Saida Ken, Fukuda Tsuyoshi, Mizuno Kana, Ogura Masao, Kamei Koichi, Ito Shuichi
Division of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan.
Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.
Front Pediatr. 2019 Dec 17;7:519. doi: 10.3389/fped.2019.00519. eCollection 2019.
Eculizumab has dramatically changed poor outcomes of complement-mediated atypical hemolytic uremic syndrome (aHUS) as first-line treatment. Discontinuation of eculizumab remains challenging, and doctor's visits every 2 weeks for intravenous injection because of standard dosing protocols is a huge burden. The Ultra-high cost of eculizumab is also an issue. We attempted to establish a personalized dosing regimen of eculizumab based on pharmacokinetics and pharmacodynamics in a 2-year-old girl with aHUS with a mutation. She developed aHUS at 5 months of age and was successfully treated with eculizumab. At 2 years of age, we measured eculizumab concentrations and performed pharmacokinetics and pharmacodynamics analysis to optimize her dosing protocol. Her blood concentrations at every 2-, 3-, and 4-week intervals were simulated. Pharmacokinetics analysis showed that her eculizumab clearance was 40% lower than the population mean reported for aHUS. Pharmacokinetic simulation suggested that the 2- and 3-week interval regimen could be sufficient to achieve an efficient trough concentration (>100 μg/mL). We simulated her individual pharmacokinetics profile at 4 years of age with consideration of her growth, which still showed complete inhibition of the alternative complement pathway with the 3-week interval regimen. We continued the 300-mg eculizumab infusion every 3 weeks while CH50 levels were constantly maintained at undetectably low concentrations with no recurrence until 6 years of age. Pharmacokinetics and pharmacodynamics estimation was useful for establishing a personalized dosing regimen for eculizumab and reducing the patient's burden and high medical costs.
依库珠单抗作为一线治疗药物，极大地改变了补体介导的非典型溶血尿毒综合征（aHUS）的不良预后。停用依库珠单抗仍然具有挑战性，并且由于标准给药方案需要每2周进行一次静脉注射，这给患者带来了巨大负担。依库珠单抗的超高成本也是一个问题。我们试图为一名患有aHUS且存在基因突变的2岁女孩，基于药代动力学和药效学建立个性化给药方案。她在5个月大时患上aHUS，并成功接受了依库珠单抗治疗。在2岁时，我们测量了依库珠单抗浓度，并进行了药代动力学和药效学分析，以优化她的给药方案。我们模拟了她每隔2周、3周和4周时的血药浓度。药代动力学分析表明，她的依库珠单抗清除率比报道的aHUS患者群体均值低40%。药代动力学模拟表明，2周和3周给药间隔方案足以达到有效的谷浓度（>100μg/mL）。我们考虑到她的生长情况，模拟了她4岁时的个体药代动力学特征，结果显示3周给药间隔方案仍能完全抑制替代补体途径。我们继续每3周输注300mg依库珠单抗，同时CH50水平持续维持在低至检测不到的浓度，直到6岁都没有复发。药代动力学和药效学评估有助于建立依库珠单抗的个性化给药方案，减轻患者负担并降低高昂的医疗成本。
