Rajoli Rajith K R, Demkovich Zach R, Flexner Charles, Owen Andrew, Siccardi Marco
Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom
RTI International, Durham, North Carolina, USA.
Antimicrob Agents Chemother. 2020 Jul 22;64(8). doi: 10.1128/AAC.00155-20.
Long-acting (LA) administration using a subcutaneous (s.c.) implant presents opportunities to simplify administration of antiretroviral drugs, improve pharmacological profiles, and overcome suboptimal adherence associated with daily oral formulations. Tenofovir alafenamide (TAF) is a highly potent nucleoside reverse transcriptase inhibitor (NRTI) and an attractive agent for LA delivery, with a high potency and long intracellular half-life. The aim of this study was to predict minimum TAF doses required to achieve concentrations effective for HIV preexposure prophylaxis (PrEP). Daily drug release requirements were then ascertained by averaging across the dosing interval. A TAF physiologically based pharmacokinetic (PBPK) model was developed and partially qualified against available oral single- and multiple-dose pharmacokinetics. The models were assumed to be qualified when simulated values were within 2-fold of the observed mean. TAF s.c. implants were simulated in five hundred individuals, reporting predicted TAF plasma and tenofovir (TFV) plasma concentrations for various release rates. Intracellular TFV diphosphate (TFV-DP) concentrations were also simulated in peripheral blood cells and cervical and rectal tissues. The minimum dose predicted to achieve intracellular TFV-DP levels above a target concentration of 48 fmol/10 cells for a month was identified. TAF, TFV, and TFV-DP concentrations for release rates between 1.0 and 1.6 mg/day were simulated. The PBPK model indicated that a minimum release of 1.4 mg/day TAF is necessary to achieve TFV-DP concentrations above the identified target in peripheral blood mononuclear cells (PBMCs). TFV-DP cervical and rectal tissue concentrations were predicted to be between 1.5 and 2.0 fmol/10 cells and 0.9 and 1.1 fmol/10 cells, respectively, for release rates between 1.3 and 1.6 mg/day. These simulations provide target minimum doses for LA TAF PrEP in humans. Based on the generated results, multiple implants delivering a total of 1.4 mg/day of TAF subcutaneously could provide protection levels for approximately 6 months to 1 year. This modeling may inform future design of s.c. implants to mitigate adherence issues for effective PrEP applications.
使用皮下植入物进行长效给药为简化抗逆转录病毒药物的给药方式、改善药理学特性以及克服与每日口服制剂相关的依从性欠佳问题提供了契机。替诺福韦艾拉酚胺（TAF）是一种高效的核苷类逆转录酶抑制剂（NRTI），因其高效力和长细胞内半衰期，是长效给药的理想药物。本研究的目的是预测实现对HIV暴露前预防（PrEP）有效的浓度所需的最低TAF剂量。然后通过在给药间隔内求平均值来确定每日药物释放要求。建立了一个基于生理药代动力学（PBPK）的TAF模型，并根据现有的口服单剂量和多剂量药代动力学数据进行了部分验证。当模拟值在观察平均值的2倍以内时，认为模型验证合格。对500名个体的TAF皮下植入物进行了模拟，报告了不同释放速率下预测的TAF血浆和替诺福韦（TFV）血浆浓度。还对外周血细胞以及宫颈和直肠组织中的细胞内TFV二磷酸（TFV-DP）浓度进行了模拟。确定了预测能使细胞内TFV-DP水平在一个月内高于48 fmol/10个细胞的目标浓度所需的最低剂量。模拟了1.0至1.6毫克/天之间释放速率下的TAF、TFV和TFV-DP浓度。PBPK模型表明，每天至少释放1.4毫克TAF对于在外周血单核细胞（PBMC）中实现高于确定目标的TFV-DP浓度是必要的。对于1.3至1.6毫克/天之间的释放速率，预测TFV-DP在宫颈和直肠组织中的浓度分别在1.5至2.0 fmol/10个细胞和0.9至1.1 fmol/10个细胞之间。这些模拟为人类长效TAF PrEP提供了目标最低剂量。根据生成的结果，皮下共递送1.4毫克/天TAF的多个植入物可为大约6个月至1年的时间提供保护水平。该建模可为未来皮下植入物的设计提供参考，以减轻有效PrEP应用中的依从性问题。
