Proposal for individualized dosing of eculizumab in atypical haemolytic uraemic syndrome: patient friendly and cost-effective. Issue 2 (3rd March 2022)

• Record Type: Journal Article
• Authors: ter Avest, Mendy; Bouwmeester, Romy N; Duineveld, Caroline; Wijnsma, Kioa L; Volokhina, Elena B; van den Heuvel, Lambertus P W J; Burger, David M; Wetzels, Jack F M; van de Kar, Nicole C A J; ter Heine, Rob
• Is Part Of: Nephrology dialysis transplantation. Volume 38:Issue 2(2023)
• Page Start: 362
• Page End: 371
• Publication Date: 2022-03-03
• Subjects: aHUS -- complement -- eculizumab -- pharmacodynamics -- pharmacokinetics; Nephrology -- Periodicals; Hemodialysis -- Periodicals; Kidneys -- Transplantation -- Periodicals; Hemodialysis; Kidneys -- Transplantation; Nephrology; Periodicals; 616.61
• DOI: 10.1093/ndt/gfac056
• Languages: English
• ISSNs: 0931-0509

Abstract

ABSTRACT: Background: Eculizumab is a lifesaving yet expensive drug for atypical haemolytic uraemic syndrome (aHUS). Current guidelines advise a fixed-dosing schedule, which can be suboptimal and inflexible in the individual patient. Methods: We evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) [classical pathway (CP) activity levels] of eculizumab in 48 patients, consisting of 849 time-concentration data and 569 CP activity levels. PK–PD modelling was performed with non-linear mixed-effects modelling. The final model was used to develop improved dosing strategies. Results: A PK model with parallel linear and non-linear elimination rates best described the data with the parameter estimates clearance 0.163 L/day, volume of distribution 6.42 L, maximal rate 29.6 mg/day and concentration for 50% of maximum rate 37.9 mg/L. The PK–PD relation between eculizumab concentration and CP activity was described using an inhibitory E max model with the parameter estimates baseline 101%, maximal inhibitory effect 95.9%, concentration for 50% inhibition 22.0 mg/L and Hill coefficient 5.42. A weight-based loading dose, followed by PK-guided dosing was found to improve treatment. On day 7, we predict 99.95% of the patients to reach the efficacy target (CP activity <10%), compared with 94.75% with standard dosing. Comparable efficacy was predicted during the maintenance phase, while the dosing interval could be prolonged in ∼33% of the population by means of individualized dosing. With a fixed-dose 4-week dosing interval to allow for holidays, treatment costs will increase by 7.1% and we predict 91% of the patients will reach the efficacy target. Conclusions: A patient-friendly individualized dosing strategy of eculizumab has the potential to improve treatment response at reduced costs.