Preclinical Considerations for Long-acting Delivery of Tenofovir Alafenamide from Subdermal Implants for HIV Pre-exposure Prophylaxis.
Preclinical Considerations for Long-acting Delivery of Tenofovir Alafenamide from Subdermal Implants for HIV Pre-exposure Prophylaxis.
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DOI：
10.1007/s11095-022-03440-6
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发表时间：
2023-07
影响因子：
3.7
通讯作者：
Baum, Marc M.
中科院分区：
文献类型：
--
作者：
Gunawardana, Manjula;Remedios-Chan, Mariana;Sanchez, Debbie;Fanter, Rob;Webster, Simon;Webster, Paul;Moss, John A.;Trinh, MyMy;Beliveau, Martin;Ramirez, Christina M.;Marzinke, Mark A.;Kuo, Joseph;Gallay, Philippe A.;Baum, Marc M.
关键词：
强效抗逆转录病毒前药替诺福韦艾拉酚胺（TAF）的长效制剂具有作为生物医学HIV预防方式的潜力。在此，我们对三种动物模型（C57 BL/6 J小鼠、比格犬和美利奴羊）进行了严格比较，以评价TAF植入物的药代动力学（PK）。在体外以及小鼠和犬中测试了在宽范围控释速率下递送TAF的植入物。我们现有的PK模型得到静脉（IV）给药犬研究的支持，适用于分析植入物TAF递送的机制方面。TAF体外释放在0.13 - 9.8 mg d-1范围内，具有零级动力学。具有等同制造参数的植入物在小鼠和绵羊中释放TAF的速率无统计学差异，但在犬中高出3倍。当将两个植入物放置在同一皮下囊袋中时，在犬中观察到全身药物和代谢物浓度的两周蠕变至Cmax，但在小鼠中未观察到。犬中IV和TAF植入物PK数据的共建模导致单植入物组中TAF的表观生物利用度为9.6（与IV组相比），但当将两个植入物置于同一皮下囊袋中时仅为1.5。基于目前的结果，我们建议使用小鼠和绵羊（猕猴作为补充种属）进行临床前TAF植入物评价，但需要注意的是，我们的观察结果可能特定于此处使用的植入物技术。我们的报告提供了基本的，可翻译的见解，通过长效植入物的多物种TAF交付。
Long-acting formulations of the potent antiretroviral prodrug tenofovir alafenamide (TAF) hold potential as biomedical HIV prevention modalities. Here, we present a rigorous comparison of three animal models, C57BL/6 J mice, beagle dogs, and merino sheep for evaluating TAF implant pharmacokinetics (PKs). Implants delivering TAF over a wide range of controlled release rates were tested in vitro and in mice and dogs. Our existing PK model, supported by an intravenous (IV) dosing dog study, was adapted to analyze mechanistic aspects underlying implant TAF delivery. TAF in vitro release in the 0.13 to 9.8 mg d−1 range with zero order kinetics were attained. Implants with equivalent fabrication parameters released TAF in mice and sheep at rates that were not statistically different, but were 3 times higher in dogs. When two implants were placed in the same subcutaneous pocket, a two-week creep to Cmax was observed in dogs for systemic drug and metabolite concentrations, but not in mice. Co-modeling IV and TAF implant PK data in dogs led to an apparent TAF bioavailability of 9.6 in the single implant groups (compared to the IV group), but only 1.5 when two implants were placed in the same subcutaneous pocket. Based on the current results, we recommend using mice and sheep, with macaques as a complementary species, for preclinical TAF implant evaluation with the caveat that our observations may be specific to the implant technology used here. Our report provides fundamental, translatable insights into multispecies TAF delivery via long-acting implants.
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影响因子：
4
作者：
Hozo SP;Djulbegovic B;Hozo I
通讯作者：
Hozo I
影响因子：
4.9
作者：
Gunawardana, Manjula;Remedios-Chan, Mariana;Bauma, Marc M.
通讯作者：
Bauma, Marc M.
DOI：
10.1126/science.1248707
发表时间：
2014-03-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Andrews CD;Spreen WR;Mohri H;Moss L;Ford S;Gettie A;Russell-Lodrigue K;Bohm RP;Cheng-Mayer C;Hong Z;Markowitz M;Ho DD
通讯作者：
Ho DD
影响因子：
--
作者：
BECKER, AB;CHUNG, KF;GOLD, WM
通讯作者：
GOLD, WM
影响因子：
3.4
作者：
CHAPMAN, EH;KUREC, AS;DAVEY, FR
通讯作者：
DAVEY, FR