Leicester School of Pharmacy, De Montfort University, Leicester LE1 9BH, U.K.
Department of Infection & Immunity, Faculty of Infectious & Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, U.K.
Mol Pharm. 2021 Dec 6;18(12):4272-4289. doi: 10.1021/acs.molpharmaceut.1c00385. Epub 2021 Nov 8.
We report the evaluation and prediction of the pharmacokinetic (PK) performance of artemisinin (ART) cocrystal formulations, that is, 1:1 artemisinin/orcinol (ART-ORC) and 2:1 artemisinin/resorcinol (ART-RES), using murine animal and physiologically based pharmacokinetic (PBPK) models. The efficacy of the ART cocrystal formulations along with the parent drug ART was tested in mice infected with . When given at the same dose, the ART cocrystal formulation showed a significant reduction in parasitaemia at day 4 after infection compared to ART alone. PK parameters including (maximum plasma concentration), (time to ), and AUC (area under the curve) were obtained by determining drug concentrations in the plasma using liquid chromatography-high-resolution mass spectrometry (LC-HRMS), showing enhanced ART levels after dosage with the cocrystal formulations. The dose-response tests revealed that a significantly lower dose of the ART cocrystals in the formulation was required to achieve a similar therapeutic effect as ART alone. A PBPK model was developed using a PBPK mouse simulator to accurately predict the behavior of the cocrystal formulations by combining dissolution profiles with the properties of the parent drug ART. The study illustrated that information from classical and experimental investigations of the parent drug of ART formulations can be coupled with PBPK modeling to predict the PK parameters of an ART cocrystal formulation in an efficient manner. Therefore, the proposed modeling strategy could be used to establish and correlations for different cocrystals intended to improve dissolution properties and to support clinical candidate selection, contributing to the assessment of cocrystal developability and formulation development.
我们报告了使用小鼠动物和基于生理学的药代动力学（PBPK）模型评估和预测青蒿素（ART）共晶配方的药代动力学（PK）性能，即 1:1 青蒿素/间苯二酚（ART-ORC）和 2:1 青蒿素/间苯二酚（ART-RES）。我们用. 感染的小鼠测试了 ART 共晶配方的疗效以及母体药物 ART。在给予相同剂量时，ART 共晶配方在感染后第 4 天与单独使用 ART 相比，寄生虫血症显著减少。通过使用液相色谱-高分辨率质谱（LC-HRMS）测定血浆中的药物浓度获得 PK 参数，包括 （最大血浆浓度）、 （达峰时间）和 AUC（曲线下面积），显示共晶配方给药后 ART 水平增强。剂量反应测试表明，共晶配方中的 ART 剂量显著降低，即可达到与单独使用 ART 相似的治疗效果。使用 PBPK 小鼠模拟器开发了一个 PBPK 模型，通过将溶解曲线与 ART 母体药物的特性相结合，准确预测共晶配方的 行为。该研究表明，ART 制剂母体药物的经典 和 实验研究信息可以与 PBPK 建模相结合，以有效地预测 ART 共晶制剂的 PK 参数。因此，所提出的建模策略可用于建立不同共晶的 和 相关性，以改善溶解性能，并支持临床候选药物的选择，有助于评估共晶的可开发性和制剂开发。
