Feasibility and safety of tailored dosing schedule for eculizumab based on therapeutic drug monitoring: Lessons from a prospective multicentric study

Abstract

Eculizumab is an anti-C5 monoclonal antibody approved for rare diseases including atypical haemolytic-uraemic syndrome. The maintenance phase dosing regimen is identical for all adult patients: 1200 mg every 2 weeks. Recent studies reported an overexposure in many patients when considering a target trough concentration range of 50-100 mg/L. The aim of the present work was to validate the feasibility of therapeutic drug monitoring of eculizumab in atypical haemolyticuraemic syndrome patients.Methods: We performed a 2-step prospective multicentre study. In the first phase, we developed a pharmacokinetic population model using data from 40 patients and identified patients for whom a 1-week lengthening of interval between infusions would lead to a trough concentration above 100 mg/L. In the second phase, selected patients were allocated a 1-week extension and eculizumab trough concentrations were monitored. Results:The model confirmed the previously reported influence of bodyweight on elimination clearance and predicted that 36 (90%) patients would be eligible for interval extension. In the second phase of the study, a 1-week lengthening of interval between infusions was performed in 15 patients whose trough concentration at the next visit was predicted with a Bayesian model to be above 100 mg/L. After interval extension, 10 patients (67%) presented measured trough concentrations over 100 mg/L. No biological or clinical recurrence of disease was observed, even in the 5 patients with concentrations below 100 mg/L in whom the initial dosing regimen was resumed. Conclusion:Safe eculizumab interval adjustment is feasible with a PK monitoring. K E Y W O R D S atypical haemolytic-uraemic syndrome, dose tailoring, eculizumab, pharmacokinetics, therapeutic drug monitoring 1 | INTRODUCTION Eculizumab (Soliris, Alexion pharmaceuticals) is a humanized monoclonal antibody that specifically binds human complement component C5 and sterically hampers its interaction with C5 convertase, and the subsequent activation of the terminal pathway. 1 Hence, eculizumab prevents the cleavage of C5, the release of inflammatory C5a mediator and the formation of terminal complement complex. 2-4 Initially

Clinical Utility and Potential Cost Savings of Pharmacologic Monitoring of Eculizumab for Complement-Mediated Thrombotic Microangiopathy

“…10 Other studies have demonstrated similar findings of supratherapeutic eculizumab levels in adult and pediatric populations 11,12 ; yet, others have also demonstrated success in decreasing the frequency of eculizumab dosing by monitoring complement serology. [13][14][15] Although other studies have reported the use of AH50 and total complement activity (CH50) to determine interval frequencies, ours is the first report using both C5 and mass spectrometric assessment of eculizumab to guide a personalized dosing strategy. We decided to implement C5 as a clinical test for eculizumab monitoring given its higher specificity.…”

“… 15 , 16 Pharmacokinetic modeling in one study showed that body weight and male gender increased eculizumab elimination clearance and suggested that trough concentrations of less than 100 μg/mL of eculizumab may be more likely in the case of the highest bodyweight tested (90 kg). 15 …”

“…11 Other studies have also suggested that Food and Drug Administration-approved doses may not be adequate for patients at high weight extremes. 15,16 Pharmacokinetic modeling in one study showed that body weight and male gender increased eculizumab elimination clearance and suggested that trough concentrations of less than 100 mg/mL of eculizumab may be more likely in the case of the highest bodyweight tested (90 kg). 15 In addition to exploring a tailored approach to eculizumab dosing, we also describe our experience with eculizumab discontinuation.…”

“…15,16 Pharmacokinetic modeling in one study showed that body weight and male gender increased eculizumab elimination clearance and suggested that trough concentrations of less than 100 mg/mL of eculizumab may be more likely in the case of the highest bodyweight tested (90 kg). 15 In addition to exploring a tailored approach to eculizumab dosing, we also describe our experience with eculizumab discontinuation. Of those discontinuing eculizumab, relapse occurred in 25% of patients.…”

Ravulizumab: Characterization and quantitation of a new C5 inhibitor using isotype specific affinity purification and high-resolution mass spectrometry

“…Therapeutic monitoring of ECUL has allowed cost-savings along with improved quality of life for patients by extending infusion intervals when drug concentrations are above therapeutic thresholds, with patients maintaining complete complement activity blockage [4] , [5] , [6] , [7] . Although not yet common practice, we expect that therapeutic monitoring of RAVUL may similarly assist in personalizing therapy regimens and contribute to improved outcomes.…”