Correspondence
More on Eculizumab for Congenital Atypical Hemolytic–Uremic Syndrome
N Engl J Med 2009; 360:2142-2143May 14, 2009
- Article
To the Editor:
In their letter to the editor about eculizumab for congenital atypical hemolytic–uremic syndrome, Gruppo and Rother (Jan. 29 issue)1 report that they used eculizumab in an 18-month-old boy at an initial dose of 300 mg and a maintenance dose of 600 mg — half and two thirds of the adult doses (600 mg and 900 mg), respectively.2 These doses may be relatively high, because this patient weighed only 12 kg, and the body-surface area is approximately 0.5 m2, which may be less than one third of the adult area. The appropriate dose and the pharmacokinetics of this drug in children or in patients with renal failure have not yet been studied. Therefore, especially in young children, eculizumab should be used cautiously because of the high risk of meningococcal infection2; the lowest effective dose of eculizumab should be determined according to the plasma drug level. Because plasma eculizumab levels of more than 35 μg per milliliter are required to block complement activation in adults,2 the initial dose should be calculated on the basis of body-surface area, with the maintenance dose adjusted according to the therapeutic response and the plasma drug level.
2 ReferencesJae Il Shin, M.D.
Jae Seung Lee, M.D.
Yonsei University College of Medicine, Seoul 120-752, Republic of South Korea
pedshin2000@yahoo.co. kr 1
Gruppo RA ,Rother RP . Eculizumab for congenital atypical hemolytic-uremic syndrome. N Engl J Med 2009;360:544-546
Full Text | Web of Science | Medline2
Davis J . Eculizumab. Am J Health Syst Pharm 2008;65:1609-1615
CrossRef | Web of Science | Medline
Author/Editor Response
Since eculizumab has not been studied in children, our initial dose was chosen on the basis of extrapolation from pharmacokinetic modeling in adults,1-3 which showed variable clearance rates not related to weight. In clinical trials of eculizumab in patients with paroxysmal nocturnal hemoglobinuria, standard dosing was associated with breakthrough of terminal complement activation, and dose adjustment was required in approximately 10% of patients.1,3 Therefore, to prevent further renal damage from thrombotic microangiopathy,4 real-time pharmacokinetic and pharmacodynamic monitoring was done to ensure complete, sustained complement blockade. Four weekly infusion doses of 300 mg, followed by doses of 600 mg every 14 days, were associated with therapeutic serum drug levels and complete inhibition of serum hemolytic capacity, effects that are similar to those observed in adults.1-3 We are currently cautiously attempting to reduce the eculizumab dose, with close pharmacokinetic monitoring. We share the concern about the potential for severe infections, but the risk of infection is related to C5 blockade, which is complete at a serum drug level of 35 μg per milliliter or more.1 An increase in the risk of infection is not expected above this level. Trials of eculizumab in children are required for additional dosing guidance.
4 ReferencesRalph A. Gruppo, M.D.
Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
ralph.gruppo@cchmc. org 1
Hillmen P ,Hall C ,Marsh JCW , et al. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med 2004;350:552-559
Full Text | Web of Science | Medline2
Hillmen P ,Young NS ,Schubert J , et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 2006;355:1233-1243
Full Text | Web of Science | Medline3
Brodsky RA ,Young NS ,Antonioli E , et al. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood 2008;111:1840-1847
CrossRef | Web of Science | Medline4
Ruggenenti P ,Noris M ,Remuzzi G . Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura. Kidney Int 2001;60:831-846
CrossRef | Web of Science | Medline
