Integrated models of population pharmacokinetics and exposure response to optimize dosage regimen for anaprazole sodium in duodenal ulcer.

Anaprazole sodium enteric-coated tablet is a novel proton pump inhibitor which has been approved for the treatment of duodenal ulcer. The aim of this study is to provide reliable information for the design of an optimal dosage regimen. Population pharmacokinetics and exposure-response models were integrated to evaluate the pharmacokinetic parameters and covariates of Anaprazole and its metabolite M21-1, and subsequently provided dosage suggestions based on clinical trials and simulation data. A pharmacokinetic model incorporating two-compartment for the parent drug and one-compartment for the metabolite, with both first-order and zero-order mixed absorption was used to describe the pharmacokinetics of Anaprazole and M21-1. Age emerged as a significant covariate affecting the elimination rate constant of M21-1, with clearance decreasing as age advances. No correlation was observed between the pharmacokinetics of Anaprazole or M21-1 and the adverse reactions under the current dosages. BMI might be the influence factor of the mild gastrointestinal adverse reactions. Meanwhile, Anaprazole had a good healing rate (94.0 %) in duodenal ulcer patients and the exposure-response analysis indicated that the cured results were not influenced by the exposure parameters of parent drug or metabolite. In conclusion, the drug is safe when dosing between 20 and 100 mg once a day.

Model informed drug development: HSK21542 PBPK model supporting dose decisions in specific populations.

HKS21542, a highly selective activator of peripheral kappa opioid receptor agonists, plays a critical role in antinociception and itch inhibition during clinical development. Due to its indication population and elimination characteristics, it is imperative to evaluate the potential HSK21542 systemic exposure in individuals with renal impairment, hepatic impairment, the elderly, and the geriatric population. Here, a physiologically-based pharmacokinetic (PBPK) model for HSK21542 was developed based on in vitro metabolism and transport characteristics and in vivo elimination mechanism. Meanwhile, the potential systemic exposure of HSK21542 in specific populations was evaluated. The predicted results indicated increased systemic exposure in patients with renal impairment, hepatic impairment and in the elderly. Compared to the healthy volunteers aged 20-60 years, the AUC0-24h increased by 52 %-71 % in population with moderate to severe renal impairment, by 46 %-77 % in those with mild to severe hepatic impairment, and by 45 %-85 % in the elderly population aged 65-95-years. Conversely, the pediatric population demonstrated a potential decrease in systemic exposure, ranging from 20 % to 37 % in patients aged 0-17 years due to the physiological characteristics. Combined with the predicted results and the exposure-response relationship observed for HSK21542 and its analog (CR845), dosage regimens were designed for the target population with renal and hepatic impairment, supporting the successfully conducted trials (CTR20201702 and CTR20211940). Moreover, the observed exposure of HSK21542 in the elderly closely matched the predicted results within the same age group. Additionally, based on the predicted results, potential reductions in systemic exposure in pediatric patients should be carefully considered to avoid potential treatment failure in future clinical trials.

Model-based exploration of the rationality of off-label use of cetirizine in Chinese pediatric patients: a prospective cohort study.

Aims: Cetirizine is frequently administered at an increased dosage in clinical practice and recommended by several guidelines. Nonetheless, the pharmacokinetic (PK) profile and real-world safety data remain insufficient in the Chinese pediatric population. The objective of the current study is to develop a population pharmacokinetic (PPK) model for cetirizine in Chinese pediatric patients and to investigate the rationale behind its off-label usage. Methods: A prospective cohort study was conducted, enrolling children who had been diagnosed with allergic diseases and prescribed cetirizine. The outcomes were safety and pharmacokinetic (PK) parameters. Cetirizine concentrations were measured using a pre-established analytical method. Subsequently, a PK model was developed, followed by model evaluation and simulation. The developed PK model was employed to investigate the drug exposure differences across various age groups and to simulate scenarios of potential overdose. Results: Sixty-three children were enrolled, and 24 of them received a cetirizine dose exceeding the recommended dosage. A PPK model, based on published literature, served as the basis of our analysis, with adjustment made to estimate certain parameters. The final model evaluation and validation indicated accurate predictive performance and robust parameter estimation. Simulations conducted for the label-dose among age 1-12 indicated median maximum concentration at steady state (Cmax,ss) of 7 year old children could be the highest. The model was also used to predict the off-label dose scenarios and overdose patient to support the clinical decision. There were no adverse drug reactions in either group. Conclusion: This study provides evidence-based and model-based exploration for optimizing cetirizine usage in Chinese pediatric patients. The cetirizine PPK model showed accurate predictive performance and could be utilized to simulate individual patient exposure in real-world clinical scenarios.

Dose Prediction and Pharmacokinetic Simulation of XZP-5610, a Small Molecule for NASH Therapy, Using Allometric Scaling and Physiologically Based Pharmacokinetic Models.

The objectives of this study were to support dose selection of a novel FXR agonist XZP-5610 in first-in-human (FIH) trials and to predict its liver concentrations in Chinese healthy adults. Key parameters for extrapolation were measured using in vitro and in vivo models. Allometric scaling methods were employed to predict human pharmacokinetics (PK) parameters and doses for FIH clinical trials. To simulate the PK profiles, a physiologically based pharmacokinetic (PBPK) model was developed using animal data and subsequently validated with clinical data. The PBPK model was employed to simulate XZP-5610 concentrations in the human liver across different dose groups. XZP-5610 exhibited high permeability, poor solubility, and extensive binding to plasma proteins. After a single intravenous or oral administration of XZP-5610, the PK parameters obtained from rats and beagle dogs were used to extrapolate human parameters, resulting in a clearance of 138 mL/min and an apparent volume of distribution of 41.8 L. The predicted maximum recommended starting dose (MRSD), minimal anticipated biological effect level (MABEL), and maximum tolerated dose (MTD) were 0.15, 2, and 3 mg, respectively. The PK profiles and parameters of XZP-5610, predicted using the PBPK model, demonstrated good consistency with the clinical data. By using allometric scaling and PBPK models, the doses, PK profile, and especially the liver concentrations were successfully predicted in the FIH study.

The multiple roles of autophagy in uveal melanoma and the microenvironment.

PURPOSE: Uveal melanoma (UM) is the most common primary malignant intraocular tumor in adults, and effective clinical treatment strategies are still lacking. Autophagy is a lysosome-dependent degradation system that can encapsulate abnormal proteins, damaged organelles. However, dysfunctional autophagy has multiple types and plays a complex role in tumorigenicity depending on many factors, such as tumor stage, microenvironment, signaling pathway activation, and application of autophagic drugs. METHODS: A systematic review of the literature was conducted to analyze the role of autophagy in UM, as well as describing the development of autophagic drugs and the link between autophagy and the tumor microenvironment. RESULTS: In this review, we summarize current research advances regarding the types of autophagy, the mechanisms of autophagy, the application of autophagy inhibitors or agonists, autophagy and the tumor microenvironment. Finally, we also discuss the relationship between autophagy and UM. CONCLUSION: Understanding the molecular mechanisms of how autophagy differentially affects tumor progression may help to design better therapeutic regimens to prevent and treat UM.

Population Pharmacokinetic/Pharmacodynamic Analysis of the Glucokinase Activator PB201 in Healthy Volunteers and Patients with Type 2 Diabetes Mellitus: Facilitating the Clinical Development of PB201 in China.

PB201 is an orally active, partial glucokinase activator targeting both pancreatic and hepatic glucokinase. As the second glucokinase activator studied beyond phase I, PB201 has demonstrated promising glycemic effects as well as favorable pharmacokinetic (PK) and safety profiles in patients with type 2 diabetes mellitus (T2DM). This study aims to develop a population PK/pharmacodynamic (PD) model for PB201 using the pooled data from nine phase I/II clinical trials conducted in non-Chinese healthy volunteers and a T2DM population and to predict the PK/PD profile of PB201 in a Chinese T2DM population. We developed the PK/PD model using the non-linear mixed-effects modeling approach. All runs were performed using the first-order conditional estimation method with interaction. The pharmacokinetics of PB201 were well fitted by a one-compartment model with saturable absorption and linear elimination. The PD effects of PB201 on reducing the fasting plasma glucose and glycosylated hemoglobin levels in the T2DM population were described by indirect response models as stimulating the elimination of fasting plasma glucose, where the production of glycosylated hemoglobin was assumed to be stimulated by fasting plasma glucose. Covariate analyses revealed enhanced absorption of PB201 by food and decreased systemic clearance with ketoconazole co-administration, while no significant covariate was identified for the pharmacodynamics. The population PK model established for non-Chinese populations was shown to be applicable to the Chinese T2DM population as verified by the PK data from the Chinese phase I study. The final population PK/PD model predicted persistent and dose-dependent reductions in fasting plasma glucose and glycosylated hemoglobin levels in the Chinese T2DM population receiving 50/50 mg, 100/50 mg, and 100/100 mg PB201 twice daily for 24 weeks independent of co-administration of metformin. Overall, the proposed population PK/PD model quantitatively characterized the PK/PD properties of PB201 and the impact of covariates on its target populations, which allows the leveraging of extensive data in non-Chinese populations with the limited data in the Chinese T2DM population to successfully supported the waiver of the clinical phase II trial and facilitate the optimal dose regimen design of a pivotal phase III study of PB201 in China.

Dose decision of HSK7653 oral immediate release tablets in specific populations clinical trials based on mechanistic physiologically-based pharmacokinetic model.

HSK7653, an oral dipeptidyl peptidase-4 inhibitor administered every 2 weeks, is a candidate for the treatment of type 2 diabetes mellitus. The major elimination pathway of HSK7653 in vivo is renal excretion, and hepatic metabolism and fecal excretion of unchanged compound contribute less to the systemic clearance of HSK7653. Considering the disposition characteristics and the potential indication population of HSK7653, evaluating the HSK7653 exposure in patients with renal impairment and geriatric populations is a prerequisite for bringing more benefits to the patients. Here, a PBPK model was developed based on in vitro experimental results, such as dissolution, permeability, and metabolism, and the in vivo renal clearance, to evaluate the effects of physiological factors and food on HSK7653 exposure in specific populations, including adult and elder individuals with renal impairment and geriatric populations. Simulation results showed that the AUC of HSK7653 increased by 46%, 82%, and 129% in adult patients with mild, moderate, and severe renal impairment, and by 56%, 78%, and 101% in patients aged 65-75, 75-85 and 85-95 years, respectively. The AUC increased in the range of 62%-83%, 98%-133%, and 153%-195% in elderly patients (65-95 years) with mild, moderate, and severe renal impairment, respectively. Moreover, two different absorption model development methods (dissolution profile method and the diffusion layer model method) predicted that food had no effect on the exposure of the same simulated population. Since the predicted AUC of HSK7653 at the 10 mg dose in various specific populations was still within the relatively flat results of the exposure-response analysis, the 10 mg dose of HSK7653 was first used to explore the exposure in the renal impairment population (CTR20221952).

Model-informed drug development: The mechanistic HSK3486 physiologically based pharmacokinetic model informing dose decisions in clinical trials of specific populations.

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.

Development of a PBPK model to quantitatively understand absorption and disposition mechanism and support future clinical trials for PB-201.

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.

A model-based meta analysis study of sodium glucose co-transporter-2 inhibitors.

Type 2 diabetes mellitus (T2DM) agent sodium-glucose co-transporter 2 (SGLT2) inhibitors show special benefits in reducing body weight and heart failure risks. To accelerate clinical development for novel SGLT2 inhibitors, a quantitative relationship among pharmacokinetics, pharmacodynamics, and disease end points (PK/PD/end points) in healthy subjects and patients with T2DM was developed. PK/PD/end point data in published clinical studies for three globally marketed SGLT2 inhibitors (dapagliflozin, canagliflozin, and empagliflozin) were collected according to pre-set criteria. Overall, 80 papers with 880 PK, 27 PD, 848 fasting plasma glucose (FPG), and 1219 hemoglobin A1c (HbA1c) data were collected. A two-compartmental model with Hill's equation was utilized to capture PK/PD profiles. A novel translational biomarker, the change of urine glucose excretion (UGE) from baseline normalized by FPG (ΔUGEc ) was identified to bridge healthy subjects and patients with T2DM with different disease statuses. ΔUGEc was found to have a similar maximum increase with different half-maximal effective concentration values of 56.6, 2310, and 841 mg/mL·h for dapagliflozin, canagliflozin, and empagliflozin respectively. ΔUGEc will change FPG based on linear function. HbA1c profiles were captured by indirect response model. Additional placebo effect was also considered for both end points. The PK/ΔUGEc /FPG/HbA1c relationship was validated internally using diagnostic plots and visual assessment and further validated externally using the fourth globally approved same-in-class drug (ertugliflozin). This validated quantitative PK/PD/end point relationship offers novel insight into long-term efficacy prediction for SGLT2 inhibitors. The novelty identified ΔUGEc could make the comparison of different SGLT2 inhibitors' efficacy characteristics easier, and achieve early prediction from healthy subjects to patients.

Development and validation of an HPLC coupled with tandem mass spectrometry method for the determination of HSK7653, a novel super long-acting dipeptidyl peptidase-4 inhibitor, in human plasma and urine and its application to a pharmacokinetic study.

HSK7653 is a novel super long-acting dipeptidyl peptidase-4 inhibitor, which is promising for the treatment of type 2 diabetes mellitus with the twice-monthly dosing regimen. In this article, a robust and sensitive HPLC coupled with tandem mass spectrometry method for determining the concentration of HSK7653 in human plasma and urine was developed and validated for the first time. Plasma and urine samples were prepared by protein precipitation. After that, the extracts were analyzed using an LC-20A HPLC system coupled with API 4000 tandem MS equipped with an electrospray ionization source in positive mode. Separation was obtained using an XBridge Phenyl column (2.1 × 50 mm, 3.5 µm) with a gradient elution of acetonitrile and water containing 0.1% formic acid and 5% acetonitrile at room temperature. This bioanalysis method has been fully validated and the results showed good sensitivity and specificity. In brief, the standard curves were linear over the concentration range of 2.00-2000 ng/ml for plasma and 20.0-20,000 ng/ml for urine, respectively. In addition, the precisions of inter- and intra-run of HSK7653 were less than 12.7% and the accuracies were -3.3% to 6.3% for both plasma and urine. Finally, this method was successfully applied to explore the pharmacokinetic characteristics of HSK7653 in Chinese healthy volunteers in a first-in-human study.

PTK6 inhibits autophagy to promote uveal melanoma tumorigenesis by binding to SOCS3 and regulating mTOR phosphorylation.

Autophagy dysfunction is one of the common causes of tumor formation and plays an important role in uveal melanoma (UM). However, little is known about the regulatory mechanisms of autophagy in UM. Here, we show that PTK6 can promote the proliferation, migration, and invasion of UM cells by inhibiting autophagy. SOCS3 can inhibit the proliferation, migration, and invasion of UM cells. Overexpression of SOCS3 can partially rescue the PTK6-induced promotion of UM cell proliferation, migration, and invasion. Mechanistically, PTK6 can bind to SOCS3, and SOCS3 can downregulate the expression of PTK6. Furthermore, PTK6 can upregulate the phosphorylation of mTOR to inhibit autophagy. Taken together, our findings demonstrate the functions of PTK6 and SOCS3 in UM cells and targeting the SOCS3-PTK6 signaling axis might be a novel and promising therapeutic strategy for patients with UM.

LINC01278 Induces Autophagy to Inhibit Tumour Progression by Suppressing the mTOR Signalling Pathway.

Uveal melanoma (UM) is an aggressive intraocular malignant tumour that is closely related to autophagic dysfunction. We aimed to identify autophagy-related long noncoding RNAs (lncRNAs) to elucidate the molecular mechanism of UM. Here, we show that LINC01278 is a new potential biomarker with clinical prognostic value in UM through bioinformatics analysis. Application of an autophagy inhibitor (3-MA) and an autophagy agonist (MG-132) indicated that LINC01278 can inhibit UM cell proliferation, migration, and invasion by inducing autophagy. A xenograft nude mouse model was used to examine the tumorigenesis of UM cells in vivo. Mechanistically, LINC01278 can inhibit the mTOR signalling pathway to activate autophagy, as shown by experiments with an mTOR agonist (MHY1485) and mTOR inhibitor (rapamycin) treatment. Our findings indicate that LINC01278 functions as a tumour suppressor by inhibiting the mTOR signalling pathway to induce autophagy. Targeting the LINC01278-mTOR axis might be a novel and promising therapeutic approach for UM.

Potential drug-drug interaction of olverembatinib (HQP1351) using physiologically based pharmacokinetic models.

Olverembatinib (HQP1351) is a third-generation BCR-ABL tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia (CML) (including T315I-mutant disease), exhibits drug-drug interaction (DDI) potential through cytochrome P450 (CYP) enzymes CYP3A4, CYP2C9, CYP2C19, CYP1A2, and CYP2B6. A physiologically-based pharmacokinetic (PBPK) model was constructed based on physicochemical and in vitro parameters, as well as clinical data to predict 1) potential DDIs between olverembatinib and CYP3A4 and CYP2C9 inhibitors or inducers 2), effects of olverembatinib on the exposure of CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4 substrates, and 3) pharmacokinetics in patients with liver function injury. The PBPK model successfully described observed plasma concentrations of olverembatinib from healthy subjects and patients with CML after a single administration, and predicted olverembatinib exposure increases when co-administered with itraconazole (strong CYP3A4 inhibitor) and decreases with rifampicin (strong CYP3A4 inducer), which were validated by observed data. The predicted results suggest that 1) strong, moderate, and mild CYP3A4 inhibitors (which have some overlap with CYP2C9 inhibitors) may increase olverembatinib exposure by approximately 2.39-, 1.80- to 2.39-, and 1.08-fold, respectively; strong, and moderate CYP3A4 inducers may decrease olverembatinib exposure by approximately 0.29-, and 0.35- to 0.56-fold, respectively 2); olverembatinib, as a "perpetrator," would have no or limited impact on CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4 enzyme activity 3); systemic exposure of olverembatinib in liver function injury with Child-Pugh A, B, C may increase by 1.22-, 1.79-, and 2.13-fold, respectively. These simulations inform DDI risk for olverembatinib as either a "victim" or "perpetrator".

Prediction of pyrotinib exposure based on physiologically-based pharmacokinetic model and endogenous biomarker.

Pyrotinib, a novel irreversible epidermal growth factor receptor dual tyrosine kinase inhibitor, is mainly (about 90%) eliminated through cytochrome P450 (CYP) 3A mediated metabolism in vivo. Meanwhile, genotype is a key factor affecting pyrotinib clearance and 4ß-hydroxycholesterol is an endogenous biomarker of CYP3A activity that can indirectly reflect the possible pyrotinib exposure. Thus, it is necessary to evaluate the clinical drug-drug interactions (DDI) between CYP3A perpetrators and pyrotinib, understand potential exposure in specific populations including liver impairment and geriatric populations, and explore the possible relationships among pyrotinib exposure, genotypes and endogenous biomarker. Physiologically-based pharmacokinetic (PBPK) model can be used to replace prospective DDI studies and evaluate external and internal factors that may influence system exposure. Herein, a basic PBPK model was firstly developed to evaluate the potential risk of pyrotinib coadministration with strong inhibitor and guide the clinical trial design. Subsequently, the mechanistic PBPK model was established and used to quantitatively estimate the potential DDI risk for other CYP3A modulators, understand the potential exposure of specific populations, including liver impairment and geriatric populations. Meanwhile, the possible relationships among pyrotinib exposure, genotypes and endogenous biomarker were explored. With the help of PBPK model, the DDI clinical trial of pyrotinib coadministration with strong inhibitor has been successfully completed, some DDI clinical trials may be waived based on the predicted results and clinical trials in specific populations can be reasonably designed. Moreover, the mutant genotypes of CYP3A4*18A and CYP3A5*3 were likely to have a limited influence on pyrotinib clearance, and the genotype-independent linear correlation coefficient between endogenous biomarker and system exposure was larger than 0.6. Therefore, based on the reliable predicted results and the linear correlations between pyrotinib exposure and endogenous biomarker, dosage adjustment of pyrotinib can be designed for clinical practice.

Quercetin Improves Mitochondrial Function and Inflammation in H2O2-Induced Oxidative Stress Damage in the Gastric Mucosal Epithelial Cell by Regulating the PI3K/AKT Signaling Pathway.

Functional dyspepsia (FD) is one of the most common functional gastrointestinal disorders, the therapeutic strategy of which it is limited due to its complex pathogenesis. Oxidative stress-induced damage in gastric mucosal epithelial cells is related to the pathogenesis and development of FD. Quercetin (Que) is one of the active ingredients of Zhishi that showed antioxidant, antiapoptotic, and anti-inflammatory effects. The aim of this study is to investigate the effect of Que on oxidative stress-induced gastric mucosal epithelial cells damage and its underlying molecular mechanism. The gastric mucosal epithelial cell line GES-1 was treated with 200 µM of H2O2 to construct an oxidative stress-induced damage model. The H2O2 cells were then administrated with different concentrations of Que. The results indicated that high concentration of Que (100 µM) showed cytotoxicity in H2O2-induced GES-1 cells. However, appropriate concentration of Que (25 and 50 µM) alleviated the oxidative stress damage induced by H2O2, as demonstrated by the increase of proliferation, decrease of ROS generation, apoptosis, inflammation, and alleviation of mitochondrial function and cell barrier. In addition, Que increased the activation of phosphorylation of PI3K and AKT decreased by H2O2. To investigate whether Que alleviated the oxidative stress damage in GES-1 cells by the PI3K/AKT signaling pathway, the GES-1 cells were treated with Que (25 µM) combined with and without LY294002, the PI3K inhibitor. The results showed that LY294002 suppressed the alleviation effect on Que in H2O2-induced GES-1 cells. In conclusion, the current study demonstrates that Que alleviates oxidative stress damage in GES-1 cells by improving mitochondrial function and mucosal barrier and suppressing inflammation through regulating the PI3K/AKT signaling pathway, indicating the potential therapeutic effects of Que on FD.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of the glucokinase activator PB-201 and its effects on the glucose excursion profile in drug-naïve Chinese patients with type 2 diabetes: a randomised controlled, crossover, single-centre phase 1 trial.

BACKGROUND: PB-201, a partial, pancreas/liver-dual glucokinase activator, showed good tolerance and glycaemic effects in multinational studies. This study determined its optimal dose, safety, pharmacokinetics, and pharmacodynamics in Chinese patients with type 2 diabetes. METHODS: In this double-blind, randomised, four-period, crossover, phase 1 trial in China, conducted at the Peking University Third Hospital, adult patients with drug-naive type 2 diabetes were randomised (1:1:1:1) to four sequence groups using a computer-generated randomisation table. In each period, they received oral placebo or PB-201 (50+50, 100+50, or 100+100 mg split doses) for 7 days. Investigators and patients were masked to treatment assignment. The primary endpoints were safety and pharmacokinetics. Continuous glucose monitoring was used to delineate the glucose excursion profile. Trial registration number: NCT03973515. FINDINGS: Between August 27, 2019 and December 19, 2019, 16 patients were randomised. PB-201 showed a dose-proportional pharmacokinetic profile without apparent accumulation in the body and induced dose-dependent lowering of blood glucose. PB-201 at 50+50, 100+50, and 100+100 mg increased mean time in range (49·210% [standard deviation 27], 56·130% [25], and 63·330% [20] with three doses, respectively) versus placebo (49·380% [27]) and reduced estimated glycated haemoglobin from baseline (-0·5445% [1·654], -1·063% [1·236], and -1·888% [1·381] vs -0·581% [1·200]). Fifteen patients (93·8%) had treatment-emergent adverse events, which were mild. No patients had hypoglycaemia with venous/capillary glucose <3·9 mmol/L or nocturnal hypoglycaemia. INTERPRETATION: PB-201 100 mg twice daily is identified as the optimal dose, which shows promising glucose-lowering effects and low risks of hypoglycaemia and other side effects. Further investigation of PB-201 100 mg twice daily in confirmatory trials is warranted. FUNDING: PegBio.

Development of a Virtual Chinese Pediatric Population Physiological Model Targeting Specific Metabolism and Kidney Elimination Pathways.

Background: Physiologically based pharmacokinetic (PBPK) modeling and simulating may be a powerful tool in predicting drug behaviors in specific populations. It is a mathematical model that relates the pharmacokinetic (PK) profile of a compound with human anatomical characteristics, physiological characteristics, and biochemical parameters. Predictions using PBPK models offer a promising way to guide drug development and can be used to optimize clinical dosing regimens. However, PK data of new drugs in the pediatric population are too limited to guide clinical therapy, which may lead to frequent adverse events or insufficient efficacy for pediatric patients, particularly in neonates and infants. Objective: The objective of this study was to establish a virtual Chinese pediatric population based on the physiological parameters of Chinese children that could be utilized in PBPK models. Methods: A Chinese pediatric PBPK model was developed in Simcyp Simulator by collecting published Chinese pediatric physiological and anthropometric data to use as system parameters. This pediatric population model was then evaluated in the Chinese pediatric population by predicting the pharmacokinetic characteristics of four probe drugs: theophylline (major CYP1A2 substrate), fentanyl (major CYP3A4 substrate), vancomycin, and ceftazidime (renal-eliminated). Results: The predicted maximum concentration (Cmax), area under the curve of concentration-time (AUC), and clearance (CL) for theophylline (CYP1A2 metabolism pathway) and fentanyl (CYP3A4 metabolism pathway) were within two folds of the observed data. For drugs mainly eliminated by renal clearance (vancomycin and ceftazidime) in the Chinese pediatric population, the ratio of prediction to observation for major PK parameters was within a 2-fold error range. Conclusion: The model is a supplement to the previous Chinese population PBPK model. We anticipate the model to be a better representative of the pediatric Chinese population for drugs PK, offering greater clinical precision for medication given to the pediatric population, ultimately advancing clinical development of pediatric drugs. We can refine this model further by collecting more physiological parameters of Chinese children.

Comprehensive PBPK model to predict drug interaction potential of Zanubrutinib as a victim or perpetrator.

A physiologically based pharmacokinetic (PBPK) model was developed to evaluate and predict (1) the effect of concomitant cytochrome P450 3A (CYP3A) inhibitors or inducers on the exposures of zanubrutinib, (2) the effect of zanubrutinib on the exposures of CYP3A4, CYP2C8, and CYP2B6 substrates, and (3) the impact of gastric pH changes on the pharmacokinetics of zanubrutinib. The model was developed based on physicochemical and in vitro parameters, as well as clinical data, including pharmacokinetic data in patients with B-cell malignancies and in healthy volunteers from two clinical drug-drug interaction (DDI) studies of zanubrutinib as a victim of CYP modulators (itraconazole, rifampicin) or a perpetrator (midazolam). This PBPK model was successfully validated to describe the observed plasma concentrations and clinical DDIs of zanubrutinib. Model predictions were generally within 1.5-fold of the observed clinical data. The PBPK model was used to predict untested clinical scenarios; these simulations indicated that strong, moderate, and mild CYP3A inhibitors may increase zanubrutinib exposures by approximately four-fold, two- to three-fold, and <1.5-fold, respectively. Strong and moderate CYP3A inducers may decrease zanubrutinib exposures by two- to three-fold or greater. The PBPK simulations showed that clinically relevant concentrations of zanubrutinib, as a DDI perpetrator, would have no or limited impact on the enzyme activity of CYP2B6 and CYP2C8. Simulations indicated that zanubrutinib exposures are not impacted by acid-reducing agents. Development of a PBPK model for zanubrutinib as a DDI victim and perpetrator in parallel can increase confidence in PBPK models supporting zanubrutinib label dose recommendations.

Pharmacokinetics analysis based on target-mediated drug distribution for RC18, a novel BLyS/APRIL fusion protein to treat systemic lupus erythematosus and rheumatoid arthritis.

BACKGROUND AND PURPOSE: RC18 is a novel recombinant fusion protein targeting on B lymphocyte stimulator (BLyS). We aimed to develop and qualify a population pharmacokinetics (PopPK) model for RC18 in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients, taking into account the mechanistic target-mediated drug disposition (TMDD) process. METHODS: A TMDD model of RC18 was developed using data from two phase I clinical trial (n = 23). The TMDD structural model was developed by simultaneous fitting of the serum free RC18 and serum RC18-BLyS complex. Potential covariates were screened using stepwise method, and predictive performance was qualified using a prediction-corrected visual predictive check (pcVPC) and bootstrap. RESULTS: A two compartment TMDD model with first order absorption for subcutaneous administration was built. The final model included a significant relationship between distribution volume of the central compartment and body weight. And the baseline of immunoglobulin IgG had significant effect on the baseline of target BLyS. The plots from goodness-of-fit and pcVPC confirmed good predictive performance of this TMDDmodel. CONCLUSIONS: This mechanistic TMDD model integrated the interaction of RC18 with its target BLyS and accurately predicts both RC18 and RC18-BLyS complex profiles in RA and SLE patients. Simulated target change profiles can be used to help guide rational dose regimen selection and used as a biomarker for efficacy evaluation.