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 (R(2) = 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.

Keywords: Eculizumab; Hemolytic uremic syndrome; Paroxysmal nocturnal hemoglobinuria; Pharmacokinetics; Thrombotic microangiopathy.

Figure 1.

Trough free serum eculizumab concentration correlated with weight in patients with atypical hemolytic–uremic syndrome (aHUS).

Figure 2.

Decrease in free serum eculizumab concentration in patient 2 after eculizumab was discontinued.

Figure 3.

Pharmacokinetic estimation of free eculizumab concentration. Observed (crosses) and model-predicted (lines) trough eculizumab concentrations as a function of time for the 9 study patients.

Figure 4.

Prediction of eculizumab concentrations and complement activity. Simulations of steady-state trough eculizumab concentrations (broken lines) and complement activity (bold lines) according to body weight for a 1200 mg maintenance dose given every 14 d (squares), every 28 d (diamonds) and every 42 d (circles).

Figure 5.

Relation between measured free serum eculizumab concentration and complement activity. Complement activity was measured using ELISA (Diasorin), and was expressed in arbitrary units. Measurements were performed in triplicate. The relationship between eculizumab concentrations and complement activity was described using regression technique (gray line).