酸相关性疾病（acid-related diseases, ARDs）是一类与胃酸攻击作用密切相关的胃肠道疾病，包括消化性溃疡、胃食管反流病等。质子泵抑制剂（proton pump inhibitors, PPIs）和钾离子竞争性酸阻滞剂（Potassium-Competitive Acid Blockers, P-CABs）在治疗ARDs中发挥了重要作用。然而，国内在该领域的创新药物研发相对滞后，原研药物多由国外制药公司研发。

对于PPIs和P-CABs类抑酸药物，其作用机制明确，靶点清晰（即H⁺-K⁺-ATPase），胃内pH值是与临床终点密切相关的药效学（Pharmacodynamics, PD）指标。因此，本研究旨在通过构建半机制化的PK/PD模型，希望在临床研发早期，基于小样本量健康人数据，利用建模与模拟的技术手段进行充分的剂量探索，明确药物暴露与效应间的关系，优化给药方案并外推至不同适应症患者人群。从而为抑酸药物的临床开发提供新的技术策略与研究方法，加速新药的研发进程。

基于此，本论文共分为三个部分：

第一部分，探讨抑酸药物的早期临床研发考虑。本部分阐述了PPIs、P-CABs类抑酸药物的作用机制、药代动力学特征及其在中国的研发现状，探讨了胃内pH值及pH持续时间百分比与不同ARDs临床终点的潜在关联。以当前抑酸药物的研发热点——静脉注射液为切入点（静脉注射液起效迅速，对于消化性溃疡出血等危急症ARDs患者的治疗至关重要），通过对既往文献的系统评价和定量分析，初步阐明了胃内pH>6持续时间百分比与消化性溃疡出血患者临床结局（再出血率）的相关性，提出模型及药效学指标驱动的抑酸药物的临床研发新策略，旨在优化该类药物的临床试验设计、加速该类药物的临床研发进程。

第二部分，建立了定量测定人血浆中PPI类药物（包括埃索美拉唑、雷贝拉唑、艾普拉唑、兰索拉唑、泮托拉唑）和P-CAB类药物（富马酸伏诺拉生）的高效液相色谱-串联质谱分析方法，并对测定方法进行了全面且系统的方法学验证。本部分建立的生物分析方法将用于支持相关P-CABs药物的临床生物样本检测及其与PPIs类阳性对照药的临床比对研究。

第三部分，建立了PPI和P-CAB抑酸药物的半机制化PK/PD模型。采用非线性混合效应模型进行Pop PK建模，综合考虑了胃内质子泵的生成与降解、药物对质子泵的抑制效应、胃酸分泌的生理节律以及食物影响等因素构建了半机制化的PD模型。基于健康人与患者胃内pH基线的生理差异进行建模参数调整，实现了模型由健康人向患者的外推。1）以CR-001（一种P-CABs类注射液，尚未上市）为模型药物，使用I期健康人单次给药研究数据成功建立并验证了上述半机制化PK/PD模型，并模拟了不同给药方案下的药物PK、PD曲线，结合关键药效学指标（胃内pH>6的时间百分比），明确了药物抑制胃酸分泌的天花板效应剂量，为后续临床研究推荐了给药方案。此外，该模型外推至消化性溃疡患者的模拟结果也得到了临床实测数据的初步验证。2）以艾普拉唑钠注射液为PPI类模型药物，在既往PK/PD模型研究的基础上，纳入更多研究数据重建和优化Pop PK模型，定量评价疾病状态、体重、性别等显著协变量对药物PK的影响，扩展了模型的适用范围可用于支持临床合理化用药。

Acid-related diseases (ARDs) refer to a group of gastrointestinal disorders closely associated with gastric acid attack, including peptic ulcers and gastroesophageal reflux disease. Proton pump inhibitors (PPIs) and potassium-competitive acid blockers (P-CABs) play crucial roles in the treatment of ARDs. However, domestic innovation in this field lags behind, with original drugs mostly developed by foreign pharmaceutical companies.

For PPIs and P-CABs drugs, which have clear mechanisms of action and clear targets (H⁺-K⁺-ATPase), intragastric pH is a pharmacodynamics (PD) indicator that is closely related to clinical endpoints. Therefore, the current study aims to establish a semi-mechanistic PK/PD model, to identify the relationship between drug exposure and effects. Performing adequate dose exploration based on small sample size healthy human data using modeling and simulation techniques in the early stage of clinical development. In addition, the optimal dosing regimen is identified and extrapolated to patient populations with different indications. The application of this model is expected to provide new strategies and methods for the clinical development of such drugs, accelerating the process of new drug approvals.

Based on this, this thesis is divided into three parts:

(1). In the first part, the early clinical development considerations of acid-suppressive drugs targeting proton pumps are reviewed. This part systematically describes the mechanism of action, pharmacokinetic characteristics of acid-suppressing drugs of the PPIs and P-CABs drugs, their current R&D status in China, and explores the correlation of intragastric pH and percentage of pH duration with clinical endpoints of different ARDs. Taking intravenous fluids, which are currently the focus of acid-suppressing drug R&D (intravenous fluids have a rapid onset of action and are crucial for the treatment of patients with critically ill ARDs such as peptic ulcer bleeding), as an entry point, we initially clarified the correlation between pH>6 holding time ratio (HTR) and clinical endpoints (rebleeding rate) in patients with peptic ulcer bleeding through systematic evaluation and quantitative analysis of the previous literature, This part proposes a new strategy for early clinical development of acid-suppressing drugs driven by models and pharmacodynamic indicators, aiming to optimize clinical trial design and accelerate the clinical development process of such drugs.

(2). In the second part, a high performance liquid chromatograph mass spectrometer (HPLC-MS/MS) analytical method for the quantitative determination of PPIs (including esomeprazole, rabeprazole, ilaprazole, lansoprazole, and pantoprazole) and P-CABs (vonoprazan fumarate) in human plasma was developed, and the assay method was comprehensively and systematically validated methodologically. The established bioanalytical methods in this study will be used to support the clinical bioanalysis of relevant P-CABs drugs and their clinical comparative studies with PPIs as positive controls.

(3). In the third part, a semi-mechanistic PK/PD model of acid-suppressing drugs was established. A nonlinear mixed-effects model was used for Pop PK modeling, and the semi-mechanistic PD model was constructed by taking into account the generation and degradation of intragastric proton pumps, the inhibitory effect of drugs on proton pumps, the physiological rhythm of gastric acid secretion, and the influence of food. The modeling parameters were adjusted based on the physiological differences between the baseline intragastric pH in healthy subjects and patients, and the extrapolation of the model from healthy subjects to patients was achieved. a) Using CR-001 (a P-CABs injection, not yet available on the market) as a model drug, the semi-mechanistic PK/PD model mentioned above was successfully established and validated using the data from the single-dose administration study in healthy subjects in phase I. The PK and PD curves of the drug were simulated with different dosing regimens and combined with the data from the single-dose administration study in healthy subjects. The PK and PD curves were simulated under different dosing regimens, and combined with the key pharmacodynamic index (the pH>6 holding time ratio), the ceiling effect dose of the drug to inhibit gastric acid secretion was clarified, and the dosing regimen was recommended for the subsequent clinical study. In addition, the simulation results of the model extrapolated to patients with peptic ulcer were also preliminarily validated by the clinical measurement data. 2) For the PPIs model drug, Ilaprazole sodium for injection, the results of the Pop PK model were updated on the basis of previous PK/PD studies using data from a wider range of studies, and the effects of significant covariates, such as disease state, body weight, and gender, on the drug PK were evaluated, which extended the applicability of the model for clinical practice.