A first-in-human study of the novel HIV-fusion inhibitor C34-PEG(4)-Chol.
A first-in-human study of the novel HIV-fusion inhibitor C34-PEG(4)-Chol.
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新型HIV融合抑制剂C34-PEG（4）-Chol的首次人类研究。
DOI：
10.1038/s41598-017-09230-0
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发表时间：
2017-08-25
影响因子：
4.6
通讯作者：
Winston A
中科院分区：
文献类型：
--
作者：
Quinn K;Traboni C;Penchala SD;Bouliotis G;Doyle N;Libri V;Khoo S;Ashby D;Weber J;Nicosia A;Cortese R;Pessi A;Winston A
具有低毒性和药物相互作用倾向的长效注射抗逆转录病毒（LA-ARV）药物是未来抗逆转录病毒治疗方案的目标。C34-PEG4-Chol是一种新型胆固醇标记的LA hiv融合抑制剂（FI）。我们评估了C34-PEG4-Chol的临床前毒理学和首次人体给药。对2种动物进行临床前毒理学研究。hiv阳性男性被随机分配到单次皮下剂量C34-PEG4-Chol或安慰剂组。详细的临床（包括注射部位反应（ISR）分级）、血浆药代动力学(至最低有效浓度时间（MEC, 25 ng/mL）和药效学（血浆HIV RNA）参数进行了评估。在小鼠和犬中，两周后以12mg /kg/剂量观察到无观察到不良反应水平（NOAEL）。入组的5名男性中，3名接受活性药物治疗（10mg， 10mg和20mg）。2例发生3级ISR，研究终止。两例ISR均在给药12小时内出现。未观察到全身毒性。10和20 mg剂量后，到达mec的时间分别为72小时和96小时，HIV RNA的平均变化为−0.9 log10拷贝/mL。这些C34-PEG-4-Chol的人体药效学和药代动力学数据虽然仅限于3名受试者，但建议继续评估该药物作为LA-ARV的作用。但是，必须探索其他给药途径。
Long-acting injectable antiretroviral (LA-ARV) drugs with low toxicity profiles and propensity for drug-drug interactions are a goal for future ARV regimens. C34-PEG4-Chol is a novel cholesterol tagged LA HIV-fusion-inhibitor (FI). We assessed pre-clinical toxicology and first-in-human administration of C34-PEG4-Chol. Pre-clinical toxicology was conducted in 2 species. HIV-positive men were randomised to a single subcutaneous dose of C34-PEG4-Chol at incrementing doses or placebo. Detailed clinical (including injection site reaction (ISR) grading), plasma pharmacokinetic (time-to-minimum-effective-concentration (MEC, 25 ng/mL) and pharmacodynamic (plasma HIV RNA) parameters were assessed. In both mice and dogs, no-observed-adverse effect level (NOAEL) was observed at a 12 mg/kg/dose after two weeks. Of 5 men enrolled, 3 received active drug (10 mg, 10 mg and 20 mg). In 2 individuals grade 3 ISR occurred and the study was halted. Both ISR emerged within 12 hours of active drug dosing. No systemic toxicities were observed. The time-to-MEC was >72 and >96 hours after 10 and 20 mg dose, respectively, and mean change in HIV RNA was −0.9 log10 copies/mL. These human pharmacodynamic and pharmacokinetic data, although limited to 3 subjects, of C34-PEG-4-Chol suggest continuing evaluation of this agent as a LA-ARV. However, alternative administration routes must be explored.
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影响因子：
6.7
作者：
Porotto M;Rockx B;Yokoyama CC;Talekar A;Devito I;Palermo LM;Liu J;Cortese R;Lu M;Feldmann H;Pessi A;Moscona A
通讯作者：
Moscona A
影响因子：
2.1
作者：
Santoprete, Alessia;Capito, Elena;Pessi, Antonello
通讯作者：
Pessi, Antonello
影响因子：
5.4
作者：
Welsch, Jeremy C.;Talekar, Aparna;Porotto, Matteo
通讯作者：
Porotto, Matteo
DOI：
10.1073/pnas.85.3.900
发表时间：
1988-02-01
影响因子：
11.1
作者：
ALOIA, RC;JENSEN, FC;GORDON, LM
通讯作者：
GORDON, LM
影响因子：
5.4
作者：
Li, Chuan-Gen;Tang, Wang;Wang, Xiao-Jia
通讯作者：
Wang, Xiao-Jia