Olivier Le Tilly (1), Philippe Gatault (2), Rebecca Sberro-Soussan (3), Dominique Bertrand (4), Sophie Caillard (5), Gilles Paintaud (1), Jean-Michel Halimi (2), Christophe Passot (6), David Ternant (1)
(1) Université de Tours, EA4245 T2I, CHRU Tours, Medical Pharmacology, France, (2) Université de Tours, EA4245 T2I, CHRU Tours, Nephrology Department, France, (3) Necker hospital, Nephrology Department, France, (4) Rouen Hospital, Nephrology Department, France, (5) Strasbourg Hospital, Nephrology Department, France, (6) Western Cancerology Institute, Biopathology Department, France
Objectives: Eculizumab is a monoclonal antibody targeting complement protein C5 approved in atypical haemolytic uremic syndrome (aHUS) with a dose regimen in adults consisting in four weekly infusions of 900 mg followed by 1,200 mg every two weeks. Trough concentrations of eculizumab above 50-100 mg/L are considered as sufficient for complete blockade of complement [1, 2]. As eculizumab treatment results in a massive financial burden, we previously used a pharmacokinetic model to predict eculizumab concentrations after increased infusion intervals [3]. However, this model seemed to over-predict concentrations lower than 150 mg/L. From an updated database, our main objective was to assess whether a nonlinear model would improve predictions of low concentrations after dose tapering.
Methods: This study consisted in a multicentre cohort of 44 adults with aHUS treated with eculizumab. A total of 374 serum samples were collected during maintenance phase before infusion (between 2 and 5 weeks), to measure trough concentrations of eculizumab using a validated in-house ELISA technique. Eculizumab pharmacokinetics was described using a one-compartment model with both first-order and Michaelis-Menten elimination terms. Model parameters were estimated using nonlinear mixed-effect modelling and Monolix suite (Lixoft®, Antony, France). Inter-occasion variability was then estimated and gender and body weight were tested as covariates on kinetic parameters. Models were compared using difference in Akaike’s information criterion (AIC). The onset of nonlinearity in patients was investigated using individual critical concentrations, defined as the concentration of drug under which a nonlinear behaviour is evidenced. They were equal to the ratio between maximum elimination rate and linear clearance [4] and computed from individual values of parameters. In order to further investigate the feasibility of dose tapering to sustain concentration higher than 100 mg/L, simulations (N = 1000) were performed for varying dosing regimens (1,200 mg every 2 to 5 weeks) and body weights (from 40 to 100 kg).
Results: Eculizumab pharmacokinetics was best described when adjusting clearance and volume of distribution to body weight (CL = 1.32 mL/day/kg, V = 72.4 mL/kg), and allowed a satisfactory description of intra-individual variability for patients with long follow-up (3 years). Parameters were not associated with gender. Individual critical concentrations were well above the target concentration (50-100 mg/L) and ranged from 144.7 to 759.7 mg/L and decreased with body weight (p = 0.013). Dose tapering was inadequate in many simulated patients. For instance, administration of eculizumab every three weeks would be sufficient in 85% and 76% of simulated 50 kg and 90 kg patients, respectively. With administration every five weeks, satisfactory treatment exposure would still be achieved in 29% and 11% of 50 kg or 90 kg patients, respectively. Therefore, dose tapering should be model-guided with therapeutic drug monitoring of eculizumab.
Conclusions: Model-guided dose tapering of eculizumab may lessen its financial burden, with higher probability of success in patients with low body weight. Because nonlinearity occurs at therapeutic concentrations, our model provides better predictions than the usual linear models, which tend to overestimate low concentrations. Reliable predictions are crucial in order to estimate the feasibility of dose tapering for a patient safely.
References:
[1] Willrich MAV, Andreguetto BD, Sridharan M, et al. The impact of eculizumab on routine complement assays. J Immunol Methods. 2018;460:63-71
[2] 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
[3] 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. Published online October 28, 2020
[4] Stein AM, Peletier LA. Predicting the Onset of Nonlinear Pharmacokinetics. CPT Pharmacomet Syst Pharmacol. 2018;7:670–7
Reference: PAGE 30 (2022) Abstr 9994 [www.page-meeting.org/?abstract=9994]
Poster: Drug/Disease Modelling - Other Topics