Zamora Nuria Padullés, Pla Rafael Vidal, Del Rio Pilar Gispert, Margaleff Rosendo Jardi, Frias Francisco Rodriguez, Ronsano Jose Bruno Montoro
Pharmacy Service, Hospital Vall d'Hebron, Barcelona, Spain.
Ann Pharmacother. 2008 May;42(5):640-6. doi: 10.1345/aph.1K505. Epub 2008 Apr 15.
Severe forms of alpha(1)-antitrypsin (AAT) deficiency require augmentation therapy by intravenous administration of purified preparations of AAT concentrate. Although standard AAT treatment schedules are widely available, pharmacokinetic studies characterizing AAT serum decay are scarce, and data on the variability of individual patients are almost nonexistent.
To establish individual AAT pharmacokinetics and develop a predictive model based on simple pharmacokinetic characterization that can be used to optimize individual AAT dosing regimens.
Seven patients with severe hereditary AAT deficiency (PI(*)ZZ phenotype) with serum AAT levels less than 0.50 g/L initially received AAT 180 mg/kg every 3 weeks. At 7, 14, and 21 days after AAT administration, serum samples were taken for quantitative AAT analysis and further one-compartment pharmacokinetic analysis. Subsequently, patients were rescheduled (dose and dosing interval) according to their individual responses. The influence of baseline AAT level, age, sex, body weight, and commercial AAT preparation was evaluated.
The mean +/- SD AAT pharmacokinetic profile was: volume of distribution 127.6 +/- 31.9 mL/kg, clearance 10.13 +/- 1.84 mL/kg/day, and half-life 8.7 +/- 1.0 days. Hence, the mean optimized final AAT dose was 123.1 mg/kg every 2 weeks (range 118.5-125.6). AAT concentrations differed by a mean (geometrical) value of 3.9% (range -4.2% to 6.7%) from the minimum desired AAT serum trough of 0.50 g/L. The impact of baseline AAT levels and commercial AAT preparation used was statistically significant (p = 0.033 and p = 0.035, respectively). Differences between estimated and actual values were slightly lower when baseline AAT levels were taken into consideration, with a mean value of 3.3% (range -4.2% to 6.1%).
AAT augmentation therapy can be effectively individualized on a pharmacokinetic basis with a simple, easily executed method.
严重形式的α1-抗胰蛋白酶（AAT）缺乏症需要通过静脉注射纯化的AAT浓缩制剂进行增强治疗。尽管标准的AAT治疗方案广泛可用，但表征AAT血清衰减的药代动力学研究却很少，而且关于个体患者变异性的数据几乎不存在。
建立个体AAT药代动力学模型，并基于简单的药代动力学特征开发一个预测模型，用于优化个体AAT给药方案。
7例严重遗传性AAT缺乏症（PI(*)ZZ表型）患者，初始血清AAT水平低于0.50 g/L，最初每3周接受180 mg/kg的AAT治疗。在给予AAT后的第7、14和21天，采集血清样本进行AAT定量分析和进一步的单室药代动力学分析。随后，根据患者的个体反应重新安排治疗计划（剂量和给药间隔）。评估基线AAT水平、年龄、性别、体重和市售AAT制剂的影响。
AAT药代动力学平均±标准差曲线为：分布容积127.6±31.9 mL/kg，清除率10.13±1.84 mL/kg/天，半衰期8.7±1.0天。因此，优化后的最终AAT平均剂量为每2周123.1 mg/kg（范围118.5 - 125.6）。AAT浓度与最低期望的AAT血清谷浓度0.50 g/L的平均（几何）差值为3.9%（范围 - 4.2%至6.7%）。所使用的基线AAT水平和市售AAT制剂的影响具有统计学意义（分别为p = 0.033和p = 0.035）。考虑基线AAT水平时，估计值与实际值之间的差异略低，平均值为3.3%（范围 - 4.2%至6.1%）。
AAT增强治疗可以通过一种简单、易于实施的方法在药代动力学基础上有效地实现个体化。
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