Segregur Domagoj, Mann James, Moir Andrea, Karlsson Eva M, Dressman Jennifer
Institute of Pharmaceutical Technology, J. W. Goethe University, 9 Max von Laue St., 60438 Frankfurt am Main, Germany (now employed at Product Design and Performance, UCB Pharma, Braine-l'Alleud, Belgium).
Oral Product Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield, United Kingdom.
J Pharm Sci. 2022 Feb;111(2):517-528. doi: 10.1016/j.xphs.2021.09.037. Epub 2021 Sep 29.
Early assessment of pH-dependent drug-drug-interactions (DDIs) for salts of poorly soluble weakly acidic compounds offers various advantages for patient safety, the pharmaceutical industry, and regulatory bodies. Biorelevant media and tests reflecting physiological changes during acid-reducing agent (ARA) co-administration can be used to explore and predict the extent of the pH effect during therapy with ARAs.
Solubility, one-stage and two-stage dissolution of tablets containing potassium raltegravir, the marketed salt form of this poorly soluble, weakly acidic drug, was investigated using biorelevant media specially designed to reflect administration without and during ARA co-therapy. The dissolution data were then converted into parameters suitable for input into an in silico model (Simcyp™) and the simulated plasma profiles were compared with available pharmacokinetic (PK) data from the literature.
Dissolution of the potassium raltegravir formulation in media reflecting ARA co-administration, and thus elevated gastric pH, was faster and more complete than in experiments reflecting the low gastric pH observed in the absence of ARA co-administration. Simulations using data from dissolution experiments with ARA media appropriately bracketed the in vivo data for ARA co-administration in healthy volunteers.
Dissolution data from in vitro experiments in biorelevant media reflecting physiological changes due to ARA co-administration provide valuable information about potassium raltegravir's behavior during concomitant ARA therapy. The approach may also be suitable for salts forms of other poorly soluble, weakly acidic drugs.
对难溶性弱酸性化合物盐类的pH依赖性药物相互作用（DDIs）进行早期评估，对患者安全、制药行业和监管机构具有诸多优势。可使用反映酸还原剂（ARA）联合给药期间生理变化的生物相关介质和试验，来探索和预测ARA治疗期间pH效应的程度。
使用专门设计的生物相关介质，研究了含钾盐拉替拉韦（该难溶性弱酸性药物的上市盐形式）片剂的溶解度、一级和二级溶出度，这些介质分别反映了无ARA联合治疗和有ARA联合治疗时的给药情况。然后将溶出数据转换为适合输入计算机模拟模型（Simcyp™）的参数，并将模拟的血浆浓度曲线与文献中可用的药代动力学（PK）数据进行比较。
与反映无ARA联合治疗时低胃pH值的实验相比，钾盐拉替拉韦制剂在反映ARA联合治疗（即胃pH值升高）的介质中的溶出更快且更完全。使用ARA介质溶出实验数据进行的模拟，恰当地涵盖了健康志愿者中ARA联合给药的体内数据。
在反映因ARA联合给药引起生理变化的生物相关介质中进行体外实验得到的溶出数据，为钾盐拉替拉韦在ARA联合治疗期间的行为提供了有价值的信息。该方法可能也适用于其他难溶性弱酸性药物的盐形式。
