Esmee Vendel1, Isabelle Mohr2, Anna Czlonkowska3, Piotr Socha4, Aurelia Poujois5, Aftab Ala6, Thomas Sandahl7, Sanjay Bansal8, Eduardo Couchonnal9, Michael Praktiknjo Praktiknjo10, Celine Leemhuis11, Carlot Kruse11, Karl-Heinz Weiss12, Anil Dhawan8, Peter Vis1
1LAP&P Consultants BV, 2Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, 3Department of Neurology, Institute of Psychiatry and Neurology , 4Departments of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, 5Département de Neurologie, Centre de Reference de la Maladie de Wilson, Hopital Fondation Adolphe de Rothschild, 6Institute of Liver Studies King's College Hospital NHS Foundation Trust, 7Dept. of Hepatology and Gastroenterology, Aarhus University Hospital, 8Department of Pediatrics and Pediatric Liver GI and Nutrition Center and Mowat Labs, King's College Hospital, 9Hospices Civils de Lyon- Hôpital Femme Mère Enfant - Hépatologie, Gastroentérologie et Nutrition pédiatrique, Centre de Référence de la maladie de Wilson, 10Department of Internal Medicine B, University Hospital , 11Univar Solutions B.V., 12Internal Medicine, Salem Medical Center
Background and Aims: In Wilson Disease (WD) patients a mutation in the ATP7B gene results in an impaired copper homeostasis and copper accumulation in the body [1-3]. Chelator treatment of patients with WD, including trientine dihydrochloride (TETA-2HCl) therapy, aims to reduce copper levels in the body by its sequestration and enhanced elimination [4]. While the effects of TETA-2HCl have been demonstrated in both non-clinical and clinical studies, no dedicated pharmacokinetic (PK) – pharmacodynamic (PD) modelling was ever performed. The aim of the present analysis was to reveal and quantify the relationships between the systemic TETA exposure and its effect on serum copper markers and urinary copper excretion, as well as the influence of patient characteristics on these relationships in a broad WD patient population by means of PK-PD modelling, based on data collected during the up-titration phase of study TR-004 (“UNITED”) [5]. Methods: A population PK-PD model was developed and fitted to data from both adult and paediatric patients, including those with predominantly hepatic symptoms and those with predominantly neurologic symptoms, collected over the first 4 weeks of treatment as part of study TR-004 (“UNITED”). In this 4-week period, the initial dose was set at 3 mg/kg, which was up-titrated to 8 and 13 mg/kg at biweekly intervals (visits 2, 3 and 4 respectively). The model was constructed as follows: first, a population PK model was developed and fitted to the data over the first 4 weeks of TETA-2HCl treatment. Then, the modelled individual TETA PK parameters were related to total 24 hour urinary copper excretion (24h-UCE) and serum non-ceruloplasmin bound copper (NCC) concentrations using an integrated population PK-PD model. As a main characteristic of the model, urinary exchangeable copper clearance (CUCL; L/h) was modelled, while the 24h-UCE and serum NCC concentrations were fitted to the data. CUCL was related to 24h-UCE (µg) through a modelled median serum NCC (µg/L). The influence of patient characteristics, like weight, age, and copper parameters, on relevant model parameters, such as apparent clearance, apparent volume of drug distribution, and copper clearance, was evaluated. Results: The final population PK model was a linear 2-compartment model with first-order absorption and intra-individual variability on the absorption rate constant Ka and bioavailability F1. Exposure for visit 2 was observed to be higher than for the other visits, which was described by a higher relative bioavailability for this visit. The final population PK-PD model described a baseline CUCL (BL), extended by a TETA-induced CUCL. Serum NCC was expressed as a balance between copper influx and copper efflux and was the driver of BL. To account for the observed relationship between serum NCC and the effect of TETA on CUCL (quantified by the slope; SL), a multiplicative model was incorporated, in which CUCL was affected by TETA in a multiplicative fashion (i.e. CUCL=BL*(1+SL*TETA)). Serum NCC was considered at steady state under baseline conditions and modelled as a balance between copper influx (Kin) and copper efflux (CUCL), such that BL could be expressed as Kin/serum NCC. Inter-individual variability (IIV) was included on Kin and serum NCC (50 and 64% CV, respectively). Kin was estimated to be 2.45 (95% CI: 2.11, 2.80) µg/h, NCC was estimated to be 84.0 (95% CI: 70.6, 97.5) µg/L, and SL, quantifying the trientine effect on CUCL, was estimated to be 0.00781 (95% CI: 0.00617, 0.00946) L²/µg. Covariate analysis revealed no effects on TETA PK, whereas for the PK-PD a positive relationship between baseline alanine transferase (ALT) and serum copper influx (Kin) (0.393 (95% CI: 0.237, 0.549)) as well as a positive relationship between body weight and SL (0.734 (95% CI: (-0.0661, 1.54)) was detected. All parameters of the model were estimated with good precision, with RSE values below 20% and 24% for all structural and random effect parameters, respectively, except for weight on SL which had a relatively high RSE of 56%. It should be borne in mind that relatively few patients having a low body weight were present in the dataset. The final population PK-PD model described TETA concentrations, as well as the 24h-UCE and serum NCC data well, as demonstrated by several numerical and graphical assessments. Conclusion: Plasma TETA concentrations in both adult and paediatric WD patients enrolled in study TR-004 (“UNITED”) were well described by a linear 2-CMT model with first-order absorption and a higher bioavailability at visit 2 relative to the other visits. No covariates, including age and body weight, were found to affect TETA PK. The final population PK-PD model described the relationship between TETA and 24h-UCE well and indicated potential effects of baseline ALT on Kin and weight on SL. The model may form the basis of a model-guided dosing paradigm for TETA-2HCl in WD.
[1] Wilson SK. Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver. Archives of Neurology 1971; 25:180–6 [2] Gitlin JD. Wilson disease. Gastroenterology 2003; 125:1868–77 [3] Ala A, Walker AP, Ashkan K, Dooley JS, and Schilsky ML. Wilson’s disease. The Lancet 2007; 369:397–408 [4] Schilsky ML, Roberts EA, Bronstein JM, Dhawan A, Hamilton JP, Rivard AM, Washington MK, Weiss KH, and Zimbrean PC. A multidisciplinary approach to the diagnosis and management of Wilson disease: 2022 practice guidance on Wilson disease from the American Association for the Study of Liver Diseases. Hepatology 2022 [5] Clinical Study Protocol for TR-004. Open label, Multicenter, Prospective Study to Characterize the Pharmacokinetics and Pharmacodynamics of Cufence (Trientine Dihydrochloride) and to Investigate the Efficacy and Safety in Wilson’s Disease Patients. Protocol TR-004, EudraCT 2020-004604-33. Version 6.0. 2023
Reference: PAGE 33 (2025) Abstr 11732 [www.page-meeting.org/?abstract=11732]
Poster: Drug/Disease Modelling - Other Topics