生物活性

• 靶点

  HIV Integrase IC50:90nM

  Integrase (S217Q PFV) IC50:40nM

• 描述Raltegravir is the first approved clinical used inhibitor of integrase which can inhibit different kind of INs with alternative IC50 values, for example, the IC50 for the wild type and S217Q prototype foamy virus(PFV) IN are 90 nM and 40 nM respectively, while it's 3.3 nM for HIV IN. In human MT-4 cells, the IC50 for raltegravir to inhibit overall IN activity was 9nM while it inhibited strand transfer step at 6.8nM. Besides, this compound could reduce HIV-1-induced CPE by 50% at the concentration of 1.4nM. At the concentration of >18 μM, MT-4 cells viability could be inhibited, suggesting a good antiviral activity for HIV. While MT-4 cells infected with SIVmac251, Raltegravir could inhibit SIVmac251 replication with a lower EC50 value (< 1nM) compared with HIV-1/HIV-2 infected MT-4 cells. In SIVmac251 infected CEMx174 cells, Raltegravir displayed reproducible anti-SIVmac251 activity by using of syncytia counts which could be still produced in the presence of this compound, while the syncytia formation induced apoptotic and necrotic cell death in MT-4 cells. In human CD4⁺ T cells, Raltegravir also showed inhibitory effect when the cell fraction showed expression of the CD4 antigen >94%. In one phase 2 study, 198 HIV-1 infected participants with the HIV-1 RNA level at >5000 copies/mL and the CD4 cell count >100 cells/μL were treated with 400 mg Raltegravir twice daily from 48 week. The result showed that the proportions of patients with an HIV-1 RNA level at <50 copies/mL were 83%. While in another phase 2 study, the 201 HIV-1 infected participants with the same RNA and CD4 levels were treated with gradient concentrations of Raltegravir twice daily showed a quicker reduction on RNA levels at week 48 that ranges in 83%-88% in a dose-independent manner.
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  human HeLa cells	-	Function assay	48 h	Antiviral activity against VSV-G pseudotyped HIV1 lentiviral particles infected in human HeLa cells incubated for 48 hrs by spectrofluorometry, IC50=10 nM	22858300
  human HOS cells	-	Function assay	-	Antiviral activity against HIV1 harboring wild-type integrase infected in human HOS cells, EC50=4 nM	21493066
  human MT2 cells	-	Function assay	5 days	Antiviral activity against HIV1 3B infected in human MT2 cells after 5 days by chemiluminescence in presence of fetal bovine serum, EC50=4 nM	19285389

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• 动物研究
  剂量	Rat: 40 mg/kg - 160 mg/kg[3] (intragastrically) Dog: 5 mg/kg - 135 mg/kg[4] (p.o.)
  给药途径	Intragastrically
  动物药代数据	Animal Rats[4] Dogs[4] Dose 6 mg/kg (p.o.) 3 mg/kg (i.v.) 5 mg/kg (p.o.) 1.5 mg/kg (i.v.) Administration p.o. i.v. p.o. i.v. F 61.6% (p.o.) 70.0% (p.o.) T1/2 0.2 h (i.v.) 1.6 h (i.v.) Tmax 0.4 h (p.o.) 0.6 h (p.o.) CLp 45.5 ml/h/kg (i.v.) 7.4 ml/h/kg (i.v.) Cmax 1.7 μg/ml (p.o.) 11.9 μg/ml (p.o.) Vdss 2.2 L/kg (i.v.) 0.4 L/kg (i.v.) AUC0→∞ 3.2 μM·h (p.o.) 2.6 μM·h (i.v.) 18.6 μM·h (p.o.) 7.9 μM·h (i.v.)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01270802	HIV	Phase 4	Completed	-	United States, Indiana ... more >> Indiana University School of Medicine Indianapolis, Indiana, United States, 46202 Collapse <<
  NCT00654147	HIV Infections	Phase 2	Completed	-	United States, Florida ... more >> University of Miami AIDS Clinical Research Unit Miami, Florida, United States, 33136 Collapse <<
  NCT01270802	-	-	Completed	-	-

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