安全性，药代动力学和药物遗传学，单一上升剂量的普拉韦

StephenW

Hepatol Int. 2017 May 30. doi: 10.1007/s12072-017-9797-y. [Epub ahead of print]
Safety, pharmacokinetics and pharmacogenetics of a single ascending dose of pradefovir, a novel liver-targeting, anti-hepatitis B virus drug, in healthy Chinese subjects.Ding Y1, Zhang H1, Li X1, Li C1, Chen G1, Chen H1, Wu M2, Niu J3.
Author information
1Phase I Clinical Trial Unit, The First Hospital of Jilin University, Changchun, No. 71 Xinmin Street, Changchun, 130021, China.2Phase I Clinical Trial Unit, The First Hospital of Jilin University, Changchun, No. 71 Xinmin Street, Changchun, 130021, China. [email protected].3Department of Hepatology, The First Hospital of Jilin University, Changchun, No. 71 Xinmin Street, Changchun, 130021, China. [email protected].

AbstractBACKGROUND: Pradefovir is efficiently converted to adefovir [9-(2-phosphonylmethoxyethyl) adenine (PMEA)], producing high hepatic PMEA concentration but low levels in the systemic circulation and kidney. The aim of this study is to evaluate the tolerability, adverse effect (AEs), pharmacokinetics and pharmacogenetics of a single ascending dose of pradefovir.
METHODS: Fifty healthy subjects were divided into five groups and randomized within each group at a ratio of 3:1:1 to receive a single ascending dose of pradefovir (10, 30, 60, 90, or 120 mg), and 10 mg adefovir dipivoxil (ADP) or placebo. Blood and urine samples were collected and analyzed. A total of 1930 polymorphic loci were analyzed in 6 blood samples collected from the 90 mg pradefovir group.
RESULTS: The single oral dose of pradefovir up to 120 mg was well tolerated. A total of 29 dose-limited mild AEs were reported in 17 subjects. The peak plasma concentration (C max) and area under the curve (AUC)0-48 of serum pradefovir ranged from (21.41 ± 12.98) to (447.33 ± 79.34) ng/mL and (46.10 ± 29.45) to (748.18 ± 134.15) ng h/mL across the dose range, respectively. The C max and AUC0-48 of serum PMEA ranged from 18.10 ± 4.96 to 312.33 ± 114.19 ng/mL and 72.65 ± 28.25 to 1095.48 ± 248.47 ng h/mL. Generally, no kidney impairment was observed. Pharmacogenetic analysis identified three metabolism-related single nucleotide polymorphism (SNP) locis, P450 (cytochrome) oxidoreductase [POR (rs6965343)], arylamine N-acetyltransferases [NAT1 (rs4986993)] and CYP2F1 (rs305968)], and one distribution-related loci, orosomucoid 2 [ORM2 (rs12685968)].
CONCLUSIONS: The single oral dose of pradefovir 10-120 mg was well tolerated. SNPs may be associated with variable rates of adverse events.
TRIAL REGISTRATION NUMBER: CTR20140341.


KEYWORDS: Hepatitis B; Pharmacogenetics; Pharmacokinetics; Pradefovir; Single ascending dose; Tolerability

PMID:28560658DOI:10.1007/s12072-017-9797-y

StephenW

Hepatol Int。 2017年5月30日。doi：10.1007 / s12072-017-9797-y。 [提前印刷]
安全性，药代动力学和药物遗传学，单一上升剂量的普拉韦韦，一种新型的肝靶向抗乙型肝炎病毒药物，在健康的中国科目。
丁Y1，张Zhang，李X1，李克，陈G1，陈H1，吴Wu，牛J 3。
作者信息

1
    吉林大学第一医院临床试验单位，长春，7100新昌街71号，长春130021。
2
    吉林大学第一医院临床试验单位，长春，7100新昌街71号，长春130021。 [email protected]。
3
    吉林大学第一医院肝脏病科长春市长春市新民街71号，长春130021。 [email protected]。

抽象
背景：

普拉德福韦有效地转化为阿德福韦[9-（2-膦酰基甲氧基乙基）腺嘌呤（PMEA）]，产生高肝脏PMEA浓度，但在全身循环和肾脏中水平较低。本研究的目的是评估单次上升剂量的普拉韦韦的耐受性，不良反应（AEs），药代动力学和药物遗传学。
方法：

将五十名健康受试者分为五组，每组中以3：1：1的比例随机分配，以接受单一上升剂量的普拉韦韦（10,30,60,90或120mg）和10mg阿德福韦酯ADP）或安慰剂。收集血液和尿液样本并进行分析。从90mg普拉维韦组收集的6个血液样品中共分析了1930个多态位点。
结果：

单次口服剂量的高达120 mg的普拉韦韦具有良好的耐受性。 17例患者共报告了29例剂量受限的轻度AE。血清pradefovir的峰值血浆浓度（C max）和曲线下面积（AUC）0-48范围为（21.41±12.98）至（447.33±79.34）ng / mL，（46.10±29.45）至（748.18±134.15） ng / mL分别在剂量范围内。血清PMEA的C max和AUC 0-48分别为18.10±4.96〜312.33±114.19ng / mL，72.65±28.25〜1095.48±248.47 ng / mL。一般来说，没有观察到肾脏损伤。药代动力学分析确定了三种代谢相关单核苷酸多态性（SNP），P450（细胞色素）氧化还原酶[POR（rs6965343）]，芳基胺N-乙酰转移酶[NAT1（rs4986993）]和CYP2F1（rs305968）]和一个分布相关基因座，脂质体2 [ORM2（rs12685968）]。
结论：

单次口服剂量的普拉韦韦10-120 mg耐受性良好。 SNP可能与不良事件的可变率相关。
试用登记号码：

CTR20140341。
关键词：

乙型肝炎药理学;药代动力学; Pradefovir;单次上升剂量;耐受性

结论：
    28560658
DOI：
    10.1007 / s12072-017-9797-Y

kite2002005

普拉德福韦有效地转化为阿德福韦。
这里好搞笑，这个新药是不是山寨版中国”阿德福韦” ？