Hendrix C W, Flexner C, Szebeni J, Kuwahara S, Pennypacker S, Weinstein J N, Lietman P S
Department of Infectious Diseases, Wilford Hall Medical Center, Lackland AFB, Texas 78236-5300.
Antimicrob Agents Chemother. 1994 May;38(5):1036-40. doi: 10.1128/AAC.38.5.1036.
Zidovudine delays the progression of infection and prolongs the survival of human immunodeficiency virus (HIV)-infected patients, but these benefits are limited by dose-related toxicity and the cost of the drug. Dipyridamole, in micromolar concentrations, acts synergistically with zidovudine, reducing the anti-HIV 95% inhibitory concentration of zidovudine 5- to 10-fold in vitro. We sought to establish a well-tolerated dose of dipyridamole for use in combination with zidovudine and to detect clinically significant pharmacokinetic interactions. Both objectives are essential for planning studies of the efficacy of the zidovudine-dipyridamole combination. Eleven asymptomatic HIV-infected subjects (median CD4+ cell count, 311 cells per mm3), 10 of whom had been on zidovudine at 500 mg/day for at least 6 months, were admitted to the study. Zidovudine pharmacokinetics were measured on day 1. Dipyridamole was then begun at 600 mg/day (subjects 1 to 3) or 450 mg/day (subjects 4 to 11), and zidovudine and dipyridamole pharmacokinetics were measured on day 5. All subjects given 600 mg of dipyridamole per day developed headache or nausea, or both. Six of eight subjects given dipyridamole at 450 mg/day developed headache or mild nausea that resolved after a median of 2 days. The area under the zidovudine concentration-time curve was not significantly different on day 1 in comparison with that on day 5 (P = 0.11). Symptoms were significantly correlated with the maximum zidovudine concentrations, which were achieved when dipyridamole was dosed concomitantly (p = 0.03). Total (free and protein-bound) dipyridamole trough concentrations were near those demonstrating synergy with zidovudine against HIV in vitro. Dipyridamole was highly protein bound, with a median free/total dipyridamole ratio of 0.7%; the percent free/total dipyridamole ratio was inversely correlated with alpha 1 acid glycoprotein concentrations (r2 =0.66). Results of the study indicate that adjustment of the zidovudine dose was not required to achieve equivalent zidovudine concentrations when zidovudine was administered in combination with dipyridamole at the doses studied. In the short study described here, the zidovudine-dipyridamole combinations was well tolerated in asymptomatic HIV-infected subjects after the occurrence of mild transient symptoms.
齐多夫定可延缓感染进展并延长人类免疫缺陷病毒（HIV）感染患者的生存期，但这些益处受到剂量相关毒性和药物成本的限制。双嘧达莫在微摩尔浓度下与齐多夫定协同作用，在体外可将齐多夫定的抗HIV 95%抑制浓度降低5至10倍。我们试图确定一种与齐多夫定联合使用时耐受性良好的双嘧达莫剂量，并检测临床上显著的药代动力学相互作用。这两个目标对于规划齐多夫定 - 双嘧达莫联合用药疗效研究至关重要。11名无症状HIV感染受试者（CD4 +细胞计数中位数为每立方毫米311个细胞）被纳入研究，其中10人已接受每日500毫克齐多夫定治疗至少6个月。在第1天测量齐多夫定的药代动力学。然后开始给予双嘧达莫，剂量为每日600毫克（受试者1至3）或每日450毫克（受试者4至11），并在第5天测量齐多夫定和双嘧达莫的药代动力学。所有每日给予600毫克双嘧达莫的受试者均出现头痛或恶心，或两者皆有。8名每日给予450毫克双嘧达莫的受试者中有6人出现头痛或轻度恶心，中位2天后症状缓解。与第1天相比，第5天齐多夫定浓度 - 时间曲线下面积无显著差异（P = 0.11）。症状与齐多夫定的最大浓度显著相关，最大浓度在同时给予双嘧达莫时达到（p = 0.03）。双嘧达莫的总（游离和蛋白结合）谷浓度接近在体外与齐多夫定协同抗HIV的浓度。双嘧达莫与蛋白高度结合，游离/总双嘧达莫比率中位数为0.7%；游离/总双嘧达莫比率百分比与α1酸性糖蛋白浓度呈负相关（r2 = 0.66）。研究结果表明，当齐多夫定与双嘧达莫按研究剂量联合使用时，无需调整齐多夫定剂量即可达到等效的齐多夫定浓度。在此处描述的短期研究中，在出现轻度短暂症状后，齐多夫定 - 双嘧达莫联合用药在无症状HIV感染受试者中耐受性良好。
