Christophe Passot1,2,3, Rebecca Sberro-Soussan4, Dominique Bertrand5, Sophie Caillard6, Betoul Schvartz7, Camille Domenger8, Cécile Contin-Bordes9, Gilles Paintaud1,2, Jean-Michel Halimi10,11, David Ternant1,2, Philippe Gatault10,11. 1. EA7501, University of Tours, France. 2. Laboratory of Pharmacology-Toxicology, CHRU de Tours, France. 3. Integrated Center for Oncology, Angers, France. 4. Service de Néphrologie et Transplantation Adulte, Hôpital Necker-Enfants Malades, Université Paris Descartes, Assistance Publique-Hôpitaux de Paris, Paris, France. 5. Department of Nephrology and Transplantation Centre, Rouen, France. 6. Nephrology and Transplant Department, Strasbourg University Hospital, Strasbourg, France. 7. Nephrology and Transplant Department, Reims, France. 8. Nephrology and Transplant Department, Grenoble, France. 9. Laboratory of Immunology and Immunogenetic, Bordeaux, France. 10. EA4245 Transplant Immunology and Inflammation, Université de Tours, Tours, France. 11. Service de Néphrologie-Hypertension artérielle, Dialyses, Transplantation rénale, CHRU Tours, France.
Abstract
AIMS: Eculizumab is an anti-C5 monoclonal antibody approved for rare diseases including atypical haemolytic-uraemic syndrome. The maintenance phase dosing regimen is identical for all adult patients: 1200 mg every 2 weeks. Recent studies reported an overexposure in many patients when considering a target trough concentration range of 50-100 mg/L. The aim of the present work was to validate the feasibility of therapeutic drug monitoring of eculizumab in atypical haemolytic-uraemic syndrome patients. METHODS: We performed a 2-step prospective multicentre study. In the first phase, we developed a pharmacokinetic population model using data from 40 patients and identified patients for whom a 1-week lengthening of interval between infusions would lead to a trough concentration above 100 mg/L. In the second phase, selected patients were allocated a 1-week extension and eculizumab trough concentrations were monitored. RESULTS: The model confirmed the previously reported influence of bodyweight on elimination clearance and predicted that 36 (90%) patients would be eligible for interval extension. In the second phase of the study, a 1-week lengthening of interval between infusions was performed in 15 patients whose trough concentration at the next visit was predicted with a Bayesian model to be above 100 mg/L. After interval extension, 10 patients (67%) presented measured trough concentrations over 100 mg/L. No biological or clinical recurrence of disease was observed, even in the 5 patients with concentrations below 100 mg/L in whom the initial dosing regimen was resumed. CONCLUSION: Safe eculizumab interval adjustment is feasible with a PK monitoring.
AIMS: Eculizumab is an anti-C5 monoclonal antibody approved for rare diseases including atypical haemolytic-uraemic syndrome. The maintenance phase dosing regimen is identical for all adult patients: 1200 mg every 2 weeks. Recent studies reported an overexposure in many patients when considering a target trough concentration range of 50-100 mg/L. The aim of the present work was to validate the feasibility of therapeutic drug monitoring of eculizumab in atypical haemolytic-uraemic syndrome patients. METHODS: We performed a 2-step prospective multicentre study. In the first phase, we developed a pharmacokinetic population model using data from 40 patients and identified patients for whom a 1-week lengthening of interval between infusions would lead to a trough concentration above 100 mg/L. In the second phase, selected patients were allocated a 1-week extension and eculizumab trough concentrations were monitored. RESULTS: The model confirmed the previously reported influence of bodyweight on elimination clearance and predicted that 36 (90%) patients would be eligible for interval extension. In the second phase of the study, a 1-week lengthening of interval between infusions was performed in 15 patients whose trough concentration at the next visit was predicted with a Bayesian model to be above 100 mg/L. After interval extension, 10 patients (67%) presented measured trough concentrations over 100 mg/L. No biological or clinical recurrence of disease was observed, even in the 5 patients with concentrations below 100 mg/L in whom the initial dosing regimen was resumed. CONCLUSION: Safe eculizumab interval adjustment is feasible with a PK monitoring.