Background: The cap-snatching mechanism of influenza virus mRNA transcription is strongly suppressed by TG-1000, a prodrug rapidly metabolized into TG-0527, is a potent cap-dependent nucleic acid endonuclease inhibitor. Herein, we aimed to assess the safety, tolerability, and pharmacokinetics of TG-1000 in healthy participants and the effect of food on the pharmacokinetics and safety of TG-1000.Method: The study was divided into 2 parts: Part A [Single Ascending-Dose (SAD) study, 10–160 mg] and Part B [Food-Effect (FE) study, 40 mg] were launched sequentially. The study included 66 participants for both investigations. We administered different TG-1000 capsules or placebo doses per the study protocol and collected blood samples for pharmacokinetic assessments at specific times. In plasma, TG-1000 and its active metabolite TG-0527 were assayed, and PK parameters were determined.Results: In SAD, the increase in AUC was less than the proportional increase in dose over the 20–160 mg dose range, while the increase in C_max was proportional to the increase in dose. In the 10–160 mg dose range, T_1/2, λz and T_max of TG-0527 were dose-independent; and T_1/2 and T_max were within 33.8–39.4 h and 3.02–6 h, respectively. In FE, the AUC_0-inf, AUC_0-last, and C_max of TG-0527 decreased by approximately 17.52%, 18.76%, and 41.35%, respectively, and the T_max delay was around 1.50 h. No serious adverse events occurred during the studies.Conclusion: Overall, TG-1000 was well tolerated and exhibited an acceptable safety and PK profile, supporting further clinical investigation of TG-1000 for the treatment of influenza.

Objective: To explore a method for evaluating the bioequivalence of acarbose based on pharmacodynamic parameters using a single-dose, randomized-sequence, three-way crossover study of acarbose test (T) and reference (R) formulations. Methods: Baseline-adjusted, pre-dose value deduction, and direct comparison methods were used to evaluate the geometric T/R ratios and 90% confidence intervals (CIs) of the ln-transformed pharmacodynamic parameters to identify the most suitable evaluation system. Twelve participants were randomly divided into three groups to receive treatment in the following sequences: TRR, RTR, and RRT, each including a 7-day washout period between treatment periods. The serum glucose concentration (baseline) was determined. Pharmacodynamic parameters, including the maximum reduction in serum glucose concentrations (ΔC_SG,max) and difference of the AUC of glucose between before and after acarbose exposure (ΔAUEC), were tested. Results: Using the direct comparison method, the geometric mean ratios of C_SG,max, AUEC_(0-2h), and AUEC_(0-4h) were 94.13%, 97.82% and 99.76%, respectively. The 90% CIs of the geometric T/R ratios for C_SG,max, AUEC_(0-2h), and AUEC_(0-4h) all fell between 80% and 125%. Conversely, ΔC_SG,max and ΔAUEC_(0-4h) were less reliable measures of acarbose bioequivalence. Conclusions: Pre-dose value deduction and direct comparison methods can be initially considered suitable for assessing acarbose bioequivalence.

Aims: To investigate the potential pharmacokinetic interactions of montmorillonite powder or loperamide on pyrotinib.Methods: This study was a single-center, open-label, single-dose, fixed-sequence clinical trial conducted with healthy volunteers. The participants were divided into two groups (A and B), each consisting of 18 subjects. Both groups received a single oral dose of 400 mg of pyrotinib on day 1. On day 9, Group A received a single dose of 400 mg of pyrotinib followed by 3 g of montmorillonite powder 2 h later, while Group B received a single dose of pyrotinib and 4 mg of loperamide after breakfast on day 9, followed by single oral doses of 2 mg of loperamide at 2 and 4 h post-administration. Blood samples were collected to determine pyrotinib blood concentrations.Results: In Group A, the combination treatment with montmorillonite powder resulted in a decrease in C_max, AUC_0-t, and AUC_0-∞ by 26.7%, 33.1%, and 32.4%, respectively, compared to pyrotinib alone. In Group B, the combination treatment with loperamide had minimal impact on pyrotinib’s absorption rate but slightly increased AUC_0-t and AUC_0-∞ by approximately 18% and 19%, respectively, while decreasing CL/F and prolonging the t_1/2.Conclusion: Even when montmorillonite powder was administered 2 h after pyrotinib dosing, it still reduced systemic exposure of pyrotinib by 32.4% in AUC_0-∞. In contrast, loperamide increased pyrotinib exposure by 19% in AUC_0-∞ when used together. Based on these findings, loperamide is recommended for symptom control, while montmorillonite powder should not be co-administered with pyrotinib or any drug requiring optimal absorption.Clinical trial registration: [ClinicalTrials.gov], identifier [NCT05252546].