ter Avest, M1. van de Kar, NCAJ2. Volohkina, EB2. Burger, DM1. Wetzels JFM4. ter Heine R1. CUREiHUS study group
1Department of Pharmacy, Radboud university medical center, Nijmegen 2Department of Pediatrics, Radboud university medical center, Nijmegen, 3Department of nephrology, Radboud university medical center, Nijmegen
Objectives: Eculizumab is a very expensive humanized monoclonal antibody against complement protein C5 for the treatment of atypical hemolytic uremic syndrome (aHUS). Today, it is the only effective and lifesaving drug for this disease. The approved dosing regimen of eculizumab in adults consists of an initial weekly loading dose of 900 mg (4 weeks) followed by a maintenance phase (1200 mg in the fifth week and every 14 days thereafter). Recent data show that exposure is often sub-therapeutic after the first dose, while being supra-therapeutic when starting the maintenance phase. Early adequate therapy is of utmost importance to stop thrombotic microangiopathy and to prevent chronic sequelae. Therefore, we aimed to develop a dosing strategy to improve early treatment response and patient-friendliness at, preferably, lower costs.
Methods: Pharmacokinetic (PK) and pharmacodynamic (PD) data from 48 aHUS patients were available, consisting of 849 eculizumab time-concentration data and 569 CP activity levels. PK-PD modeling was performed by means of non-linear mixed effects modeling by using NONMEM. The final model was used to investigate alternative dosing strategies through Monte Carlo simulations in 2000 virtual patients. The optimal strategy was defined as the strategy with the highest percentage of patients with a CP <10%, without increasing the cumulative dose.
Results: A PK-PD model with parallel first order and Michaelis-Menten elimination rates best described the PK data. The estimates of the model were clearance 0.163 L/day (RSE 8%), volume of distribution 6.42 L (RSE 6%), maximum rate (Vmax ) 29.6 mg/day (RSE 7%), plasma concentration for 50% of maximum rate (Km ) 37.9 mg/L (RSE 19%). After establishing the model that best described the pharmacokinetics of eculizumab, a sequential PK-PD model was developed to describe the relationship between the free eculizumab concentration and the degree of complement blockade. The PK-PD relation was described with an inhibitory Emax model, with an estimated baseline of 101% (RSE 6%), maximum inhibition (Imax) of 0.959 (RSE 0.3%), a plasma concentration for 50% inhibition (IC50) of 22.0 mg/L (RSE 9%) and Hill Coefficient (γ) of 5.42 (RSE 5%). To improve therapy, a weight-based loading on day 1, followed by the maintenance dose on day 14 was found to improve the effectiveness of treatment with eculizumab. Therapy could be further improved by individualizing the dose interval, based on the estimated half-life after the first dose. We predict that with this new regimen 99.95% patients reach the efficacy target on day 7, compared to 94.75% with standard dosing. During maintenance phase, comparable percentages of target attainment were predicted, while the dose interval could be prolonged in 28.8% of the patients. This new dosing regimen also resulted in an overall dose reductions of 13.6% compared to the standard dosing regimen in the first 133 days of treatment.
Conclusions: A patient-friendly individualized dosing strategy of eculizumab results in better treatment response and lower costs.
Reference: PAGE () Abstr 9325 [www.page-meeting.org/?abstract=9325]
Poster: Drug/Disease Modelling - Other Topics