EFFECT OF 2',3'-DIDEHYDRO-3'-DEOXYTHYMIDINE IN AN IN-VITRO HOLLOW-FIBER PHARMACODYNAMIC MODEL SYSTEM CORRELATES WITH RESULTS OF DOSE-RANGING CLINICAL-STUDIES
EFFECT OF 2',3'-DIDEHYDRO-3'-DEOXYTHYMIDINE IN AN IN-VITRO HOLLOW-FIBER PHARMACODYNAMIC MODEL SYSTEM CORRELATES WITH RESULTS OF DOSE-RANGING CLINICAL-STUDIES
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DOI：
10.1128/aac.38.6.1386
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发表时间：
1994-06-01
影响因子：
4.9
通讯作者：
DRUSANO, GL
中科院分区：
文献类型：
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作者：
BILELLO, JA;BAUER, G;DRUSANO, GL
我们试图验证一个体外系统，可以预测抗逆转录病毒药物的最小作用剂量。在模拟D4 T在患者中的血浆浓度-时间曲线的中空纤维模型中，将未感染的CEM细胞和慢性感染人类免疫缺陷病毒（HIV）1型MN的CEM细胞的混合物体外暴露于2 '，3'-二氨基-3 '-脱氧胸苷（D-IT）。调整药物浓度以模拟连续静脉输注或每日两次静脉推注。使用病毒感染性、p24抗原和逆转录酶或PCR检测未整合HN DNA，测量给药方案的效果。每日两次给药方案的剂量递减研究预测最小效应剂量为0.5 mg/kg体重/天，这与临床试验结果相关。与连续输注相比，每12小时给药一次的抗病毒作用与时间表无关。最后，在或接近最小效应剂量时，疗效似乎取决于病毒载量。这种体外药效学模型评估HIV感染细胞对不同剂量和时间表的抗病毒剂的反应的能力可用于设计临床试验的最佳给药方案，但需要用其他类型的抗逆转录病毒药物进行验证。
We sought to validate an in vitro system which could predict the minimal effect dose of antiretroviral agents. Mixtures of uninfected CEM cells and CEM cells chronically infected with human immunodeficiency virus (HIV) type 1 MN were exposed to 2',3'-didehydro-3'-deoxythymidine (D-IT) in vitro in a hollow-fiber model which simulates the plasma concentration-time profile of D4T in patients. Drug concentration was adjusted to simulate continuous intravenous infusion, or an intravenous bolus administered twice daily. The effect of the dosing regimen was measured with viral infectivity, p24 antigen, and reverse transcriptase or PCR for unintegrated HN DNA. Dose deescalation studies on a twice-daily dosing schedule predicted a minimum effect dose of 0.5 mg/kg of body weight per day which correlated with the results of a clinical trial. Antiviral effect was demonstrated to be independent of schedule for every 12-h dosing versus continuous infusion. Finally, at or near the minimal effect dose, efficacy appeared to depend on the viral load. The ability of this in vitro pharmacodynamic model to assess the response of HIV-infected cells to different doses and schedules of antiviral agents mag be useful in the design of optimal dosing regimens for clinical trials but requires validation with other types of antiretroviral agents.