Therapeutic drug monitoring of eculizumab: Rationale for an individualized dosing schedule

Abstract

The annual cost of eculizumab maintenance therapy in paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic–uremic syndrome (aHUS) exceeds $300,000 per patient. A better understanding of eculizumab pharmacokinetics and subsequent individual dose adjustment could reduce this cost. We measured the trough eculizumab concentration in 9 patients with maintenance therapy (aHUS, n = 7; PNH, n = 2) and determined: 1) the intra- and inter-individual variability; 2) the influence of weight on eculizumab pharmacokinetics; and 3) the rate of elimination of eculizumab following discontinuation. A one-compartment model was developed to describe the pharmacokinetics of eculizumab and predicted complement activity by body weight. Trough eculizumab concentrations were >50 µg/mL in 9/9, >100 µg/mL in 8/9, and >300 µg/mL in 5/9 of patients. Intra-individual variability was low but eculizumab concentrations, closely correlated with patient weight (R2 = 0.66, p = 0.034), varied broadly (55 ± 12 to 733 ± 164 µg/mL). Pharmacokinetic modeling showed that the elimination half-life varied greatly, with an increase from 7.8 d in a patient weighing 100 kg to 19.5 d in a 40 kg patient. We predicted that infusions of 1200 mg could be spaced every 4 or 6 weeks in patients weighing <90 and <70 kg, respectively. In this pilot study, the current recommended use of a fixed eculizumab dose for maintenance therapy is associated with excessively high trough concentrations in many patients. Further prospective larger studies are now required to support an individualized schedule adjusted for patient weight and based on the observed trough serum eculizumab concentration.

Monitoring of complement activation biomarkers and eculizumab in complement-mediated renal disorders

“…It appears that especially patients with an altered therapy regimen and children have a tendency to accumulate eculizumab towards trough levels partially exceeding 1000 lg/ml [30,45]. Levels above 500 mg/ml were confirmed recently in a case of long-term application of eculizumab in aHUS [46], and pharmacokinetic modelling correlated drug accumulation to low body weight [47]. A trough level is recommended which should not undercut 50-100 lg/ml [48].…”

Atypical Hemolytic‐Uremic Syndrome: An Update on Pathophysiology, Diagnosis, and Treatment

“…The cost of eculizumab must be considered, as it is very expensive at > $300 000/year of treatment and many insurance companies have budget restrictions. Van den Brand et al performed a cost‐effectiveness analysis of treatment alternatives for aHUS patients with ESRD.…”

Influence of Antigen Mass on the Pharmacokinetics of Therapeutic Antibodies in Humans

“…TMDD models may be used to estimate the dose and/or schedule necessary to saturate target antigenin each patient individually. For instance, eculizumab concentration leading to a good clinical response [132] (with a total saturation and inactivation of C5 component of complement) and concentration associated with departure from linearity [60] are the same (100 mg/L). A good 20 strategy would be to calculate eculizumab dose and/or dosing interval so that each patient has trough concentrations always > 100 mg/L.…”