Bilello J A, Bauer G, Dudley M N, Cole G A, Drusano G L
Department of Medicine, Albany Medical College, New York 12208.
Antimicrob Agents Chemother. 1994 Jun;38(6):1386-91. doi: 10.1128/AAC.38.6.1386.
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 (D4T) 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 HIV 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 may be useful in the design of optimal dosing regimens for clinical trials but requires validation with other types of antiretroviral agents.
我们试图验证一种体外系统，该系统能够预测抗逆转录病毒药物的最小有效剂量。将未感染的CEM细胞与长期感染1型人类免疫缺陷病毒（HIV）MN的CEM细胞的混合物，在一种模拟患者体内司他夫定血浆浓度-时间曲线的中空纤维模型中进行体外暴露于2'，3'-二脱氢-3'-脱氧胸苷（D4T）。调整药物浓度以模拟持续静脉输注或每日两次静脉推注。用药方案的效果通过病毒感染性、p24抗原以及针对未整合HIV DNA的逆转录酶或PCR来测定。在每日两次给药方案的剂量递减研究中预测出最小有效剂量为每天0.5mg/kg体重，这与一项临床试验的结果相关。对于每12小时给药与持续输注而言，抗病毒效果被证明与给药方案无关。最后，在最小有效剂量或接近最小有效剂量时，疗效似乎取决于病毒载量。这种体外药效学模型评估HIV感染细胞对抗病毒药物不同剂量和给药方案反应的能力，可能在设计临床试验的最佳给药方案中有用，但需要用其他类型的抗逆转录病毒药物进行验证。
