GS-9620安全性，药代动力学和药效学

StephenW

Here is a single ascending dose human phase I study[from studyforhope]

Antivir Ther. 2013 Feb 12. doi: 10.3851/IMP2548. [Epub ahead of print]
Safety, pharmacokinetics and pharmacodynamics of GS-9620, an oral Toll-like receptor 7 agonist.


Lopatin U, Wolfgang G, Tumas D, Frey CR, Ohmstede C, Hesselgesser J, Kearney B, Moorehead L, Subramanian GM, McHutchison JG.
Source
Gilead Sciences, Foster City, CA, USA.
Abstract
BACKGROUND:
GS-9620 is a novel oral agonist of toll-like receptor 7 (TLR7) in development for the treatment of chronic viral hepatitis. TLR7 is a highly conserved innate immune receptor expressed primarily on plasmacytoid dendritic cells and B lymphocytes. The aim of this double-blind placebo-controlled, single ascending dose study was to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of GS-9620 in healthy volunteers.
METHODS:
Seventy five healthy volunteers (8 subjects in each of 10 cohorts, 5 subjects participated in 2 cohorts) were randomized (6:2) to receive a single dose of GS-9620 (0.3, 1, 2, 4, 6, 8, or 12 mg) or placebo.
RESULTS:
GS-9620 was well absorbed and well tolerated in oral doses up to 12 mg. Minimal treatment related adverse events were seen at doses up to 8 mg. Serum interferon-alpha was only detected in subjects who received 8 or 12 mg doses, and the adverse event profile at 8 and 12 mg doses was generally consistent with that associated with interferon-alpha exposure (flu-like symptoms), consistent with the mechanism of TLR7 agonism. All adverse events resolved within 72 hours. Induction of chemokines/cytokines and interferon-stimulated genes (ISGs) were seen at GS-9620 doses ≥2mg, well below doses that induced serum IFN-α or led to clinical adverse events.
CONCLUSIONS:
GS-9620 demonstrates safety and pharmacodynamic activity at doses up to 12 mg. Pharmacodynamic activity is seen before adverse events, suggesting the potential for induction of an antiviral response without systemic adverse events in patients with chronic viral hepatitis.

StephenW

背景：
GS-9620是一种新型的口服激动剂Toll样受体7（TLR7）用于治疗慢性病毒性肝炎的发展。 TLR7是一种高度保守的先天免疫受体主要表达于浆细胞树突状细胞和B淋巴细胞。这项双盲安慰剂对照，单剂量递增研究的目的是调查的安全性，耐受性，药代动力学和药效学研究在健康志愿者中的GS-9620。
方法：
七十名健康志愿者（8个科目中每10个队列，5人参加了两个世代），随机（6:2）接受单剂量的GS-9620（0.3，1，2，4，6，8，或12 mg）或安慰剂。
结果：
GS-9620很好地吸收和耐受性良好，在口服剂量12毫克。最小的治疗相关的不良事件被认为在剂量高达8毫克。只检测血清α-干扰素在8或12毫克剂量，并在8和12毫克剂量的不良事件是基本一致的，一致的机制与α-干扰素曝光（流感样症状）的TLR7激动。所有不良事件，在72小时内解决。诱导的趋化因子/细胞因子和干扰素刺激基因（ISGs）被发现在GS-9620剂量≥2毫克，远低于血清IFN-α诱导或导致临床不良反应的剂量。
结论：
GS-9620演示安全性和药效活性的剂量高达12毫克。药效活性见过的潜在诱导的抗病毒反应的不良事件，这表明在慢性病毒性肝炎患者无全身不良反应事件。

咬牙硬挺

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