Pharmacokinetics of Long-Acting Tenofovir Alafenamide (GS-7340) Subdermal Implant for HIV Prophylaxis
Pharmacokinetics of Long-Acting Tenofovir Alafenamide (GS-7340) Subdermal Implant for HIV Prophylaxis
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DOI：
10.1128/aac.00656-15
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发表时间：
2015-07-01
影响因子：
4.9
通讯作者：
Bauma, Marc M.
中科院分区：
文献类型：
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作者：
Gunawardana, Manjula;Remedios-Chan, Mariana;Bauma, Marc M.
对易感人群中的HIV-1阴性个体每日口服或局部给予抗逆转录病毒（ARV）药物是预防HIV-1的一种有希望的策略。对给药方案的依从性已成为决定临床试验疗效结局的关键因素。由于治疗依从性与给药周期呈负相关，因此缓释或长效ARV制剂通过减少给药频率，有望显著提高HIV-1暴露前预防（PrEP）的有效性。描述了一种新型的皮下植入剂，其递送具有受控、持续、零级（线性）释放特性的强效前药替诺福韦艾拉酚胺（TAF）。在比格犬中评价了体外递送0.92 mg/天（-1）TAF的候选器械的药代动力学和初步安全性，持续40天。在研究过程中未观察到与供试品给药相关的不良事件，也未观察到显著异常。该植入物保持了较低的TAF（中位数，0.85 ng ml（-1）;四分位数间距[IQR]，0.60至1.50 ng ml（-1））和替诺福韦（TFV;中位数，15.0 ng ml（-1）; IQR，8.8至23.3 ng ml（-1）），体内TAF水解的产物的全身暴露。在外周血单核细胞中观察到高浓度（前35天的中位数为512 fmol/10（6）个细胞）的活性代谢物TFV二磷酸盐，其水平比人体中HIV-1 PrEP有效性相关的水平高30倍以上。我们关于第一个用于全身给药的缓释核苷逆转录酶抑制剂（NRTI）的报告证明了成功的原理证明，并作为脆弱人群中HIV-1预防的候选药物具有重大前景。
Oral or topical daily administration of antiretroviral (ARV) drugs to HIV-1-negative individuals in vulnerable populations is a promising strategy for HIV-1 prevention. Adherence to the dosing regimen has emerged as a critical factor determining efficacy outcomes of clinical trials. Because adherence to therapy is inversely related to the dosing period, sustained release or long-acting ARV formulations hold significant promise for increasing the effectiveness of HIV-1 preexposure prophylaxis (PrEP) by reducing dosing frequency. A novel, subdermal implant delivering the potent prodrug tenofovir alafenamide (TAF) with controlled, sustained, zero-order (linear) release characteristics is described. A candidate device delivering TAF at 0.92 mg day(-1) in vitro was evaluated in beagle dogs over 40 days for pharmacokinetics and preliminary safety. No adverse events related to treatment with the test article were noted during the course of the study, and no significant, unusual abnormalities were observed. The implant maintained a low systemic exposure to TAF (median, 0.85 ng ml(-1); interquartile range [IQR], 0.60 to 1.50 ng ml(-1)) and tenofovir (TFV; median, 15.0 ng ml(-1); IQR, 8.8 to 23.3 ng ml(-1)), the product of in vivo TAF hydrolysis. High concentrations (median, 512 fmol/10(6) cells over the first 35 days) of the pharmacologically active metabolite, TFV diphosphate, were observed in peripheral blood mononuclear cells at levels over 30 times higher than those associated with HIV-1 PrEP efficacy in humans. Our report on the first sustained-release nucleoside reverse transcriptase inhibitor (NRTI) for systemic delivery demonstrates a successful proof of principle and holds significant promise as a candidate for HIV-1 prophylaxis in vulnerable populations.