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

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 mu g/mL in 9/9, >100 mu g/mL in 8/9, and >300 mu g/mL in 5/9 of patients. Intra-individual variability was low but eculizumab concentrations, closely correlated with patient weight (R-2 = 0.66, p = 0.034), varied broadly (55 +/- 12 to 733 +/- 164 mu g/mL). Pharmacokinetic modeling showed that the elimination half-life varied greatly, with an increase from 7.8d in a patient weighing 100kg to 19.5d in a 40kg patient. We predicted that infusions of 1200mg could be spaced every 4 or 6weeks in patients weighing <90 and <70kg, 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.