Benno G. ;
Cooper, Garth J. S. .
JOURNAL OF CLINICAL PHARMACOLOGY, 2010, 50 (06) :647-658