Peter J. Ruane MD Inc, Los Angeles, CA 90036, USA.
J Acquir Immune Defic Syndr. 2013 Aug 1;63(4):449-55. doi: 10.1097/QAI.0b013e3182965d45.
To evaluate the antiviral activity, safety, pharmacokinetics, and pharmacokinetics/pharmacodynamics of short-term monotherapy with tenofovir alafenamide (TAF), a next-generation tenofovir (TFV) prodrug.
A phase 1b, randomized, partially blinded, active- and placebo-controlled, dose-ranging study.
Treatment-naive and experienced HIV-1-positive adults currently off antiretroviral therapy were randomized to receive 8, 25, or 40 mg TAF, 300 mg tenofovir disoproxil fumarate (TDF), or placebo, each once daily for 10 days.
Thirty-eight subjects were enrolled. Baseline characteristics were similar across dose groups. Significant reductions in plasma HIV-1 RNA from baseline to day 11 were observed for all TAF dose groups compared with placebo (P < 0.01), with a median decrease of 1.08-1.73 log10 copies per milliliter, including a dose-response relationship for viral load decrease up to 25 mg. At steady state, 8, 25, and 40 mg TAF yielded mean TFV plasma exposures [area under the plasma concentration-time curve (AUCtau)] of 97%, 86%, and 79% lower, respectively, as compared with the TFV exposures observed with 300 mg TDF. For 25 and 40 mg TAF, the mean intracellular peripheral blood mononuclear cell tenofovir diphosphate AUCtau was ∼7-fold and ∼25-fold higher, relative to 300 mg TDF.
Compared with 300 mg TDF, TAF demonstrated more potent antiviral activity, higher peripheral blood mononuclear cell intracellular tenofovir diphosphate levels, and lower plasma TFV exposures, at approximately 1/10th of the dose. This may translate into greater antiviral efficacy, a higher barrier to resistance, and an improved safety profile relative to TDF, supporting further investigation of TAF dosed once daily in HIV-infected patients.
评估新一代替诺福韦（TFV）前药替诺福韦艾拉酚胺（TAF）短期单药治疗的抗病毒活性、安全性、药代动力学和药代动力学/药效学。
一项 1b 期、随机、部分盲、活性和安慰剂对照、剂量范围研究。
未经治疗和有经验的 HIV-1 阳性成人，目前已停止抗逆转录病毒治疗，随机接受 8、25 或 40 mg TAF、300 mg 替诺福韦二吡呋酯（TDF）或安慰剂，每日一次，共 10 天。
共纳入 38 名受试者。各剂量组间的基线特征相似。与安慰剂相比，所有 TAF 剂量组的血浆 HIV-1 RNA 从基线到第 11 天均显著下降（P < 0.01），中位数下降 1.08-1.73 log10 拷贝/毫升，包括病毒载量下降的剂量反应关系，最高可达 25 mg。在稳态时，8、25 和 40 mg TAF 与 300 mg TDF 相比，分别使 TFV 血浆暴露量[血浆浓度-时间曲线下面积（AUCtau）]降低 97%、86%和 79%。对于 25 和 40 mg TAF，相对于 300 mg TDF，外周血单个核细胞内替诺福韦二磷酸 AUCtau 的平均浓度约高 7 倍和 25 倍。
与 300 mg TDF 相比，TAF 表现出更强的抗病毒活性、更高的外周血单个核细胞内替诺福韦二磷酸水平和更低的血浆 TFV 暴露量，剂量约为 TDF 的 1/10。这可能转化为更高的抗病毒疗效、更高的耐药屏障和更好的安全性，相对于 TDF 支持进一步研究在 HIV 感染患者中每天一次给予 TAF。
