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 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.
a Service de Néphrologie et Immunologie clinique ; CHRU de Tours ; France.|b Laboratoire d'Immunologie ; CHRU de Tours ; France.|c EA 4245; Université François-Rabelais de Tours ; France.
Philippe
P
Gatault
b Laboratoire d'Immunologie ; CHRU de Tours ; France.|d UMR 7292; Université François-Rabelais de Tours ; France.|e UMR 7292 GICC; CNRS.
Guillaume
G
Brachet
d UMR 7292; Université François-Rabelais de Tours ; France.|e UMR 7292 GICC; CNRS.|f Laboratoire de Pharmacologie-Toxicologie ; CHRU de Tours ; France.
David
D
Ternant
b Laboratoire d'Immunologie ; CHRU de Tours ; France.|d UMR 7292; Université François-Rabelais de Tours ; France.|e UMR 7292 GICC; CNRS.
Danielle
D
Degenne
b Laboratoire d'Immunologie ; CHRU de Tours ; France.
Guillaume
G
Récipon
a Service de Néphrologie et Immunologie clinique ; CHRU de Tours ; France.
Christelle
C
Barbet
d UMR 7292; Université François-Rabelais de Tours ; France.|e UMR 7292 GICC; CNRS.|g Service d'Hématologie et Thérapie Cellulaire ; CHRU de Tours ; France.
Emmanuel
E
Gyan
b Laboratoire d'Immunologie ; CHRU de Tours ; France.|d UMR 7292; Université François-Rabelais de Tours ; France.|e UMR 7292 GICC; CNRS.
Valérie
V
Gouilleux-Gruart
h CHU de Bordeaux; France; Laboratoire d'Immunologie et d'Immunogénétique ; France.|i Université de Bordeaux; UMR 5164 CIRID ; France.
Cécile
C
Bordes
d UMR 7292; Université François-Rabelais de Tours ; France.|e UMR 7292 GICC; CNRS.
Alexandra
A
Farrell
a Service de Néphrologie et Immunologie clinique ; CHRU de Tours ; France.|c EA 4245; Université François-Rabelais de Tours ; France.
Jean Michel
JM
Halimi
b Laboratoire d'Immunologie ; CHRU de Tours ; France.|d UMR 7292; Université François-Rabelais de Tours ; France.|e UMR 7292 GICC; CNRS.
Hervé
H
Watier
D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D065766:Atypical Hemolytic Uremic Syndrome / Q000188:drug therapy* / Q000378:metabolism; D001835:Body Weight; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D006207:Half-Life; D006457:Hemoglobinuria, Paroxysmal / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D060046:Maintenance Chemotherapy; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010865:Pilot Projects; D057285:Precision Medicine / Q000379:methods*; D012189:Retrospective Studies; D055815:Young Adult
D061067:Antibodies, Monoclonal, Humanized; C481642:eculizumab
Eculizumab; Hemolytic uremic syndrome; Paroxysmal nocturnal hemoglobinuria; Pharmacokinetics; Thrombotic microangiopathy