PI-060 - ECULIZUMAB COMPLEMENT-MEDIATED PK/PD MODEL-INFORMED SIMULATIONS REVEAL THE NEED FOR ALTERNATIVE DOSING REGIMENS DURING MAINTENANCE THERAPY FOR STEM CELL TRANSPLANT-ASSOCIATED THROMBOTIC MICROANGIOPATHY (TA-TMA).

K. Mizuno^1,2, C. Dandoy^1,2, A. Teusink-Cross¹, S. Davies^1,2, A. Vinks^1,2, S. Jodele^1,2; ¹Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA, ²University of Cincinnati, Cincinnati, OH, USA.

Background: Eculizumab is a complement C5 blocker effective for TA-TMA, a fatal post-transplant complication. Patients with severe complement activation showed extensive target-mediated eculizumab clearance at the start of therapy, which decreased over time with complement suppression. We previously developed eculizumab PK/PD models to inform precision dosing throughout treatment. In the first step, we developed algorithms for intensified therapeutic dose induction based on different pretreatment TMA activities. Here we aimed to develop model-informed optimal dosing regimens for use during TA-TMA maintenance therapy.

Methods: PK/PD model-informed simulations were conducted in virtual patients over a wide range of bodyweight cohorts (3-100kg) using realistic age-weight data randomly sampled from the CDC-NHANES database. Similar sC5b-9 levels were assumed as observed in our previous studies. Our published model was used for the simulations with the goal to maintain eculizumab concentrations >100 µg/mL with at least a 75% probability of target attainment (PTA). As PTA% with the FDA-approved dosing regimens for other diseases was suboptimal, alternate dosing schedules were explored by increasing the dose in mg or shortening the dosing interval.

Results: With the FDA-approved q14d dosing regimens, the PTA% was achieved at less than 40%, except for patients weighing less than 10 kg. In patients with higher body weights (10 kg- < 40 kg), q7d dosing regimens with an additional 300 mg dose were needed for more than 75% PTA. Further shortening of the dosing interval (q4-6d) was required for optimal target attainment in patients weighing equal to or more than 40kg.

Conclusion: Our data show that patients with TA-TMA require more frequent eculizumab dosing during maintenance therapy to successfully control complement activation.

Jodele S et al. Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab. Blood
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Mizuno K et al. Eculizumab precision-dosing algorithm for thrombotic microangiopathy in children and young adults undergoing HSCT. Blood Adv 6 (5): 1454–1463 (2022)