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Abstract: TH-PO362

Improved Early Treatment Response of Eculizumab with a Patient-Friendly Dosing Scheme in Adult Patients with Atypical Hemolytic Uremic Syndrome

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • ter Avest, Mendy, Radboud university medical center, Nijmegen, Netherlands
  • Van De Kar, Nicole, Radboud university medical center, Nijmegen, Netherlands
  • De Vries, Aiko P.J., Leiden University Medical Center, Leiden, Netherlands
  • Moes, Dirk jan, Leiden University Medical Center, Leiden, Netherlands
  • Volokhina, Elena, Radboud university medical center, Nijmegen, Netherlands
  • Smeets, Ruben L., Radboud university medical center, Nijmegen, Netherlands
  • Brüggemann, Roger, Radboud university medical center, Nijmegen, Netherlands
  • Burger, David M., Radboud university medical center, Nijmegen, Netherlands
  • Wetzels, Jack F., Radboud university medical center, Nijmegen, Netherlands
  • Ter heine, Rob, Radboud university medical center, Nijmegen, Netherlands

Group or Team Name

  • the CUREiHUS study group
Background

With the currently approved dosing schedule of eculizumab in adult aHUS patients (900mg weekly, followed by 1200mg in the fifth week and every 14 days thereafter), exposure is often sub-therapeutic after the first dose, while being supra-therapeutic when starting the maintenance phase. We aimed to develop a dosing strategy to improve early treatment response.

Methods

Pharmacokinetic (PK) and pharmacodynamic (PD) data from 30 aHUS patients were available, consisting of 647 eculizumab time-concentration data and 504 classical pathway (CP) activity levels. PK-PD modeling was performed by means of non-linear mixed effects modeling. The final model was used to investigate alternative dosing strategies through Monte Carlo simulations in 1000 virtual patients to develop a dosing strategy with a higher percentage of patients with a CP activity <10%, without increasing the dose during the initial phase.

Results

A PK-PD model with parallel first order and Michaelis-Menten elimination rates best described the data. The estimates of the model were CL 0.167 L/day (RSE 6%), Vd 7.11 L (RSE 8%), Vmax 27.7 mg/day (RSE 6%), Km 20.8 mg/L (RSE 28%). The PK-PD relation was described with an inhibitory Emax model, with an IC50 of 21.3 mg/L (RSE 17.1%). A weight-based loading dose of eculizumab (<60kg: 1500mg, 60-<90kg: 1800mg, 90-<120kg: 2100mg and ≥120kg: 2400mg) on day 1, followed by 1200mg on day 14 and 28 was found to improve treatment. In total, 96.6% of the patients reached the CP target on day 7, compared to 81.3% with standard dosing (Figure 1). This also resulted in a dose reduction of 12.5% compared to the first 28 days of the approved dosing regimen.

Conclusion

A patient-friendly weight-based dosing strategy of eculizumab results in better treatment response during the initial phase at lower costs.

Figure 1: Predicted percentage of patients with a CP activity <10% for standard and improved dosing

Funding

  • Government Support - Non-U.S.