Proposal for individualized dosing of eculizumab in atypical haemolytic uraemic syndrome: patient friendly and cost-effective

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 Emax 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.

Keywords: aHUS; complement; eculizumab; pharmacodynamics; pharmacokinetics.

FIGURE 1:

Graphical display of the pharmacokinetic model of eculizumab.

FIGURE 2:

Prediction-corrected visual predictive check of the final PK model of eculizumab. The black dots represent the observed concentrations. The dashed lines represent the 5th, median, 95th percentile of the predictions. The shaded grey areas represent the corresponding 95% CIs. The majority of the predicted concentrations are in line with the observed concentrations, indicating appropriate validity of the model.

FIGURE 3:

Prediction-corrected visual predictive check for the final model. The black dots represent the observed CP activity at corresponding eculizumab concentrations. The dashed lines represent the 5th, median and 95th percentile of the predictions. The majority of the predicted concentrations are in line with the observed concentrations, indicating appropriate validity of the model.

FIGURE 4:

Percentage of patients with a CP activity <10% over time for the standard loading dose (grey line) and alternative loading dose (black line).

FIGURE 5:

Percentage of patients with a CP activity <10% over time for the standard dosing regimen (grey line) and an individualized, TDM-based dosing regimen (black line).

FIGURE 6:

Percentage of patients with a CP activity <10% over time for the standard dosing regimen (grey line) and a standard 4-week interval (black line).