Qi Yulan, Mould Diane R, Zhou Huiyu, Merilainen Markus, Musson Donald G
BioMarin Pharmaceutical Inc., 105 Digital Dr., 94949, Novato, CA, USA,
Clin Pharmacokinet. 2015 Feb;54(2):195-207. doi: 10.1007/s40262-014-0196-4.
Untreated phenylketonuria (PKU), a hereditary metabolic disorder caused by a genetic mutation in phenylalanine hydroxylase (PAH), is characterized by elevated blood phenylalanine (Phe) and severe neurologic disease. Sapropterin dihydrochloride, a synthetic preparation of naturally occurring PAH cofactor tetrahydrobiopterin (BH4), activates residual PAH in a subset of patients, resulting in decreased blood Phe and increased Phe tolerance. The objective of this study was to determine the appropriate dose of sapropterin in pediatric patients (0-6 years). The study design used D-optimization and was prospectively powered to achieve precise estimates of clearance and volume of distribution.
Oral sapropterin (5 or 20 mg/kg) was administered once daily. Sapropterin plasma concentrations were measured by a validated method. Population pharmacokinetic analysis was performed with NONMEM(®) version 7.2 on pooled data from 156 pediatric and adult PKU patients in two phase III clinical studies.
The best pharmacokinetic model was a one-compartment model with an absorption lag, first-order input, and linear elimination, with a factor describing endogenous BH4 levels. Body weight was the only covariate significantly affecting sapropterin pharmacokinetics. Based on recommended dosing, exposure across age groups was comparable. The absorption rate and terminal half-life suggest flip-flop pharmacokinetic behavior where absorption is rate limiting.
The effect of weight on sapropterin pharmacokinetics was significant and exposure was comparable across age groups; thus, weight-based dosing is appropriate. The doses selected for pediatric patients provided similar exposure as in adults. Given the slow absorption and elimination half-life, once-daily dosing is justified.
未经治疗的苯丙酮尿症（PKU）是一种由苯丙氨酸羟化酶（PAH）基因突变引起的遗传性代谢紊乱疾病，其特征为血苯丙氨酸（Phe）水平升高及严重的神经系统疾病。盐酸沙丙蝶呤是天然存在的PAH辅因子四氢生物蝶呤（BH4）的合成制剂，可激活部分患者体内残余的PAH，从而降低血Phe水平并提高Phe耐受性。本研究的目的是确定儿科患者（0至6岁）的沙丙蝶呤合适剂量。研究设计采用D优化法，前瞻性地进行功效分析以精确估计清除率和分布容积。
口服沙丙蝶呤（5或20mg/kg），每日一次。采用经过验证的方法测定沙丙蝶呤血浆浓度。使用NONMEM®7.2版对两项III期临床研究中156例儿科和成人PKU患者的汇总数据进行群体药代动力学分析。
最佳药代动力学模型为具有吸收延迟、一级输入和线性消除的单室模型，并有一个描述内源性BH4水平的因子。体重是唯一显著影响沙丙蝶呤药代动力学的协变量。根据推荐剂量，各年龄组的暴露量相当。吸收速率和末端半衰期表明存在吸收为限速因素的反翻转药代动力学行为。
体重对沙丙蝶呤药代动力学有显著影响，各年龄组的暴露量相当；因此，基于体重给药是合适的。为儿科患者选择的剂量与成人的暴露量相似。鉴于吸收缓慢和消除半衰期长，每日一次给药是合理的。
