Stein D S, Fish D G, Bilello J A, Preston S L, Martineau G L, Drusano G L
Albany Medical College, Clinical Pharmacology Studies Unit, NY 12208, USA.
AIDS. 1996 May;10(5):485-92. doi: 10.1097/00002030-199605000-00006.
To investigate the safety, pharmacokinetics, and activity of the orally bio-available protease inhibitor MK-639.
An open-label Phase I/II trial of medically stable subjects with screening CD4 lymphocyte counts < or = 300 x 10(6)/I and > or = 20,000 HIV RNA copies/ml. Pharmacokinetics were performed at days 1 and 15. In order to better understand the relationships between drug exposure, baseline activity markers, and their changes during the study, mathematical modeling was performed using the traditional sigmoid-Emax relationship of pharmacologic effect and first order inhomogeneous differential equations for a two compartment system.
The five men enrolled had extensive prior nucleoside therapy (mean, 32.6 +/- 25.6 months), a low mean CD4 lymphocyte cell count (CD4 count, 66.1 +/- 61 x 10(6)/I and CD4 percentage, 4.4 +/- 3.1%), high soluble tumor necrosis factor-alpha type II (sTNFII) receptor concentration (6.23 +/- 2.76 ng/ml) and high viral load (5.13 +/- 0.46 log10 RNA copies/ ml; geometric mean, 133,941 copies/ml). The drug was well tolerated at a dose of 600 mg every 6 h. The steady state concentrations Cmax and Cmin were 4.94 +/- 2.16 microM and 0.28 +/-0.1 microM, respectively, which are approximately equal to 50 and 3 times the 95% inhibitory concentration (IC95) for clinical isolates, respectively. The mean increase in CD4 cell count was 143 x 10(6)/ (217% increase ), the mean increase in CD4 percentage was 5.2 percentage points (118%), mean decrease in HIV RNA was 1.55 log10 RNA copies/ml (a geometric mean difference of 130,120 copies/ml or 97% decrease) with a slow upward drift on continued therapy to a mean 0.64 log10 RNA copies/ml decrease by week 24 (a geometric mean difference of 103,084 copies/ml or 77% decrease), and a mean decrease in sTNFII receptors of 2.78 ng/ml (45% decrease). The mean CD4 counts per week as a function of the starting CD4 counts fit a sigmoid-Emax relationship (r2 = 0.998, P < 0.0001) with the return of CD4 cells being strongly related to the number of CD4 cells at baseline. Drug exposure as measured by either the total exposure (area under the concentration/time curve) or as the Cmin gave similar significant relationships to the fractional inhibition of HIV generation (r2 = 0.999, P < 0.0001, and r2 = 0.996, P < 0.0001, respectively).
MK-639 appears to have significant dose-related antiviral activity and is well tolerated.
研究口服生物可利用蛋白酶抑制剂MK-639的安全性、药代动力学及活性。
一项针对医学状况稳定、筛选时CD4淋巴细胞计数≤300×10⁶/I且HIV RNA拷贝数/ml≥20,000的受试者的开放标签I/II期试验。在第1天和第15天进行药代动力学研究。为了更好地理解药物暴露、基线活性标志物及其在研究期间变化之间的关系，使用药理学效应的传统S形Emax关系和两室系统的一阶非齐次微分方程进行数学建模。
入组的5名男性此前接受过广泛的核苷治疗（平均32.6±25.6个月），平均CD4淋巴细胞计数较低（CD4计数为66.1±61×10⁶/I，CD4百分比为4.4±3.1%），可溶性肿瘤坏死因子-α II型（sTNFII）受体浓度较高（6.23±2.76 ng/ml）且病毒载量较高（5.13±0.46 log₁₀ RNA拷贝/ml；几何平均数为133,941拷贝/ml）。该药物每6小时服用600 mg时耐受性良好。稳态浓度Cmax和Cmin分别为4.94±2.16 μM和0.28±0.1 μM，分别约为临床分离株95%抑制浓度（IC95）的50倍和3倍。CD4细胞计数平均增加143×10⁶/（增加217%），CD4百分比平均增加5.2个百分点（增加118%），HIV RNA平均下降1.55 log₁₀ RNA拷贝/ml（几何平均差异为130,120拷贝/ml或下降97%），持续治疗至第24周时缓慢上升至平均下降0.64 log₁₀ RNA拷贝/ml（几何平均差异为103,084拷贝/ml或下降77%），sTNFII受体平均下降2.78 ng/ml（下降45%）。每周平均CD4计数与起始CD4计数的函数关系符合S形Emax关系（r² = 0.998，P < 0.0001），CD4细胞的恢复与基线时CD4细胞数量密切相关。通过总暴露量（浓度/时间曲线下面积）或Cmin测量的药物暴露与HIV产生的分数抑制具有相似的显著关系（分别为r² = 0.999，P < 0.0001和r² = 0.996，P < 0.0001）。
MK-639似乎具有显著的剂量相关抗病毒活性且耐受性良好。
