Miao Zhang

Background: SYHA1805 is a potent farnesoid X receptor (FXR) agonist currently in development for Metabolic Dysfunction-Associated Steatohepatitis (MASH). Methods: To determine the first-in-human (FIH) dose and guide its clinical development, an integrated approach combining in vitro and in vivo ADME and toxicological characterizations, cross-species allometric scaling (AS), and physiologically based pharmacokinetic (PBPK) modeling was employed. Results: Using monkeys and rats as extrapolation species, AS predicted a human intravenous clearance of 20.7 L/h and a steady-state volume of distribution of 15.1 L. Based on body surface area and exposure-based modeling, an FIH dosing regimen for single-dose administration was proposed, ranging from a 30 mg starting dose to a 3000 mg maximum, with an effective dose of 1150 mg. These dosing strategies were further supported by PBPK models, which accurately estimated human systemic exposure. The model simulations were subsequently validated by clinical trial data from a single ascending dose (SAD) study (CTR20202354). Conclusions: These findings establish a robust pharmacokinetic foundation for the continued clinical advancement of SYHA1805.

Although precipitation of poorly soluble drugs in the gastrointestinal (GI) tract is often considered detrimental to bioavailability, the solid‐state nature of the precipitate, either crystalline or amorphous, may critically redefine its impact. Contrasting with reported crystalline precipitates of weakly basic drugs, this study investigates XZP8257 (C ₂₇ H ₂₃ Cl ₂ N ₃ O ₄ S), a poorly soluble weakly acidic/zwitterionic compound (BCS II), to explore how GI fluid composition governs precipitate formation and its resulting physicochemical properties. Precipitates were generated in simulated intestinal media with varied bile salt concentrations and pH values. Their solid‐state forms were characterized using XRD, SEM, FTIR, and DSC, whereas dissolution performance was evaluated via equilibrium solubility and intrinsic dissolution rate (IDR) measurements. Elevated bile salt concentrations induced a molecular structural transition in XZP8257 and facilitated the formation of crystalline–amorphous mixed precipitates, a phenomenon distinct from the crystalline precipitates typically reported. These novel precipitates exhibited a 5.29‐ to 22.1‐fold increase in equilibrium solubility and a 0.7‐ to 2.35‐fold improvement in IDR compared to the crystalline API. This study reveals that for weakly acidic compounds like XZP8257, precipitate formation in the GI tract can lead to high energy, readily redissolving solid forms, potentially enhancing rather than limiting absorption. This challenges the uniform negative view of precipitation and underscores the necessity of compound‐specific precipitate characterization to accurately predict oral absorption, especially in physiologically based biopharmaceutics models.

Messenger RNA (mRNA) technology has emerged as a transformative modality in modern therapeutics and vaccine development, offering a versatile platform for targeted protein expression. This manuscript proposes a clinical and quantitative pharmacology framework to facilitate the development of mRNA therapies from preclinical research to clinical development. We discuss the unique pharmacological and ADME properties of mRNA and its lipid nanoparticle (LNP) delivery system, along with key bioanalytical and regulatory considerations. Specific clinical pharmacology strategies and quantitative approaches are illustrated through real‐world examples in oncology, rare metabolic diseases, and vaccines. Finally, we propose a forward‐looking clinical and quantitative pharmacology framework that integrates translational modeling, population modeling, physiological‐based pharmacokinetic (PBPK), quantitative systems pharmacology (QSP), and Artificial Intelligence (AI)/Machine Learning (ML)‐assisted predictive modeling. This integrated approach aims to build platform knowledge of mRNA‐based therapies and inform decision making across the drug discovery and development lifecycle in an evolving regulatory landscape.

The abundance of drug metabolic enzymes (DMEs) and transporters (DTs) in the human gastrointestinal tract significantly affects xenobiotic exposure in the circulating system, the basis of these compounds acting on humans. However, accurately predicting individual exposure in healthy subjects remains challenging due to limited data on protein levels throughout the gastrointestinal tract within the same individuals and inadequate assessment of factors influencing these levels. Therefore, we conducted a clinical study to obtain biopsy samples from 8 different gastrointestinal segments in 24 healthy Chinese volunteers. Concurrently, blood and fecal samples were collected for genotypic analysis and fecal microbiota metagenomic sequencing. Using an optimized LC–MS/MS method, we quantified the absolute protein abundance of CYP2C9, CYP2C19, CYP2D6, CYP3A4, P‐gp, and BCRP from the stomach to the colon. Our results revealed significant regional differences in protein expression: CYP3A4 was the most abundant in the small intestine, whereas CYP2C9 was predominantly found in the colon. CYP2D6 was primarily located in the ileum, while other DMEs/DTs showed higher concentrations in the jejunum. Meanwhile, the enzyme abundance in the small intestine and colon and the relative ratio of transporters in different regions to the jejunum were accurately calculated, providing valuable data for refining the physiological parameters in the virtual gastrointestinal tract of Chinese healthy population in PBBMs. Additionally, BMI, IBW, sex, age, genotype, and fecal microbiota were identified as critical factors influencing the protein levels of these DMEs/DTs throughout the gastrointestinal tract, with notable regional differences. Consequently, this study provides a unique foundation for understanding xenobiotic absorption in humans.

Background/Objectives: Physiologically based pharmacokinetic (PBPK) absorption models are instrumental for assessing drug absorption prior to clinical food effect studies, though discrepancies in predictive and actual outcomes are observed. This study focused on immediate release formulations of weakly basic water-insoluble compounds, namely rivaroxaban, ticagrelor, and PB-201, to investigate factors that could improve the predictive accuracy of PBPK models regarding food effects. Methods: Comprehensive in vitro experimental results provided the basis for the development of mechanistic absorption models, which were then combined with mechanistic disposition models to predict the systemic exposure of the model drugs in both fasted and fed states. Results: The developed PBPK models showed moderate to high predictive accuracy for food effects in Caucasian populations. For the Chinese population, the ticagrelor model’s initial overestimation of fed-state absorption was addressed by updating the permeability parameters from Caco-2 cell assays to those derived from parallel artificial membrane permeability assays in FaSSIF and FeSSIF media. This refinement was also applied to the rivaroxaban and ticagrelor models, leading to a more accurate representation of absorption in Caucasians. Conclusions: This study highlights the importance of apparent permeability in enhancing the predictive accuracy of PBPK absorption models for weakly basic water-insoluble compounds. Furthermore, the precipitation of PB-201 in the two-stage transfer experiments suggests that precipitation may not be a universal phenomenon for such compounds in vivo. Consequently, the precipitation rate constant, a theoretically essential parameter, should be determined based on experimental evidence to avoid overparameterization and ensure robust predictive accuracy of PBPK models.

HSK3486, a central nervous system inhibitor, has demonstrated superior anesthetic properties in comparison with propofol. Owing to the high liver extraction ratio of HSK3486 and the limited susceptibility to the multi‐enzyme inducer, rifampicin, the indicated population of HSK3486 is substantial. Nevertheless, in order to expand the population with indications, it is crucial to assess the systemic exposure of HSK3486 in specific populations. Moreover, the main metabolic enzyme of HSK3486 is UGT1A9, which shows a gene polymorphism in the population. Thus, to scientifically design the dose regimen for clinical trials in specific populations, a HSK3486 physiologically based pharmacokinetic model was developed in 2019 to support model‐informed drug development (MIDD). Several untested scenarios of HSK3486 administration in specific populations, and the effect of the UGT1A9 gene polymorphism on HSK3486 exposure were estimated as well. The predicted systemic exposure was increased slightly in patients with hepatic impairment and in the elderly, consistent with later clinical trial data. Meanwhile, there was no change in the systemic exposure of patients with severe renal impairment and in neonates. However, under the same dose, the predicted exposure of pediatric patients aged 1 month to 17 years was decreased significantly (about 21%–39%). Although these predicted results in children have not been validated by clinical data, they are comparable to clinical findings for propofol in children. The dose of HSK3486 in pediatrics may need to be increased and can be adjusted according to the predicted results. Moreover, the predicted HSK3486 systemic exposure in the obese population was increased by 28%, and in poor metabolizers of UGT1A9 might increase by about 16%–31% compared with UGT1A9 extensive metabolizers. Combined with the relatively flat exposure–response relationship for efficacy and safety (unpublished), obesity and genetic polymorphisms are unlikely to result in clinically significant changes in the anesthetic effect at the 0.4 mg/kg dose in adults. Therefore, MIDD can indeed provide supportive information for dosing decisions and facilitate the efficient and effective development of HSK3486.

PB‐201 is the second glucokinase activator in the world to enter the phase III clinical trials for the treatment of type 2 diabetes mellitus (T2DM). Combined with the efficacy advantages and the friendly absorption, distribution, metabolism, and excretion characteristics, the indication population of PB‐201 will be broad. Because the liver is the primary organ for PB‐201 elimination, and the elderly account for 20% of patients with T2DM, it is essential to estimate PB‐201 exposure in specific populations to understand the pharmacokinetic characteristics and avoid hypoglycemia. Despite the limited contribution of CYP3A4 to PB‐201 metabolism in vivo, the dual effects of nonspecific inhibitors/inducers on PB‐201 (substrate for CYP3A4 and CYP2C9 isoenzymes) exposure under fasted and fed states also need to be evaluated to understand potential risks of combination therapy. To grasp the unknown information, the physiologically‐based pharmacokinetic (PBPK) model was first developed and the influence of internal and external factors on PB‐201 exposure was evaluated. Results are shown that the predictive performance of the mechanistic PBPK model meets the predefined criteria, and can accurately capture the absorption and disposition characteristics. Impaired liver function and age‐induced changes in physiological factors may significantly increase the exposure under fasted state by 36%–158% and 48%–82%, respectively. The nonspecific inhibitor (fluconazole) and inducer (rifampicin) may separately increase/decrease PB‐201 systemic exposure by 44% and 58% under fasted state, and by 78% and 47% under fed state. Therefore, the influence of internal and external factors on PB‐201 exposure deserves attention, and the precision dose can be informed in future clinical studies based on the predicted results.