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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers.
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Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers.

机译：对健康的男性和女性成年志愿者进行单剂量和多剂量给药后，非氨基糖苷无义突变抑制剂PTC124的安全性，耐受性和药代动力学。

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摘要

Nonsense (premature stop codon) mutations are causative in 5% to 15% of patients with monogenetic inherited disorders. PTC124, a 284-Dalton 1,2,4-oxadiazole, promotes ribosomal readthrough of premature stop codons in mRNA and offers therapeutic potential for multiple genetic diseases. The authors conducted 2 phase I studies of PTC124 in 62 healthy adult volunteers. The initial, single-dose study evaluated doses of 3 to 200 mg/kg and assessed fed-fasting status on pharmacokinetics following a dose of 50 mg/kg. The subsequent multiple-dose study evaluated doses from 10 to 50 mg/kg/dose twice per day (bid) for up to 14 days. PTC124 administered orally as a liquid suspension was palatable and well tolerated through single doses of 100 mg/kg. At 150 and 200 mg/kg, PTC124 induced mild headache, dizziness, and gastrointestinal events. With repeated doses through 50 mg/kg/dose bid, reversible transaminase elevations <2 times the upper limit of normal were sometimes observed. Immunoblot analyses of peripheral blood mononuclear cell extracts revealed no protein elongation due to nonspecific ribosomal readthrough of normal stop codons. PTC124 plasma concentrations exceeding the 2- to 10-microg/mL values associated with activity in preclinical genetic disease models were safely achieved. No sex-related differences in pharmacokinetics were seen. No drug accumulation with repeated dosing was apparent. Diurnal variation was observed, with greater PTC124 exposures after evening doses. PTC124 excretion in the urine was <2%. PTC124 pharmacokinetics were described by a 1-compartment model. Collectively, the data support initiation of phase II studies of PTC124 in patients with nonsense mutation-mediated cystic fibrosis and Duchenne muscular dystrophy.
机译：无义（过早终止密码子）突变是造成单基因遗传性疾病患者的5％至15％。 PTC124是一种284道尔顿的1,2,4-恶二唑，可促进核糖体对mRNA中过早终止密码子的通读，并为多种遗传疾病提供了治疗潜力。作者在62位健康的成年人志愿者中进行了PTC124的2期I期研究。最初的单剂量研究评估了3至200 mg / kg的剂量，并评估了50 mg / kg的剂量后药物动力学的禁食状态。随后的多剂量研究评估了每天两次10至50 mg / kg /剂量的剂量（出价），最多持续14天。口服PTC124作为液体混悬液可口且可耐受100 mg / kg的单剂量。在150和200 mg / kg时，PTC124引起轻度头痛，头晕和胃肠道事件。在重复剂量达到50 mg / kg /剂量出价的情况下，有时观察到可逆转氨酶升高低于正常上限的2倍。外周血单核细胞提取物的免疫印迹分析显示，由于正常终止密码子的非特异性核糖体通读，因此没有蛋白质伸长。安全地达到了与临床前遗传疾病模型中的活性相关的PTC124血浆浓度超过2至10微克/毫升的值。没有观察到与性别相关的药代动力学差异。重复给药没有明显的药物积累。观察到昼夜变化，晚上服用PTC124后暴露量更大。尿中PTC124的排泄<2％。 PTC124的药代动力学由1室模型描述。总体而言，数据支持对无意义突变介导的囊性纤维化和杜氏肌营养不良症患者进行PTC124的II期研究。

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