Safety, tolerability, pharmacokinetics, and pharmacodynamics of TG103 injection in participants who are overweight or obese: a randomized, double-blind, placebo-controlled, multiple-dose phase 1b study.

BACKGROUND: TG103, a glucagon-like peptide-1 analog, is being investigated as an option for weight management. We aimed to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of TG103 injection in participants who are overweight or obese without diabetes. METHODS: In this randomized, double-blind, placebo-controlled, multiple-dose phase 1b study, participants aged 18-75 years with a body-mass index (BMI) ≥ 26.0 kg/m2 and body weight ≥ 60 kg were enrolled from three centers in China. The study included three cohorts, and in each cohort, eligible participants were randomly assigned (3:1) to one of three once-weekly subcutaneous TG103 groups (15.0, 22.5 and 30.0 mg) or matched placebo, without lifestyle interventions. In each cohort, the doses of TG103 were escalated in 1-week intervals to the desired dose over 1 to 4 weeks. Then participants were treated at the target dose until week 12 and then followed up for 2 weeks. The primary endpoint was safety and tolerability assessed by the incidence and severity of adverse events (AEs) from baseline to the end of the follow-up period. Secondary endpoints included pharmacokinetic and pharmacodynamic profiles of TG103 and the occurrence of anti-drug antibodies to TG103. RESULTS: A total of 147 participants were screened, and 48 participants were randomly assigned to TG103 (15.0, 22.5 and 30.0 mg groups, n = 12 per group) or placebo (n = 12). The mean (standard deviation, SD) age of the participants was 33.9 (10.0) years; the mean bodyweight was 81.65 (10.50) kg, and the mean BMI was 29.8 (2.5) kg/m2. A total of 466 AEs occurred in 45 of the 48 participants, with 35 (97.2%) in the TG103 group and 10 (83.3%) in the pooled placebo group. Most AEs were grade 1 or 2 in severity, and there were no serious adverse events (SAEs), AEs leading to death, or AEs leading to discontinuation of treatment. The steady-state exposure of TG103 increased with increasing dose and was proportional to Cmax,ss, AUCss, AUC0-t and AUC0-inf. The mean values of Cmax,ss ranged from 951 to 1690 ng/mL, AUC0-t ranged from 150 to 321 µg*h/mL, and AUC0-inf ranged from 159 to 340 µg*h/mL. TG103 had a half-life of 110-116 h, with a median Tmax of 36-48 h. After treatment for 12 weeks, the mean (SD) values of weight loss from baseline in the TG103 15.0 mg, 22.5 mg and 30.0 mg groups were 5.65 (3.30) kg, 5.35 (3.39) kg and 5.13 (2.56) kg, respectively, and that in the placebo group was 1.37 (2.13) kg. The least square mean percent weight loss from baseline to D85 in all the TG103 groups was more than 5% with p < 0.05 for all comparisons with placebo. CONCLUSIONS: In this trial, all three doses of once-weekly TG103 were well tolerated with an acceptable safety profile. TG103 demonstrated preliminary 12-week body weight loss without lifestyle interventions, thus showing great potential for the treatment of overweight and obesity. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04855292. Registered on April 22, 2021.

The randomized, single- and multiple- ascending dose studies of the safety, tolerability, pharmacokinetics of CSPCHA115 in healthy Chinese subjects.

CSPCHA115 is a highly selective and potent antagonist of chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2). This study aimed to evaluate the pharmacokinetics (PKs), safety, and tolerability of single and multiple ascending doses of CSPCHA115 in Chinese healthy subjects. Two phase I studies both adopted a randomized, double-blind, placebo-controlled, single-center, and ascending-dose design. In the single ascending dose (SAD) study, subjects were randomly allocated to receive a single dose of CSPCHA115 (25-1000 mg) or a placebo. In the multiple ascending dose (MAD) study, 100, 200, 400, or 600 mg of CSPCHA115 or placebo were given to subjects once daily for 7 days. PK parameters were estimated by noncompartmental analysis. Safety was assessed by monitoring treatment-emergent adverse events (TEAEs), clinical laboratory tests, electrocardiograms, vital signs, and physical examinations throughout the study period. Forty-eight healthy subjects were enrolled in the SAD study, and 40 healthy subjects were in the MAD study. Following single and multiple administrations, CSPCHA115 was rapidly absorbed with a median time to maximum concentration of ~0.5-3.5 h; and the systemic exposure of CSPCHA115 generally increased dose-proportionally within the dose range studied. Steady-state was approximately achieved by day 5, and <1.5-fold accumulation was observed following multiple doses. Mean terminal half-life was ~8.16-16.43 h after a single dose. CSPCHA115 was well-tolerated in both studies, with a low overall incidence of TEAEs. The most common TEAE related to CSPCHA115 was hypertriglyceridemia. No significant safety concerns were identified in healthy subjects.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of SPH3127: A Phase I, Randomized, Double-Blind, Placebo-Controlled Trial.

PURPOSE: To evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of single- and multiple-dose SPH3127 in healthy individuals. METHODS: This was a randomized, double-blind, placebo-controlled, Phase I dose-escalation study. FINDINGS: SPH3127 exposure, expressed as Cmax, AUC0-t, and AUC0-∞, was proportionally increased with dose for a range of 25-800 mg (single ascending dose [SAD]) and 100-400 mg daily (multiple ascending doses [MADs]). In an SAD, the Cmax values with 25, 50, 100, 200, 400, and 800 mg of SPH3127 were 90.67, 344.50, 523.50, 1239.50, 2445.00, and 5753.33 ng/mL, respectively. The corresponding AUC0-t values were 294.48, 843.62, 1109.33, 2858.56, 6697.50, and 13057.83 h × ng/mL. In MADs, after the first dose of SPH3127, the Cmax values with 100, 200, and 400 mg of SPH3127 were 421.50, 969.00, and 2468.33 ng/mL, respectively. The corresponding AUC0-t values were 1279.28, 2275.77, and 5934.26 h × ng/mL. At steady state, the Cmax values with 100, 200, and 400 mg of SPH3127 were 514.67, 1419.17, and 2513.33 ng/mL, respectively. The corresponding AUC0-24 values were 1638.14, 3096.20, and 7577.70 h × ng/mL. The median Tmax range from 0.33 to 1.0 h and the median t1/2 from 3 to 4 h. In an SAD, when the dose was >100 mg, plasma renin activity inhibition of up to 90% lasted up to 24 h. In MADs, renin activity was continuously inhibited by up to 90% in each group for 24 h after the last administration. Treatment-emergent adverse events (AEs) were reported in 29.2% of individuals receiving the SAD and 33.3% of those receiving MADs. Only mild adverse events occurred. IMPLICATIONS: SPH3127 was well tolerated and had robust and sustained suppression of plasma renin activity. CLINICALTRIALS. GOV IDENTIFIERS: NCT03128138 (SAD study) and NCT03255993 (MAD study).

Pharmacokinetics and Pharmacodynamics of Esomeprazole/Sodium Bicarbonate Immediate-Release Capsules in Healthy Chinese Volunteers: A Cross-Over, Randomized Controlled Trial.

INTRODUCTION: Esomeprazole delayed release tablets (ESO) are one of the most effective treatments for acid-related disorders. The purpose of this study is to compare the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of an immediate-release capsule formulation containing esomeprazole 20 mg and sodium bicarbonate 1100 mg (IR-ESO) compared to those of the esomeprazole delayed release tablet 20 mg (ESO). In addition, the impact of CYP2C19 gene polymorphisms on PK and PD was evaluated. METHODS: A single-center, open-label, randomized, 2-treatment, 2-sequence, and 2-period crossover study was conducted in 40 healthy Chinese subjects. Subjects received either IR-ESO or ESO for 5 days. After single- and multiple-dosing administration, blood samples were collected for PK analysis, and intragastric pH was assessed by 24-h pH monitoring. The CYP2C19 gene polymorphisms were analyzed by Sanger sequencing. RESULTS: The geometric mean ratios (90% confidence interval) [GMR (95%CI)] of IR-ESO/ESO for AUCinf [single dose: 103.60% (96.58%, 111.14%), multiple doses: 101.65% (97.88%, 105.57%)] were within the range of 80.00-125.00%. The AUCinf showed an increasing trend between CYP2C19 extensive metabolizer (EM), intermediate metabolizer (IM), and poor metabolizer (PM) after single-dose and multiple-dose administration (p < 0.05). The GMR (95%CI) of IR-ESO/ESO for 24-h integrated gastric acidity from baseline [single dose: 101.07% (96.56%, 105.78%), multiple doses: 101.24% (97.74%, 104.86%)] were within the range of 80.00-125.00%. The percentage changes in 24-h integrated gastric acidity from baseline was significant difference between EM, IM, and PM after single-dose IR-ESO and ESO (p < 0.05). Drugs were all well tolerated, and there were no significant differences in adverse events between IR-ESO and ESO. CONCLUSION: This study showed that IR-ESO can inhibit the secretion of gastric acid rapidly and continuously, and that the PK and PD of IR-ESO are affected by CYP2C19 genotypes. The GMR (95% CI) of IR-ESO/ESO for AUCinf and the percentage changes in 24-h integrated gastric acidity from baseline were all within the range of 80.00-125.00%. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR1900024935.

Time-Course of the Effects of QSYQ in Promoting Heart Function in Ameroid Constrictor-Induced Myocardial Ischemia Pigs.

We aim to investigate the therapeutic effects of QSYQ on a pig myocardial ischemia (MI) model and to determine its mechanism of action. The MI model was induced by Ameroid constriction of the left anterior descending coronary (LAD) in Ba-Ma miniature pigs. Four groups were created: model group, digoxin group, QSYQ group, and sham-operated group. Heart function, Ang II, CGMP, TXB2, BNP, and cTnT were evaluated before (3 weeks after operation: 0 weeks) and at 2, 4, and 8 weeks after drug administration. After 8 weeks of administration, the pigs were sacrificed for cardiac injury measurements. Pigs with MI showed obvious histological changes, including BNP, cTnT, Ang II, CGRP, TXB2, and ET, deregulated heart function, and increased levels of apoptotic cells in myocardial tissue. Treatment with QSYQ improved cardiac remodeling by counteracting those events. The administration of QSYQ was accompanied by a restoration of heart function and of the levels of Ang II, CGRP, TXB2, ET BNP, and cTnT. In addition, QSYQ attenuated administration, reduced the apoptosis, and decreased the level of TNF- α and active caspase-3. In conclusion, administration of QSYQ could attenuate Ameroid constrictor induced myocardial ischemia, and TNF- α and active caspase-3 seemed to be the critical potential target of QSYQ.

Pharmacokinetics of pilsicainide hydrochloride for injection in healthy Chinese volunteers: a randomized, parallel-group, open-label, single-dose study.

BACKGROUND: Pilsicainide hydrochloride is a class IC antiarrhythmic agent used for the treatment of supraventricular and ventricular arrhythmias and atrial fibrillation. OBJECTIVE: The objective of the present study was to determine the pharmacokinetics (PK) of a pilsicainide hydrochloride injection in healthy Chinese adults. The study was conducted to meet China State Food and Drug Administration requirements for the marketing of the new generic formulation of pilsicainide hydrochloride. METHODS: This Phase I, randomized, parallel-group, open-label, single-dose PK study was conducted in healthy Chinese volunteers. Subjects were randomized to receive a single dose of 0.25-, 0.50-, and 0.75-mg/kg pilsicainide hydrochloride with a 10-minute intravenous infusion. Serial blood and urine samples were collected up to 24 hours after dosing; drug concentrations in plasma and urine were then determined by using LC-MS/MS. The PK parameters of pilsicainide were calculated from the plasma concentration-time data according to noncompartmental methods. Safety profile was evaluated by monitoring adverse events, clinical laboratory parameters, and the results of 12-lead ECGs. RESULTS: Thirty healthy volunteers (mean [SD] age, 28.0 [4.95] years; weight, 59.3 [6.51] kg; height, 165.0 [7.25] cm; body mass index, 21.7 [1.94] kg/m(2)) were randomly divided into 3 groups, each consisting of 5 men and 5 women. After single-dose intravenous administration of 0.25, 0.50, and 0.75 mg/kg of pilsicainide hydrochloride, mean Cmax was 0.34 (0.11), 0.54 (0.15), and 1.05 (0.19) µg/mL, respectively; AUC0-24 was 0.76 (0.12), 1.61 (0.37), and 2.61 (0.46) h · µg/mL; and AUC0-∞ was 0.79 (0.13), 1.71 (0.46), and 2.72 (0.50) h · µg/mL. The ranges for t½z, CL, and Vz were 5.19 to 5.98 hours, 4.73 to 5.44 mL/min/kg, and 2.23 to 0.58 L/kg, respectively. The mean urinary recovery rate within 24 hours was 75.0% (12.0%), 65.0% (19.2%), and 66.4% (14.1%). Men and women had significantly different AUC0-24 values in the 0.50-mg/kg dose group (P = 0.044), and Vz showed significant differences between men and women in all 3 dose groups (P = 0.001). According to ECG parameters, PR intervals were significantly prolonged after administration at all 3 doses (P = 0.034, P < 0.001, and P = 0.034); no significant changes were seen in QRS width, QTc interval, or other parameters. CONCLUSIONS: Pilsicainide hydrochloride demonstrated linear PK, and the increase in the exposure of pilsicainide (AUC0-24 and AUC0-∞) was dose proportional after single doses of 0.25, 0.50, and 0.75 mg/kg. All 3 pilsicainide hydrochloride doses were well tolerated in these Chinese volunteers. ChiCTR-ONC-13003546.

[Pharmacokinetics and bioequivalence of domestic trimetazidine formulations].

OBJECTIVE: To compare the pharmacokinetics and bioequivalence between domestic hydrochloric trimetazidine capsules and imported hydrochloric trimetazidine tablets in healthy male Chinese volunteers after single oral administration. METHODS: A single oral dose (test and reference formulations) was given to 24 healthy male Chinese subjects according to an open randomized crossover design. The blood samples were collected before and after administration. Plasma trimetazidine concentration was determined by HPLC-MS/MS. The pharmacokinetic parameters were calculated by WinNonlin Ver 6.2.1 software. RESULTS: The main pharmacokinetic parameters of domestic and imported formulation of trimetazidine were similar: C(max) (70.9 ± 15.3), (66.4 ± 13.8) µg/ml; t(max) (1.70 ± 0.72), (1.85 ± 0.55) h; t(1/2z) (4.70 ± 1.75), (4.77 ± 1.96) h; AUC(0-24 h) (481 ± 176), (469 ± 171) µg×h×ml(-1); AUC(0-∞) (511 ± 189), (500 ± 188) µg×h×ml(-1). The estimated 90% CIs for the ratio of C(max) and AUC(0-24 h) were also similar: 101.9% - 112.5% and 99.4% - 104.9%. The relative bioavailability of domestic formulation was (102.2 ± 8.3)%. CONCLUSION: The results demonstrates that the domestic hydrochloric trimetazidine capsules and imported hydrochloric trimetazidine tablets are bioequivalent.