Berlin Mark, Ruff Aaron, Kesisoglou Filippos, Xu Wei, Wang Michael Hong, Dressman Jennifer B
Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany.
Biopharmaceutics, Pharmaceutical Sciences and Clinical Supply, Merck & Co., Inc., West Point, PA, USA.
Eur J Pharm Biopharm. 2015 Jun;93:267-80. doi: 10.1016/j.ejpb.2015.03.031. Epub 2015 Apr 11.
Many active pharmaceutical ingredients (APIs) exhibit a highly variable pharmacokinetic (PK) profile. This behavior may be attributable to pre-absorptive, absorptive and/or post-absorptive factors. Pre-absorptive factors are those related to dosage form disintegration, drug dissolution, supersaturation, precipitation and gastric emptying. Absorptive factors are involved with drug absorption and efflux mechanisms, while drug distribution and clearance are post-absorptive factors. This study aimed to investigate the relative influence of the aforementioned parameters on the pharmacokinetic profile of atazanavir, a poorly soluble weakly basic compound with highly variable pharmacokinetics. The pre-absorptive behavior of the drug was examined by applying biorelevant in vitro tests to reflect upper gastrointestinal behavior in the fasted and fed states. The in vitro results were implemented, along with permeability and post-absorptive data obtained from the literature, into physiologically based pharmacokinetic (PBPK) models. Sensitivity analysis of the resulting plasma profiles revealed that the pharmacokinetic profile of atazanavir is affected by an array of factors rather than one standout factor. According to the in silico model, pre-absorptive and absorptive factors had less impact on atazanavir bioavailability compared to post-absorptive parameters, although active drug efflux and extraction appear to account for the sub-proportional pharmacokinetic response to lower atazanavir doses in the fasted state. From the PBPK models it was concluded that further enhancement of the formulation would bring little improvement in the pharmacokinetic response to atazanavir. This approach may prove useful in assessing the potential benefits of formulation enhancement of other existing drug products on the market.
许多活性药物成分（API）呈现出高度可变的药代动力学（PK）特征。这种行为可能归因于吸收前、吸收中和/或吸收后因素。吸收前因素与剂型崩解、药物溶解、过饱和、沉淀和胃排空有关。吸收因素涉及药物吸收和外排机制，而药物分布和清除则是吸收后因素。本研究旨在调查上述参数对阿扎那韦药代动力学特征的相对影响，阿扎那韦是一种难溶性弱碱性化合物，药代动力学高度可变。通过应用生物相关性体外试验来检查药物的吸收前行为，以反映禁食和进食状态下的上消化道行为。将体外结果与从文献中获得的渗透性和吸收后数据一起应用于基于生理学的药代动力学（PBPK）模型。对所得血浆谱的敏感性分析表明，阿扎那韦的药代动力学特征受一系列因素影响，而非单一突出因素。根据计算机模拟模型，与吸收后参数相比，吸收前和吸收因素对阿扎那韦生物利用度的影响较小，尽管活性药物外排和提取似乎是禁食状态下阿扎那韦较低剂量药代动力学反应不成比例的原因。从PBPK模型得出的结论是，进一步改进制剂对阿扎那韦药代动力学反应的改善不大。这种方法可能被证明有助于评估市场上其他现有药品制剂改进的潜在益处。
