Abstract：
Gefapixant is a weakly basic drug which has been formulated as an immediate release tablet for oral administration. A physiologically based biopharmaceutics model (PBBM) was developed based on gefapixant physicochemical properties and clinical pharmacokinetics to aid formulation selection, bioequivalence safe space assessment and dissolution specification settings. In vitro dissolution profiles of different free base and citrate salt formulations were used as an input to the model. The model was validated against the results of independent studies, which included a bioequivalence and a relative bioavailability study, as well as a human ADME study, all meeting acceptance criteria of prediction errors ≤ 20% for both Cmax and AUC. PBBM was also applied to evaluate gastric pH-mediated drug-drug-interaction potential with co-administration of a proton pump inhibitor (PPI), omeprazole. Model results showed good agreement with clinical data in which omeprazole lowered gefapixant exposure for the free base formulation but did not significantly alter gefapixant pharmacokinetics for the citrate based commercial drug product. An extended virtual dissolution bioequivalence safe space was established. Gefapixant drug product batches are anticipated to be bioequivalent with the clinical reference batch when their dissolution is > 80% in 60 minutes. PBBM established a wide dissolution bioequivalence space as part of assuring product quality.
摘要：
Gefapixant是一种弱碱性药物，已被配制为口服速释片剂。根据gefapixant的理化性质和临床药代动力学，开发了基于生理的生物制药模型（PBBM），以帮助选择配方。生物等效性安全空间评估和溶解规范设置。不同游离碱和柠檬酸盐制剂的体外溶出曲线用作模型的输入。该模型与独立研究的结果进行了验证，其中包括生物等效性和相对生物利用度研究，以及一项人类ADME研究，所有符合Cmax和AUC的预测误差≤20%的验收标准。PBBM还用于评估与质子泵抑制剂（PPI）共同给药的胃pH介导的药物-药物相互作用潜力，奥美拉唑。模型结果显示与临床数据具有良好的一致性，其中奥美拉唑降低了游离碱制剂的gefapixant暴露，但没有显着改变基于柠檬酸盐的商业药物产品的gefapixant药代动力学。建立了扩展的虚拟溶解生物等效性安全空间。当Gefapixant药物产品批次在60分钟内溶出>80%时,预期其与临床参考批次生物等效。作为确保产品质量的一部分，PBBM建立了广泛的溶解生物等效性空间。
