Drug Product Science and Technology, Bristol-Myers Squibb Company, New Brunswick, New Jersey, USA.
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey, USA.
Pharm Res. 2019 Oct 21;36(12):164. doi: 10.1007/s11095-019-2698-0.
To describe a stepwise approach to evaluate the pH effect for a weakly basic drug by in vitro, in vivo and in silico techniques and identify a viable mitigation strategy that addresses the risk.
Clinical studies included assessment of the pH effect with famotidine. In vitro dissolution was evaluated in various biorelevant media and in a pH-shift test. PK studies in dogs were conducted under pentagastrin or famotidine pre-treatment and GastroPlus was employed to model human and dog PK data and simulate the performance in human.
Clinical data indicated considerable pH dependent absorption of the drug when dosed in the presence of H2-antagonists. In vitro dissolution and in vivo dog data confirmed that the observed pH effect was due to reduced dissolution rate and lower solubility at increased gastric and intestinal pH. A salt form was identified to overcome the effect by providing fast dissolution and prolonged supersaturation. GastroPlus simulations predicted a mitigation of the pH effect by the salt.
The drug exhibited a strong pH-effect in humans. The in vitro, in vivo and modeling approach provides a systematic workflow to evaluate the risk of a new drug and identify a strategy able to mitigate the risk.
描述一种通过体外、体内和计算技术逐步评估弱碱性药物 pH 效应的方法，并确定可行的缓解策略以应对风险。
临床研究包括评估法莫替丁的 pH 效应。在各种生物相关介质和 pH 转移试验中评估了体外溶出度。在五肽胃泌素或法莫替丁预处理下进行了狗的 PK 研究，并使用 GastroPlus 对人和狗的 PK 数据进行建模并模拟人体性能。
临床数据表明，当在 H2 拮抗剂存在下给药时，药物存在明显的 pH 依赖性吸收。体外溶出度和体内狗数据证实，观察到的 pH 效应是由于在增加的胃和肠道 pH 下溶解速率降低和溶解度降低所致。确定了一种盐形式来克服该效应，提供快速溶解和延长过饱和。GastroPlus 模拟预测盐形式可缓解 pH 效应。
该药物在人体中表现出强烈的 pH 效应。体外、体内和建模方法提供了一种系统的工作流程，用于评估新药的风险并确定能够减轻风险的策略。
