Eculizumab dose tapering should take into account the nonlinearity of its pharmacokinetics.

Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 7503323 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1365-2125 (Electronic) Linking ISSN: 03065251 NLM ISO Abbreviation: Br J Clin Pharmacol Subsets: MEDLINE

Publication: Oxford : Wiley-Blackwell
Original Publication: London, Macmillan Journals Ltd.

Antibodies, Monoclonal, Humanized*/pharmacokinetics ; Antibodies, Monoclonal, Humanized*/administration & dosage ; Models, Biological* ; Drug Monitoring*/methods ; Atypical Hemolytic Uremic Syndrome*/drug therapy ; Nonlinear Dynamics*; Humans ; Male ; Female ; Middle Aged ; Adult ; Aged ; Dose-Response Relationship, Drug ; Young Adult ; Complement Inactivating Agents/pharmacokinetics ; Complement Inactivating Agents/administration & dosage ; Computer Simulation ; Adolescent

Aims: Eculizumab is a monoclonal antibody targeting complement protein C5 used in renal diseases. As recommended dosing regimen leads to unnecessarily high concentrations in some patients, tailored dosing therapeutic drug monitoring was proposed to reduce treatment cost. The objectives of the present work were (i) to investigate the target-mediated elimination of eculizumab and (ii) whether a pharmacokinetic model integrating a nonlinear elimination allows a better prediction of eculizumab concentrations than a linear model.
Methods: We analysed 377 eculizumab serum concentrations from 44 patients treated for atypical haemolytic uraemic syndrome and C3 glomerulopathy with a population pharmacokinetic approach. Critical concentrations (below which a non-log-linear decline of concentration over time is evidenced) were computed to estimate the relevance of the target-mediated elimination. Simulations of dosing regimens were then performed to predict probabilities of target attainment (i.e. trough >100 mg/L).
Results: Pharmacokinetics of eculizumab was nonlinear and followed a mixture of first-order (CL = 1.318 mL/day/kg) and Michaelis-Menten elimination (V max  = 26.07 mg/day, K m  = 24.06 mg/L). Volume of distribution (72.39 mL/kg) and clearance were weight-dependent. Critical concentrations (V max /CL) ranged from 144.7 to 759.7 mg/L and were inversely related to body weight (P = .013). Nonlinearity was thus noticeable at therapeutic concentrations. Simulations predicted that 1200 mg of eculizumab every 21 days would allow 85% and 76% of patients to maintain a therapeutic exposure, for 50 or 90 kg body weight, respectively.
Conclusions: Our study investigates the nonlinear elimination of eculizumab and discusses the importance of accounting for eculizumab target-mediated elimination in therapeutic drug monitoring.
(© 2024 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

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LabEx MAbImprove ANR-10-LABX-53-01 French Higher Education and Research ministry

Keywords: dose–response relationship; eculizumab; model‐informed precision dosing; monoclonal antibody; nonlinear pharmacokinetics; target‐mediated disposition; therapeutic drug monitoring

A3ULP0F556 (eculizumab)
0 (Antibodies, Monoclonal, Humanized)
0 (Complement Inactivating Agents)

Date Created: 20240219 Date Completed: 20240429 Latest Revision: 20240429

20240429

10.1111/bcp.16019

38373846