Physiologically Based Pharmacokinetic Modelling of Cabotegravir Microarray Patches in Rats and Humans.
Physiologically Based Pharmacokinetic Modelling of Cabotegravir Microarray Patches in Rats and Humans.
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DOI：
10.3390/pharmaceutics15122709
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发表时间：
2023-11-30
期刊：
影响因子：
5.4
通讯作者：
Owen A
中科院分区：
文献类型：
--
作者：
Kinvig H;Rajoli RKR;Pertinez H;Vora LK;Volpe-Zanutto F;Donnelly RF;Rannard S;Flexner C;Siccardi M;Owen A
微阵列贴片（MAP）目前正在研究中，作为一种自我管理，无痛替代用于实现长效（LA）药物输送。Cabotegravir是一种有效的抗逆转录病毒药物，其效果上级目前的暴露前预防（PrEP）方案。本研究旨在应用基于生理学的药代动力学（PBPK）建模来描述溶解双层MAP平台的药代动力学，并预测每周一次卡替拉韦MAP的最佳给药策略。将MAP的数学描述实施到PBPK模型中，并利用经验模型进行参数估计。皮内PBPK模型针对先前发表的肌内（IM）和MAP施用的体内大鼠数据以及LA卡替拉韦IM施用的体内人数据进行验证。经验证的模型用于预测300 mg、150 mg和75 mg每周一次MAP给药。将卡博特韦血浆浓度>4 ×蛋白质调整的90%抑制浓度（PA-IC 90）（0.664 µg/mL）和>8 × PA-IC 90（1.33 µg/mL）设定为目标。预计75 mg、150 mg和300 mg每周一次卡替拉韦MAP方案可维持血浆浓度>4 × PA-IC 90，而300 mg和150 mg方案可达到血浆浓度>8 × PA-IC 90。这些数据证明了使用人体实际贴剂大小每周一次的cabotegravir MAP的潜力，并为进一步开发用于HIV PrEP的cabotegravir MAP提供了信息。
Microarray patches (MAPs) are currently under investigation as a self-administered, pain-free alternative used to achieve long-acting (LA) drug delivery. Cabotegravir is a potent antiretroviral that has demonstrated superior results over current pre-exposure prophylaxis (PrEP) regimens. This study aimed to apply physiologically based pharmacokinetic (PBPK) modelling to describe the pharmacokinetics of the dissolving bilayer MAP platform and predict the optimal dosing strategies for a once-weekly cabotegravir MAP. A mathematical description of a MAP was implemented into a PBPK model, and empirical models were utilised for parameter estimation. The intradermal PBPK model was verified against previously published in vivo rat data for intramuscular (IM) and MAP administration, and in vivo human data for the IM administration of LA cabotegravir. The verified model was utilised for the prediction of 300 mg, 150 mg and 75 mg once-weekly MAP administration in humans. Cabotegravir plasma concentrations >4 × protein-adjusted 90% inhibitory concentration (PA-IC90) (0.664 µg/mL) and >8 × PA-IC90 (1.33 µg/mL) were set as targets. The 75 mg, 150 mg and 300 mg once-weekly cabotegravir MAP regimens were predicted to sustain plasma concentrations >4 × PA-IC90, while the 300 mg and 150 mg regimens achieved plasma concentrations >8 × PA-IC90. These data demonstrate the potential for a once-weekly cabotegravir MAP using practical patch sizes for humans and inform the further development of cabotegravir MAPs for HIV PrEP.
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影响因子：
168.9
作者：
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