Eculizumab dose tapering should take into account the nonlinearity of its pharmacokinetics.
dose-response relationship
eculizumab
model-informed precision dosing
monoclonal antibody
nonlinear pharmacokinetics
target-mediated disposition
therapeutic drug monitoring
Journal
British journal of clinical pharmacology
ISSN: 1365-2125
Titre abrégé: Br J Clin Pharmacol
Pays: England
ID NLM: 7503323
Informations de publication
Date de publication:
19 Feb 2024
19 Feb 2024
Historique:
revised:
15
01
2024
received:
18
10
2023
accepted:
23
01
2024
medline:
20
2
2024
pubmed:
20
2
2024
entrez:
19
2
2024
Statut:
aheadofprint
Résumé
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. 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). Pharmacokinetics of eculizumab was nonlinear and followed a mixture of first-order (CL = 1.318 mL/day/kg) and Michaelis-Menten elimination (V Our study investigates the nonlinear elimination of eculizumab and discusses the importance of accounting for eculizumab target-mediated elimination in therapeutic drug monitoring.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : French Higher Education and Research ministry
ID : LabEx MAbImprove ANR-10-LABX-53-01
Informations de copyright
© 2024 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
Références
Le Quintrec M, Lapeyraque A-L, Lionet A, et al. Patterns of clinical response to eculizumab in patients with C3 glomerulopathy. Am J Kidney Dis. 2018;72(1):84-92. doi:10.1053/j.ajkd.2017.11.019
Passot C, Sberro-Soussan R, Bertrand D, et al. Feasibility and safety of tailored dosing schedule for eculizumab based on therapeutic drug monitoring: lessons from a prospective multicentric study. Br J Clin Pharmacol. 2021;87(5):2236-2246. doi:10.1111/bcp.14627
Willrich MAV, Andreguetto BD, Sridharan M, et al. The impact of eculizumab on routine complement assays. J Immunol Methods. 2018;460:63-71. doi:10.1016/j.jim.2018.06.010
Legendre CM, Licht C, Muus P, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 2013;368(23):2169-2181. doi:10.1056/NEJMoa1208981
Laurence J. Defining treatment duration in atypical hemolytic uremic syndrome in adults: a clinical and pathological approach. Clin Adv Hematol Oncol. 2020;18:221-230.
Raina R, Grewal MK, Radhakrishnan Y, et al. Optimal management of atypical hemolytic uremic disease: challenges and solutions. Int J Nephrol Renov Dis. 2019;12:183-204. doi:10.2147/IJNRD.S215370
Fakhouri F, Fila M, Provôt F, et al. Pathogenic variants in complement genes and risk of atypical hemolytic uremic syndrome relapse after eculizumab discontinuation. Clin J Am Soc Nephrol. 2017;12(1):50-59. doi:10.2215/CJN.06440616
Zuber J, Frimat M, Caillard S, et al. Use of highly individualized complement blockade has revolutionized clinical outcomes after kidney transplantation and renal epidemiology of atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2019;30(12):2449-2463. doi:10.1681/ASN.2019040331
Olson SR, Lu E, Sulpizio E, Shatzel JJ, Rueda JF, DeLoughery TG. When to stop eculizumab in complement-mediated thrombotic microangiopathies. Am J Nephrol. 2018;48(2):96-107. doi:10.1159/000492033
Wijnsma KL, Duineveld C, Wetzels JFM, van de Kar NCAJ. Eculizumab in atypical hemolytic uremic syndrome: strategies toward restrictive use. Pediat Nephrol. 2019;34(11):2261-2277. doi:10.1007/s00467-018-4091-3
Volokhina E, Wijnsma K, van der Molen R, et al. Eculizumab dosing regimen in atypical HUS: possibilities for individualized treatment. Clin Pharmacol Ther. 2017;102(4):671-678. doi:10.1002/cpt.686
Wijnsma KL, ter Heine R, Moes DJAR, et al. Pharmacology, pharmacokinetics and pharmacodynamics of eculizumab, and possibilities for an individualized approach to eculizumab. Clin Pharmacokinet. 2019;58(7):859-874. doi:10.1007/s40262-019-00742-8
Gatault P, Brachet G, Ternant D, et al. Therapeutic drug monitoring of eculizumab: rationale for an individualized dosing schedule. MAbs. 2015;7(6):1205-1211. doi:10.1080/19420862.2015.1086049
Krippendorff B-F, Kuester K, Kloft C, Huisinga W. Nonlinear pharmacokinetics of therapeutic proteins resulting from receptor mediated endocytosis. J Pharmacokinet Pharmacodyn. 2009;36(3):239-260. doi:10.1007/s10928-009-9120-1
ter Avest M, Bouwmeester RN, Duineveld C, et al. Proposal for individualized dosing of eculizumab in atypical haemolytic uraemic syndrome: patient friendly and cost-effective. Nephrol Dial Transplant. 2023;38(2):362-371. doi:10.1093/ndt/gfac056
Ternant D, Azzopardi N, Raoul W, Bejan-Angoulvant T, Paintaud G. Influence of antigen mass on the pharmacokinetics of therapeutic antibodies in humans. Clin Pharmacokinet. 2018;58(2):169-187. doi:10.1007/s40262-018-0680-3
Peffault de Latour R, Brodsky RA, Ortiz S, et al. Pharmacokinetic and pharmacodynamic effects of ravulizumab and eculizumab on complement component 5 in adults with paroxysmal nocturnal haemoglobinuria: results of two phase 3 randomised, multicentre studies. Br J Haematol. 2020;191(3):476-485. doi:10.1111/bjh.16711
Passot C, Desvignes C, Ternant D, et al. Development and validation of an enzyme-linked immunosorbent assay to measure free eculizumab concentration in serum. Bioanalysis. 2017;9(16):1227-1235. doi:10.4155/bio-2017-0070
Stein AM, Peletier LA. Predicting the onset of nonlinear pharmacokinetics. CPT Pharmacometrics Syst Pharmacol. 2018;7(10):670-677. doi:10.1002/psp4.12316
van der Meer F, Marcus M, Touw D, Proost J, Neef C. Optimal sampling strategy development methodology using maximum a posteriori Bayesian estimation. Ther Drug Monit. 2011;33(2):133-146. doi:10.1097/FTD.0b013e31820f40f8
Harding S, Armstrong J, Faccenda E, et al. The IUPHAR/BPS guide to pharmacology in 2024. Nucleic Acids Res. 2024;52(D1):D1438-D1449. doi:10.1093/nar/gkad944
Gibiansky L, Gibiansky E, Kakkar T, Ma P. Approximations of the target-mediated drug disposition model and identifiability of model parameters. J Pharmacokinet Pharmacodyn. 2008;35(5):573-591. doi:10.1007/s10928-008-9102-8
Bensalem A, Ternant D. Pharmacokinetic variability of therapeutic antibodies in humans: a comprehensive review of population pharmacokinetic modeling publications. Clin Pharmacokinet. 2020;59(7):857-874. doi:10.1007/s40262-020-00874-2
Sridharan M, Go RS, Willrich MAV. Clinical utility and potential cost savings of pharmacologic monitoring of eculizumab for complement-mediated thrombotic microangiopathy. Mayo Clin Proc Innov Qual Outcomes. 2022;6(5):458-464. doi:10.1016/j.mayocpiqo.2022.03.005
Saida K, Fukuda T, Mizuno K, Ogura M, Kamei K, Ito S. Pharmacokinetics and pharmacodynamics estimation of eculizumab in a 2-year-old girl with atypical hemolytic uremic syndrome: a case report with 4-year follow-up. Front Pediatr. 2019;7:519. doi:10.3389/fped.2019.00519
Greenbaum LA, Fila M, Ardissino G, et al. Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome. Kidney Int. 2016;89(3):701-711. doi:10.1016/j.kint.2015.11.026
Kistler AD. Eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 2014;369(14):1377-1380. doi:10.1056/NEJMc1308826#SA3
US Food and Drug Administration (FDA). Soliris-pharmacometrics review. Silver Spring: US FDA; 2007.
Bouwmeester RN, Ter Avest M, Wijnsma KL, et al. Case report: variable pharmacokinetic profile of eculizumab in an aHUS patient. Front Immunol. 2020;11:612706. doi:10.3389/fimmu.2020.612706
Wehling C, Amon O, Bommer M, et al. Monitoring of complement activation biomarkers and eculizumab in complement-mediated renal disorders. Clin Exp Immunol. 2017;187(2):304-315. doi:10.1111/cei.12890
ter Avest M, Steenbreker H, Bouwmeester RN, et al. Proteinuria and exposure to eculizumab in atypical hemolytic uremic syndrome. Clin J Am Soc Nephrol. 2023;18(6):759-766. doi:10.2215/CJN.0000000000000145
Anderson BJ, Holford NHG. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol. 2008;48(1):303-332. doi:10.1146/annurev.pharmtox.48.113006.094708
Ahn JE, Birnbaum AK, Brundage RC. Inherent correlation between dose and clearance in therapeutic drug monitoring settings: possible misinterpretation in population pharmacokinetic analyses. J Pharmacokinet Pharmacodyn. 2005;32(5-6):703-718. doi:10.1007/s10928-005-0083-6
Goodship T, Cook T, Fakhouri F, et al. Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference. Kidney Int. 2017;91(3):539-551. doi:10.1016/j.kint.2016.10.005