效果没有CYP3A4的CYP3A4抗病诱导剂和抑制剂的药物动力学maraviroc在健康志愿者。
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亚伯,詹金斯TM、怀特洛克拉Ridgway CE、Muirhead GJ
效果没有CYP3A4的CYP3A4抗病诱导剂和抑制剂的药物动力学maraviroc在健康志愿者。
Br中国新药杂志。2008年4月,65增刊1:38-46。doi: 10.1111 / j.1365-2125.2008.03134.x。
- PubMed ID
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18333864 (在PubMed]
- 文摘
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目的:评估潜在的CYP3A4诱发者,有或没有CYP3A4抑制剂,改变maraviroc的药动学特征。方法:两个独立、开放、随机、安慰剂对照的研究在健康受试者进行的。研究1是28天与这些相应平行的组织研究有三个治疗组,每组12个科目。天1 - 7,所有受试者接受maraviroc 100毫克b.i.d。;在8至21天,受试者接受maraviroc 100毫克b.i.d. +利福平600毫克q.d。,依法韦伦(EFV) 600毫克q.d。,或安慰剂q.d.分配;天22,maraviroc剂量增加到200毫克b.i.d.病人接受利福平或EFV。研究2是21天,双向交叉研究有三个军团(12主题队列)。1日到21日在天,受试者接受maraviroc 300毫克b.i.d.和提高lopinavir (LPV / r, lopinavir 400毫克+例如100毫克)或安慰剂b.i.d.在队列1中,maraviroc 100毫克b.i.d.和提高saquinavir (SQV / r, saquinavir 1000毫克+例如100毫克)或安慰剂b.i.d.在队列2中,b.i.d. maraviroc 100毫克和1000毫克saquinavir + LPV / r(400毫克/ 100毫克)或安慰剂b.i.d.组3。在8至21天,受试者在所有三个军团还收到了EFV 600毫克或安慰剂q.d。结果:Maraviroc(100毫克b.i.d)接触(AUC(12)和C (max))的存在降低了利福平与EFV约70%和50%,分别。 Maraviroc AUC(12) and C(max) approached preinduction values when the maraviroc dose was increased to 200 mg b.i.d. for both the rifampicin-treated and EFV-treated groups. Co-administration of LPV/r with maraviroc (300 mg b.i.d.) resulted in geometric mean ratios (GMRs) of 395% and 197% for maraviroc AUC(12) and C(max), respectively, compared with placebo; addition of EFV resulted in GMRs of 253% and 125% for AUC(12) and C(max), respectively. Co-administration of SQV/r with maraviroc (100 mg b.i.d.) resulted in GMRs of 977% and 478% for maraviroc AUC(12) and C(max), respectively, compared with placebo; addition of EFV resulted in GMRs of 500% and 226% for AUC(12) and C(max), respectively. No pharmacokinetic data are reported for cohort 3 because all subjects were discontinued during period 1 due to poor toleration of the drug regimen. There were no serious adverse events reported in either study, and most adverse events were mild or moderate in severity and resolved without intervention. CONCLUSION: As expected with a CYP3A4 substrate, maraviroc exposure (C(max) and AUC(12)) was significantly reduced by the known CYP3A4 inducers, rifampicin and EFV, by approximately 70% and 50%, respectively. Upward adjustment of the maraviroc dose during co-administration with rifampicin or EFV appears to compensate for this reduction. Protease inhibitors (PIs) significantly increased maraviroc exposure; however, the addition of EFV to the maraviroc + PI regimens reduced the magnitude of PI-mediated increase in maraviroc exposure (by approximately 50%), but the net effect was still CYP3A4 inhibition.
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