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Eculizumab dose tapering should take into account the nonlinearity of its pharmacokinetics.
Le Tilly, Olivier; Gatault, Philippe; Semlali, Saida; Sberro-Soussan, Rebecca; Passot, Christophe; Bertrand, Dominique; Desvignes, Céline; Caillard, Sophie; Paintaud, Gilles; Halimi, Jean-Michel; Ternant, David.
Affiliation
  • Le Tilly O; Inserm U1327 ISCHEMIA "Membrane signalling and inflammation in reperfusion injuries", Université de Tours, Tours, France.
  • Gatault P; Medical Pharmacology, CHRU Tours, Tours, France.
  • Semlali S; Inserm U1327 ISCHEMIA "Membrane signalling and inflammation in reperfusion injuries", Université de Tours, Tours, France.
  • Sberro-Soussan R; Nephrology, Arterial Hypertension, Dialysis and Transplant Department, CHRU Tours, Tours, France.
  • Passot C; Medical Pharmacology, CHRU Tours, Tours, France.
  • Bertrand D; Necker-Enfants Malades Institute, French National Institute of Health and Medical Research, Paris, France.
  • Desvignes C; Integrated Center for Oncology, Angers, France.
  • Caillard S; Nephrology Department and Transplantation Center, Rouen University Hospital, Rouen, France.
  • Paintaud G; Inserm U1327 ISCHEMIA "Membrane signalling and inflammation in reperfusion injuries", Université de Tours, Tours, France.
  • Halimi JM; Pilot Centre for Therapeutic Antibodies Monitoring (PiTAM), CHRU Tours, Tours, France.
  • Ternant D; Nephrology and Transplantation Department, Strasbourg University Hospital, Strasbourg, France.
Br J Clin Pharmacol ; 90(5): 1312-1321, 2024 May.
Article in En | MEDLINE | ID: mdl-38373846
ABSTRACT

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 (Vmax = 26.07 mg/day, Km = 24.06 mg/L). Volume of distribution (72.39 mL/kg) and clearance were weight-dependent. Critical concentrations (Vmax/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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Drug Monitoring / Nonlinear Dynamics / Antibodies, Monoclonal, Humanized / Atypical Hemolytic Uremic Syndrome / Models, Biological Limits: Adolescent / Adult / Aged / Female / Humans / Male / Middle aged Language: En Journal: Br J Clin Pharmacol Year: 2024 Document type: Article Affiliation country: France Country of publication: United kingdom

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Drug Monitoring / Nonlinear Dynamics / Antibodies, Monoclonal, Humanized / Atypical Hemolytic Uremic Syndrome / Models, Biological Limits: Adolescent / Adult / Aged / Female / Humans / Male / Middle aged Language: En Journal: Br J Clin Pharmacol Year: 2024 Document type: Article Affiliation country: France Country of publication: United kingdom