ABSTRACT Netanasvir Phosphate is a novel second-generation NS5A inhibitor used for the treatment of chronic hepatitis C virus (HCV) infection. This study investigated the absorption, distribution, metabolism, and excretion (ADME), and the metabolite profile of [¹⁴C]Netanasvir Phosphate. In a single-dose, open-label study, six healthy Chinese male volunteers received an oral dose of 100 mg/200 µCi of [¹⁴C]Netanasvir Phosphate under fed conditions. Blood, urine, and fecal samples were collected for up to 336 h post-dose. Total radioactivity was measured using oxidative combustion and liquid scintillation counting, and the parent drug and its metabolites were analyzed by validated liquid chromatography–tandem mass spectrometry and low-energy radiometric detection and mass spectrometry methods. The pharmacokinetic profile showed a median T max of 5.5 h and a mean terminal half-life of 30.6 ± 8.52 h. The average total recovery of radioactivity was 97.73% ± 1.90%, with feces accounting for 97.71% of the administered dose and urine only 0.02%, indicating that fecal excretion is the primary elimination pathway. The parent drug was the predominant circulating and excreted component, representing 93.89% of plasma radioactivity and 78.78% of the administered dose in feces. Only minor metabolites were detected, including demethylated and oxidized derivatives. The drug was well tolerated, with no serious adverse events (SAEs) or dose-limiting toxicities observed. This mass balance and metabolite profiling study provides essential evidence supporting the favorable pharmacokinetic characteristics and metabolic stability of [¹⁴C]Netanasvir Phosphate and offers a scientific foundation for further clinical development in HCV-infected populations.

Fat-soluble vitamins (A, D, and E) are essential micronutrients whose absorption critically depends on bile acid–mediated solubilization. However, studies associating bile acids and these vitamins remain limited, partly due to methodological challenges. Therefore, we developed a novel and rapid LC-MS/MS method for the simultaneous quantification of these vitamins in serum, based on 2-nitrosopyridine (PyrNo) click derivatization. This strategy employs Diels-Alder cycloaddition for vitamin A/D and acid-catalyzed oxidative dehydrogenation for vitamin E, enabling one-step protein precipitation followed by a 15-min room-temperature reaction. The method significantly enhanced sensitivity (>350-fold for vitamin D), allowing analysis within 6 min, and demonstrated excellent performance: linearity (R > 0.99), accuracy (96.1–110.2

PURPOSE:Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with a median survival of only 2-3 years after diagnosis. Yinfenidone (HEC585) possesses the potential to inhibit the proliferation of pulmonary fibroblasts, making it a promising candidate for the treatment of IPF. This study assessed the safety, tolerability, pharmacokinetics, and metabolic profile of Yinfenidone hydrochloride capsule in healthy Chinese subjects. METHODS:This single-center, randomized, double-blind, placebo-controlled, single ascending-dose trial included seven dose groups(20, 50, 100, 200, 400, 600, and 800 mg). Each group enrolled8 healthy subjects: 6 received Yinfenidone hydrochloride capsules and 2 received matching placebo under fasting conditions. Serial pharmacokinetic (PK) blood samples were collected pre-dose and post-dose, liquid chromatography-tandem mass spectrometry was used to analyze the plasma concentrations of Yinfenidone. Additionally, metabolic biotransformation of Yinfenidone in plasma were conducted in the 100 mg dose group. Safety and tolerability endpoints were monitored via physical examinations, vital signs measurements, clinical laboratory tests, 12-lead electrocardiography (ECG), and adverse events (AEs) documentation throughout the trial. FINDINGS:Yinfenidone was rapidly absorbed, with a median maximum plasma concentration (Tmax) of 1.8-3.0 hours, and had a mean half-life (t1/2) ranging from 31.9 to 62.0 hours. Within the 20-100 mg dose range, systemic drug exposure generally increased with ascending dose, above 100 mg, exposure increased less than proportionally to dose. Metabolite profiling in the 100 mg group revealed that the parentcompound predominated in plasma, with metabolic pathways including mono-oxygenation and N-dealkylation. All reported AEswere mild, classified as Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 grade 1. No serious AEs observed; no subject discontinued the trial due to AEs. Single oral doses of 20-800 mg Yinfenidone hydrochloride capsules administered under fasting conditions demonstrated favorable safety and tolerability profiles in healthy Chinese subjects. IMPLICATIONS:Yinfenidone exhibited rapid absorption (median Tmax, 1.8-3.0 hours) and a long terminal t1/2 ranging from 31.9 to 62.0 hours in this single ascending-dose study, indicating that Yinfenidone can be taken once a day in subsequent clinical studies. Yinfenidone mainly exists in human plasma as the original drug and is metabolized through a variety of metabolic pathways. The AEs observed with Yinfenidone in this study, such as diarrhea, nausea, and dizziness, were similar to those reported with pirfenidone. Overall, Yinfenidone demonstrated a favorable safety and tolerability profile in this cohort of healthy subjects.

ABSTRACT TPN171 is a potent phosphodiesterase type 5 inhibitor used to treat pulmonary arterial hypertension and erectile dysfunction, primarily metabolized by CYP3A4. This study aimed to evaluate its drug–drug interaction (DDI) potential and determine the optimal dosing when co‐administered with CYP3A4 modulators. A physiologically based pharmacokinetic (PBPK) model was developed and validated using clinical DDI data for itraconazole (strong CYP3A4 inhibitor) and rifampin (strong CYP3A4 inducer). The model was then applied to predict DDIs with moderate (diltiazem, fluconazole) and mild (fluvoxamine) inhibitors, as well as moderate (efavirenz) and mild (zanubrutinib) inducers. Predicted AUC0−t ratios aligned with observed data: itraconazole (2.42‐fold predicted vs. 2.67‐ fold observed) and rifampicin (0.14‐fold predicted vs. 0.096‐fold observed). For other modulators, geometric mean AUC0−t ratios were 2.40 with diltiazem, 3.27 with fluconazole (400 mg), 2.07 with fluconazole (100 mg), 1.16 with fluvoxamine, 0.53 with efavirenz, and 0.70 with zanubrutinib. These simulations indicate that strong and moderate CYP3A4 inhibitors and inducers significantly alter TPN171 exposure, whereas weak modulators have no clinically meaningful impact. These findings provide a scientific basis for dose recommendations when TPN171 is used with CYP3A4 modulators.

Introduction:This clinical trial aimed to assess the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of LW402, a preferential JAK1 inhibitor, in healthy participants, so as to provide support for its further development in treating autoimmune diseases. Methods:The study included two phases: a single ascending dose (10-400 mg) with 54 participants and a multiple ascending dose (50-150 mg, b.i.d for 6 days plus a single dose on day 7) with 36 participants. Safety, PK (from timed blood samples), and PD (JAK1/JAK2 signaling) were evaluated. Results:No serious adverse events were reported; only mild treatment-emergent adverse events (TEAEs), such as sinus bradycardia and gastrointestinal issues, occurred. LW402 was rapidly absorbed (median tmax: 0.42-1.0 hours), with slightly super-proportional exposure and minimal accumulation, and preferentially inhibited JAK1-mediated signaling. Discussion:LW402's favorable safety profile, predictable PK characteristics, and selective JAK1 inhibition collectively support its continued development for the treatment of autoimmune diseases. Clinical Trial Registration:http://www.chinadrugtrials.org.cn, identifier CTR20201897.

Background and Objective:Cap-dependent endonuclease (CEN) inhibitors are a promising novel class of antiviral agents for influenza treatment. This phase I study aimed to evaluate the mass balance, excretion pathways, and pharmacokinetics of pixavir marboxil (TG-1000), a novel CEN inhibitor prodrug, in healthy humans. Methods:Six healthy Chinese male participants received a single oral dose of 40 mg (100 μCi) [14C]pixavir marboxil. Blood, urine, and fecal samples were collected at predefined intervals up to 384 h post-dose. Total radioactivity was determined using oxidative combustion and liquid scintillation counting. Pharmacokinetic parameters were calculated using non-compartmental analysis, and metabolite profiling was conducted using high-performance liquid chromatography coupled with radiochemical detection and high-resolution mass spectrometry. Results:Intact pixavir marboxil was undetectable in plasma. Systemic exposure primarily consisted of its active metabolite, pixavir (TG-0527), and a subsequent glucuronide conjugate, TG-0600771. The geometric mean areas under the curve ( A U C 0 - ∞ ) for total radioactivity, pixavir, and TG-0600771 in six participants were 4,220 hng Eq./mL, 2,490 hng/mL, and 981 hng/mL, respectively. The administered radioactive dose demonstrated a mean cumulative recovery of 91.29%, with 85.62% recovered in feces and 5.68% in urine. Metabolite profiling identified pixavir and TG-0600771 as the major metabolites, with no major cytochrome P450 (CYP)-mediated oxidative metabolites observed in plasma. The single dose of [14C]pixavir marboxil was safe and well-tolerated. Conclusion:Pixavir marboxil exhibits a favorable pharmacokinetic profile characterized by rapid systemic conversion to its active metabolite, CYP-independent metabolism, and predominantly non-renal clearance. These favorable pharmacokinetic characteristics support a well-characterized disposition profile with limited reliance on CYP-mediated metabolism and renal excretion of active pixavir. Trial Registration:This study was registered with Drug Clinical Trial Registration and Information Disclosure Platform, National Medical Products Administration (NMPA), number CTR20231822 (http://www.chinadrugtrials.org.cn/).

PURPOSE:This Phase I drug-drug interaction study in healthy Chinese male subjects evaluated: (1) the perpetrator effects of D-1553 (garsorasib) on cytochrome P450 enzymes (CYP3A4, CYP1A2), hepatic (OATP1B1/1B3), renal uptake transporters (OAT1/3), and efflux transporter P-glycoprotein (P-gp); and (2) the victim potential with itraconazole (200 mg daily) or omeprazole (20 mg daily). METHODS:The study comprised three cohorts. Cohort 1 received D-1553 tablets (400 mg twice daily) co-administered with a cocktail of probe substrates: midazolam, caffeine, rosuvastatin, furosemide, and digoxin. Cohort 2 received D-1553 co-administered with the strong CYP3A4 and P-gp inhibitor itraconazole. Cohort 3 received D-1553 co-administered with the proton-pump inhibitor omeprazole. A total of 45 healthy male subjects were enrolled in the study, and 44 subjects were included in the safety and pharmacokinetic (PK) analyses. Plasma concentrations of D-1553 and concomitant drugs were quantified using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. Tolerability was also evaluated. RESULTS:In the substrate cocktail assessment, D-1553 significantly inhibited CYP3A4 (midazolam AUC ratio: 2.04) but not CYP1A2 (caffeine AUC ratio: 1.18), and reduced exposures of rosuvastatin and furosemide (AUC ratio: 0.59 and 0.41, respectively), likely via intestinal OATP2B1 inhibition. Meanwhile, no clinically relevant effect on P-gp was shown (digoxin AUC ratio: 1.19). Co-administration with itraconazole increased D-1553 exposure (AUC ratio: 1.46), whereas omeprazole decreased its exposure (AUC ratio: 0.85). All AEs were mild and no serious AEs were reported. CONCLUSION:D-1553 acts as a moderate inhibitor of CYP3A4 and a weak inhibitor of P-gp, while reducing the absorption of specific transporter substrates, likely via intestinal OATP2B1. Co-administration with strong CYP3A4 inhibitors moderately increases D-1553 exposure, whereas acid-reducing agents like omeprazole have no clinically relevant effect. These findings provide a targeted scientific basis for guiding the clinical co-administration of D-1553 with concomitant medications.

Amino acid sufficiency is critical for T cell metabolic reprogramming, yet how T cells maintain amino acid homeostasis remains poorly defined. Here, we identify the CORVET and HOPS (CORVET/HOPS) tethering complexes as essential upstream regulators. In activated T cells, they sustain intracellular amino acid levels by promoting macropinocytosis to acquire extracellular nutrients. This function enables dual signaling outcomes: suppression of the integrated stress response (ISR) and activation of mTORC1, which together license metabolic plasticity and effector function. Genetic ablation of core subunits (VPS18 or VPS11) of CORVET/HOPS induces severe amino acid scarcity, triggers pathological ISR activation, and impairs mTORC1 signaling, leading to reduced peripheral T cell numbers and abrogating both inflammatory and protective immunity in vivo. These defects are mechanistically linked: BIM deletion or enforced mTORC1 activity rescues the survival and proliferative failures, respectively, of CORVET/HOPS-deficient T cells. Our work establishes CORVET/HOPS as fundamental couplers linking nutrient acquisition to immune signaling, revealing a targetable node for immuno-metabolic therapy.

PURPOSE:TPN171, a novel, highly selective, and potent phosphodiesterase type 5 (PDE5) inhibitor, is currently under clinical development for the treatment of pulmonary arterial hypertension (PAH) and erectile dysfunction (ED). The drug is mainly metabolized by the cytochrome P450 (CYP) enzyme 3A4. We evaluated the pharmacokinetic (PK) profile and safety of TPN171, both alone and in combination with itraconazole (a CYP3A4 potent inhibitor) or rifampin (a CYP3A4 potent inducer), in healthy Chinese volunteers. METHODS:In this open-label, fixed-sequence study, TPN171 (10 mg) was administered orally once daily on Days 1 and 6 in Cohort 1, followed by oral itraconazole (200 mg) once daily from Days 3 to 6. Cohort 2 received oral TPN171 (20 mg) once daily on Days 1 and 10, with concurrent oral rifampin (600 mg) once daily administered from Days 3 to 10. Twenty-four healthy subjects were enrolled (12 per cohort). The PK parameters of TPN171 were estimated through noncompartmental analysis with its plasma concentration detection. Comparisons of the maximum plasma concentration (Cmax) and the area under the concentration-time curve extrapolated to infinity (AUC0-∞) for TPN171 were conducted between conditions with and without coadministration of itraconazole or rifampin. FINDINGS:The Cmax and AUC0-∞ for TPN171 were increased by 76.00% (least squares geometric mean ratios (LSGMR), 176.00% [90% CI, 160.37%-193.15%]) and 185.67% (LSGMR, 285.67% [90% CI, 261.87%-311.64%]) when combined with itraconazole versus TPN171 alone. The Cmax and AUC0-∞ of TPN171 were reduced by 74.53% (LSGMR, 25.47% [90% CI, 21.98%-29.50%]) and 90.14% when combined with rifampin versus TPN171 alone (LSGMR, 9.86% [90% CI, 9.08%-10.71%]). Spontaneous penile erection was the most frequently reported adverse event, occurring in 17 (70.83%) of the 24 subjects. IMPLICATIONS:CYP3A4 potent inhibitors and inducers can significantly affect the exposure level of TPN171, especially the inducers. Therefore, when taking TPN171, it is recommended to avoid concomitant administration with CYP3A4 potent inhibitors or potent/moderate inducers, or adjust the dosage of TPN171.

ABSTRACT This study aimed to evaluate the effects of the concomitant administration of TPN171 and alcohol on hemodynamic and pharmacokinetic characteristics in healthy Chinese male subjects. Fifteen eligible subjects were randomly assigned to one of three sequences, each comprising three treatments: Treatment A (placebo +0.5 g/kg alcohol), Treatment B (TPN171 + 0.5 g/kg alcohol), and Treatment C (TPN171 + placebo). Enrolled subjects were administered with 10 mg TPN171 and/or 0.5 g/kg alcohol in fasting state in a randomized crossover design. Blood pressure, pulse rate (PR), blood samples, and breath alcohol test were measured at designated time points for hemodynamic and pharmacokinetic analyses. Compared with 10 mg TPN171 alone, administration of 10 mg TPN171 + 0.5 g/kg alcohol significantly lowered the area under the effect–time curve from 0 to 4 h (AUEC0‐4h) of systolic blood pressure (95% confidence interval [CI]: −29.75 to −0.83, p = 0.039) and significantly increased AUEC0–4h of PR (95% CI: 7.47–28.92, p = 0.003). Compared with 0.5 g/kg alcohol alone, administration of 10 mg TPN171 + 0.5 g/kg alcohol contributed to significantly higher maximal increase of PR (95% CI: 2.78–9.44, p = 0.002) and AUEC0‐4h of PR (95% CI: 1.08–24.52, p = 0.035). Alcohol had no influence on the pharmacokinetics of TPN171, and vice versa. Though the concomitant administration of TPN171 and alcohol induced a more pronounced increase in PR, this did not result in clinical symptoms or heart rate increase‐related adverse events, indicating that the combined use was generally safe and well‐tolerated.

Purpose: To study the pharmacokinetic characteristics of progesterone (GenSci070) in healthy Chinese postmenopausal women volunteers and to evaluate the bioequivalence and safety of GenSci070 and reference formulation. Methods: In this randomized, open-label, single-center, single-dose, 2-period, 2-sequence, 2-way crossover study, 50 postmenopausal healthy women were recruited and received a single subcutaneous injection of test (GenSci070) or reference formulation 25 mg, respectively. Plasma progesterone concentrations were measured using liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters were calculated by non- compartmental analysis method using Phoenix WinNonlin 8.3.1 software to evaluate the bioequivalence. The safety profile was evaluated by adverse events, physical examination, vital signs, laboratory tests, 12-lead ECG, etc. Findings: The geometric mean ratios (90% CIs) for Cmax, AUC0-t, and AUC0-infinity of the test and reference formulations were 92.70% (87.29%-98.44%), 96.26% (94.02%-98.55%), and 95.46% (93.27%-97.71%), respectively. They were all within the acceptable bioequivalence range of 80% to 125%. Thirty-one treatment-emergent adverse events occurred in 22 participants (44.0%) who received test formulation and 21 treatment-emergent adverse events occurred in 16 participants (32.0%) who received reference formulation, all events were mild. Implications: The water-soluble progesterone injection (GenSci070) demonstrated bioequivalence to the marketed progesterone injection (Lubion) and exhibited a good safety profile in this study.

Suraxavir marboxil (GP681) is a prodrug of a novel polymerase acidic protein inhibitor, and its metabolite GP1707D07 prevents the replication of influenza virus by selectively inhibiting the cap-dependent nucleic acid endonuclease of influenza virus. This study evaluates the safety, tolerability, and pharmacokinetics of suraxavir marboxil after a single dose and assesses the effect of a high-fat, high-calorie meal on the pharmacokinetics of suraxavir marboxil in healthy Chinese subjects. The study included two parts: single ascending-dose study (SAD) and food effect study (FE). In SAD, subjects were randomized to single-dose suraxavir marboxil (20, 40, 60, or 80 mg) or placebo. In FE, subjects (n = 16) were randomized to single-dose suraxavir marboxil 40 mg in fasting and fed states. Safety assessment and sample collection were in accordance with the protocol. Suraxavir marboxil was well tolerated in healthy Chinese subjects in both SAD and FE, and all adverse events recovered without treatment after discontinuation of suraxavir marboxil. In SAD, after administration of suraxavir marboxil in the dosage range of 20-80 mg, the time to maintain the clinically defined effective target blood concentration is about 72-136 h. In FE, a high-fat, high-calorie meal reduced Cmax by approximately 19% and AUC0-∞ by approximately 15%. Suraxavir marboxil was well tolerated in healthy Chinese subjects. Based on the safety and pharmacokinetic data, 20-80 mg single oral dosing was supported for further clinical development. Food intake may slightly reduce the rate and extent of absorption of suraxavir marboxil.The study was registered on https://classic.clinicaltrials.gov/ (registration no.: NCT04729764).

Urothelial carcinoma (UC) is a highly malignant disease with significant public health implications. Despite advancements in oncology, early diagnosis and effective prognostic tools remain limited. This study aimed to develop a machine learning model using complete blood count (CBC) data to predict clinical outcomes in UC patients. A retrospective, two-center cohort study was conducted, analyzing 23 CBC variables from 477 UC patients at Xuhui Hospital of Fudan University (discovery cohort) and 297 UC patients from Putuo People's Hospital of Tongji University (validation cohort). CBC data were collected before treatment and three months posttreatment, with overall survival (OS) as the primary endpoint. Nine machine learning models were developed in the discovery cohort and validated independently. Feature selection identified a logistic regression (LR) model incorporating white blood cell (WBC) count and lymphocyte percentage (LYMPH%) as the optimal predictor. The model achieved high performance, with an area under the ROC curve (AUC) of 0.93 (95 %CI: 0.90-0.97), area under the precision-recall curve (AUPRC) of 0.94 (95 %CI: 0.89-0.99), positive predictive value (PPV) of 0.87 (95 %CI: 0.75-0.98), negative predictive value (NPV) of 0.82 (95 %CI: 0.78-0.87), accuracy of 0.83 (95 %CI: 0.80-0.88), and F1 score of 0.82 (95 %CI: 0.79-0.86) in the discovery cohort, and comparable results in the validation cohort (AUC 0.88 [95 %CI: 0.84-0.93], AUPRC 0.81 [95 %CI: 0.75-0.86], PPV 0.77 [95 %CI: 0.71-0.84], NPV 0.89 [95 %CI: 0.84-0.95], accuracy 0.84 [95 %CI: 0.80-0.89], and F1 score 0.80 [95 %CI: 0.74-0.87]). Decision curve analysis demonstrated consistent net benefits, while Kaplan-Meier analysis indicated significantly shorter OS in the "predict worse outcomes" subgroup. Posttreatment, WBC counts increased and LYMPH% decreased in deceased patients, whereas survivors showed the opposite trends (P < 0.05). These findings suggest that a simple, cost-effective CBC-based machine learning model can effectively predict UC prognosis, aiding clinical decision-making.

PurposeHEC113995PA·H2O is a novel, potent and selective serotonin (5-HT) reuptake inhibitor and a 5-HT1A receptor partial agonist, and thus is categorized as a serotonin partial agonist-reuptake inhibitor. The objective of this study was to evaluate the safety, tolerability, and pharmacokinetics of HEC113995PA·H2O in healthy subjects after single and multiple dosing, as well as the food effect on pharmacokinetics and safety of HEC113995PA·H2O.MethodsThe entire study was comprised of three parts: Part I (single ascending-dose study), Part II (food effect study), and Part III (multiple ascending-dose study). A total of 121 healthy subjects were enrolled in the study. HEC113995PA·H2O tablet or placebo was administered per protocol requirements. Blood samples were collected at the designated time points for pharmacokinetic analysis. Safety was assessed by clinical examinations and adverse events.ResultsIn Part I, AUC and Cmax were found to by and large linear within the 2.5–80 mg dose range. t1/2 of HEC113995PA·H2O was 27.17∼38.58 h. In Part II, we revealed that HEC113995PA·H2O administration post meal could increase Cmax and AUC0-t. In Part III, multiple administration led to accumulated body exposure and the PK of healthy subjects reached a steady state after 7 days of continuous administration in each dose group.ConclusionHEC113995PA·H2O was safe and generally well-tolerated in healthy subjects. Based on the pharmacokinetic and safety data mentioned above, we expect that postprandial administration will favorably increase drug concentrations in the body and reduce gastrointestinal adverse events.

Objective:This Phase I study evaluated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of BGT-002, a novel ATP-citrate lyase (ACLY) inhibitor, in healthy Chinese adults. Methods:This study included three parts: Part I (single-ascending-dose study), Part II (multiple-ascending-dose study), and Part III (food effect study). A total of 104 healthy subjects were enrolled in the study and were given BGT-002 tablet or placebo per protocol requirements. Blood samples were collected for pharmacokinetic and pharmacodynamic analysis. Safety was assessed by clinical examinations and adverse events. Results:In Part I, BGT-002 demonstrated rapid absorption with a Tmax of 0.67 to 1.75 hours, and slow elimination with a T1/2 of 24.53 to 72.86 hours, prolonged with increased dosages. Cmax and AUC0-∞ ranged from 1.55 to 48.39 μg/mL, and 31.09 to 2930.69 h·μg/mL, respectively. In Part II, the accumulation index (Rac) of Cmax and AUCtau following 14 days of consecutive administration were 3.53 to 3.62 and 5.29 to 5.59, respectively, with a dose-proportionality PK profile. The levels of total cholesterol (TC), non-high-density lipoprotein cholesterol (non-HDL-C), and low-density lipoprotein cholesterol (LDL-C) were maximally decreased by 15.80%, 18.50%, and 22.37%, respectively. In Part III, the geometric mean ratio (90% CI) of fed to fasting condition in Cmax and AUC0-∞ of BGT-002 were 73.11% and 98.36%, respectively, indicating a minor food effect on the absorption rate. Across the study, two cases of Grade 3 adverse events (elevated blood triglycerides) were reported, both of which were assessed as not related to BGT-002. No serious adverse events were observed. Conclusion:BGT-002 demonstrated favorable safety, tolerability, and lipid-lowering effects, supporting its potential for further clinical development. Clinical Trial Registration:ChiCTR2200057793(https://www.chictr.org.cn/showproj.html?proj=160210); ChiCTR2300067474(https://www.chictr.org.cn/showproj.html?proj=182183); ChiCTR2300067472(https://www.chictr.org.cn/showproj.html?proj=184079).

Heart failure is the most costly cardiovascular disorder. New treatments are urgently needed. This study aims to evaluate the safety, pharmacokinetics, and pharmacodynamic profile of HEC95468, a soluble guanylate cyclase (sGC) stimulator, in healthy volunteers. Sixty-two, eighteen, and forty-eight participants were enrolled in the single ascending dose (SAD) study, the food effect (FE) study, and the multiple ascending dose (MAD) study, respectively. The study conforms to good clinical practice and the Declaration of Helsinki. Overall, HEC95468 was safe and tolerable; a higher proportion of HEC95468-treated participants reported mild headaches, dizziness, decreased blood pressure, increased heart rate, and gastrointestinal-related treatment-emergent adverse events (TEAEs), similar to the sGC stimulators riociguat and vericiguat. In terms of pharmacokinetic parameters, the maximum observed plasma concentration (Cmax) and the area under the concentration-time curve (AUC0-t) were dose-proportional over the dose range. Moderate accumulation was observed after multiple administrations of HEC95468. Systolic blood pressure (SBP) and diastolic blood pressure decreased, while 3′,5′-cyclic guanosine monophosphate (cGMP) concentration in plasma increased and heart rate was induced. Vasoactive hormones (renin, angiotensin II, and norepinephrine) in plasma were compensatorily elevated after oral administration. These data supported further clinical trials of HEC95468 in the treatment of heart failure and pulmonary arterial hypertension.Systematic Review Registration:http://www.chinadrugtrials.org.cn, identifier CTR20210064.

AbstractThis study evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and food effects (FE) of SC0062, a highly active endothelin‐A (ETA) receptor antagonist, in healthy subjects. The primary objectives of this first‐in‐human phase I study, comprised of single‐ascending‐dose, multiple‐ascending‐dose, and FE parts, were to characterize the safety and tolerability of SC0062, and FE. The secondary objectives were to determine the PK behavior of SC0062 and its major active metabolite M18, whereas exploratory objectives focused on PD effects, principally effects on endothelin‐1 (ET‐1) and total bile acids (TBA). Single doses of 10 to 100 mg and multiple daily doses of 20 and 50 mg for 6 days were well tolerated. SC0062 was rapidly absorbed and plasma exposure of SC0062 and M18 increased disproportionately with dose, achieving steady state by day 3, with accumulation ratios of 1.22 and 1.89 on day 6 for SC0062 and M18, respectively. The geometric mean (geometric standard deviation) terminal elimination half‐life (t1/2) values of SC0062 and M18 were 7.25 (1.70) h and 13.73 (1.32) h, respectively. Plasma ET‐1 concentrations were dose‐proportional, whereas plasma TBA concentrations behaved erratically. Following a single 50 mg dose of SC0062 after a high‐fat meal, Cmax values for SC0062 and M18 increased by 41% and 32%, respectively, and median Tmax values for SC0062 were 3 h longer than fasting values; exposure was unaffected. These favorable safety, PK, and PD results provide a foundation for further studies of SC0062 in pulmonary arterial hypertension, chronic kidney disease, and other relevant indications.

IntroductionAmdizalisib (HMPL-689) is an ATP-competitive PI3Kδ inhibitor currently under investigation for treating Hodgkin’s lymphoma. This study aimed to evaluate the metabolism, excretion, pharmacokinetics, and safety profile of amdizalisib in healthy human subjects to support its clinical application.MethodsThis Phase I clinical trial included six healthy Chinese male volunteers who received a single oral dose of 30 mg/100 µCi [14C]amdizalisib suspension. Blood, urine, and fecal samples were collected to analyze pharmacokinetics, metabolic pathways, and excretion patterns.ResultsAmdizalisib was rapidly absorbed, with a median Tmax of 2.5 h. The Cmax of 244 ± 48.9 ng/mL, and AUC0-t was 1870 ± 474 h ng/mL after a single oral dose. The blood-to-plasma total radioactivity ratio ranged from 0.561 to 0.645, indicating no significant affinity of [14C]amdizalisib and its metabolites to blood cells and the radioactive material is mainly distributed in plasma. Excretion was primarily via feces and urine, with 62.08% ± 3.00% and 37.15% ± 2.84% of the dose recovered, respectively, and over 94% of the drug excreted within 96 h. The parent drug was the main radioactive component in plasma (51.45% of total radioactivity). Additionally, 11 metabolites were identified, and the metabolic pathways include oxidation on the benzene or pyrimidine rings and conjugation with cysteine or glucuronic acid. The major metabolites in plasma were the di-oxidized and hydrogenated product (M424) and the mono-oxidized product (M406-2), accounting for 16.67% and 20.91%, respectively. Both of them are also the major radioactive components in urine and feces, among of which M424 accounted for 21.01% and 14.26%, M406-2 accounted for 8.08% and 11.30%, of the administered dose in urine and feces, respectively. In addition, the di-oxidized and methylated product (M436) was one of the major metabolites in feces accounting for 17.7% of the administered dose. Few of the parent drug was found in urine and feces, suggesting primary metabolized in the liver. No serious adverse events or drug-related deaths occured, with diarrhea as the most common adverse event.DiscussionThese findings demonstrate that amdizalisib is rapidly absorbed, extensively metabolized, and primarily excreted via feces and urine, supporting its continued development as a potential therapeutic for Hodgkin's lymphoma.Systematic Review Registration:https://www.chinadrugtrials.org.cn/, identifier CTR20212448.

AIMS:This study aimed to assess the safety, pharmacokinetics and pharmacodynamics of noiiglutide (SHR20004), a novel glucagon-like peptide-1 receptor agonist, in Chinese obese participants without diabetes mellitus (DM). MATERIALS AND METHODS:This phase 1, randomised, double-blind, placebo-controlled study enrolled adult participants with body mass index (BMI) ≥28 kg/m2. The study used a titration method, each subject received daily noiiglutide injection for 3-6 weeks, until reaching the final dose of 0.18, 0.24, 0.30 or 0.36 mg per day. Each dose group consisted of 10 participants, with eight receiving noiiglutide and two receiving placebos. Safety assessments were conducted throughout the study, and pharmacokinetics and pharmacodynamics were evaluated. RESULTS:Most treatment-emergent adverse events were of mild to moderate in severity, with no serious adverse event or adverse event led to withdraw. Blood concentration of noiiglutide reached a steady state after daily administration for 4 days, with no significant accumulation. Mean elimination half-life (t1/2) was between 9.90 and 11.8 h at steady state. At the end of treatment, the mean weight loss compared to baseline for the placebo group and each treatment group was -1.89, -3.26, -5.45, -4.35 and -7.46 kg respectively. The weight and BMI reductions observed in each noiiglutide treatment group were greater than those in the placebo group and exhibited an increasing trend with extended administration duration. CONCLUSIONS:Daily administration of noiiglutide using a titration method was well tolerated by Chinese obese participants without DM and showed potential therapeutic effect for weight loss.

Purpose: Henagliflozin is an original, selective sodium-glucose cotransporter 2 (SGLT2) inhibitor. Hydrochlorothiazide (HCTZ) is a common anti-hypertensive drug. This study aimed to evaluate the potential interaction between henagliflozin and HCTZ. Methods: This was a single-arm, open-label, multi-dose, three-period study that was conducted in healthy Chinese volunteers. Twelve subjects were treated in three periods, period 1: 25 mg HCTZ for four days, period 2: 10 mg henagliflozin for four days and period 3: 25 mg HCTZ + 10 mg henagliflozin for four days. Blood samples and urine samples were collected before and up to 24 hours after drug administrations on day 4, day 10 and day 14. The plasma concentrations of henagliflozin and HCTZ were analyzed using LC-MS /MS. The urine samples were collected for pharmacodynamic glucose and electrolyte analyses. Tolerability was also evaluated. Results: The 90% CI of the ratio of geometric means (combination: monotherapy) for AUC tau,ss of henagliflozin and HCTZ was within the bioequivalence interval of 0.80-1.25. For henagliflozin, co-administration increased Css, max by 24.32% and the 90% CI of the GMR was (108.34%, 142.65%), and the 24-hour urine volume and glucose excretion decreased by 0.43% and 19.6%, respectively. For HCTZ, co-administration decreased Css, max by 19.41% and the 90% CI of the GMR was (71.60%, 90.72%), and the 24-hour urine volume and urinary calcium, potassium, phosphorus, chloride, and sodium excretion decreased by 11.7%, 20.8%, 11.8%, 11.9%, 22.0% and 15.5%, respectively. All subjects (12/12) reported adverse events (AEs), but the majority of theses AEs were mild and no serious AEs were reported. Conclusion: Although Css,max was affected by the combination of henagliflozin and HCTZ, there was no clinically meaningful safety interaction between them. Given these results, coadministration of HCTZ should not require any adaptation of henagliflozin dosing. sodium-glucose cotransporter 2