Contezolid acefosamil (also known as MRX-4), a prodrug of contezolid, is under development for treatment of multidrug-resistant Gram-positive bacterial infections. A phase I single ascending dose (SAD) and multiple-dose placebo-controlled study was conducted to assess the safety, tolerability, and pharmacokinetics (PK) of contezolid acefosamil in healthy Chinese subjects following intravenous (IV) and oral administration. Adverse events (AEs) and PK parameters were assessed appropriately. All subjects ( n = 70) completed the trial. Overall, 67 cases of treatment-emergent adverse events (TEAEs) were observed in 49.1% (27 of 55) of the subjects receiving contezolid acefosamil. All TEAEs were mild in severity. No serious AEs or deaths were reported. After IV SAD (500–2,000 mg), the corresponding C _max of the active drug contezolid increased from 1.95 ± 0.57 to 15.61 ± 4.88 mg/L, AUC _0–inf from 40.25 ± 10.12 to 129.41 ± 38.30 h·mg/L, median T _max from 2.00 to 2.75 h, and mean t _1/2 from 13.33 to 16.74 h. Plasma contezolid reached steady state on day 6 after multiple IV doses, with an accumulation ratio of 2.20–2.96. Oral SAD of 500 and 1,500 mg resulted in contezolid C _max of 8.66 ± 2.60 and 37.10 ± 8.66 mg/L, AUC _0–inf of 30.44 ± 7.33 and 162.36 ± 47.08 h·mg/L, and median T _max of 2.50 and 2.98 h. Contezolid reached steady state on day 5 after multiple oral doses of 1,500 mg without significant accumulation. Contezolid C _max and AUC _0–inf increased with the dose of contezolid acefosamil. The good safety and PK profiles in this SAD and multiple-dose study can support further clinical development of contezolid acefosamil.

Background. The HS016 is an adalimumab biosimilar related to the immunoglobulin G1 (IgG1) antibody, with a similar amino acid sequence. Objectives. To quantify the differences in the pharmacokinetic (PK) parameters of HS016 and adalimumab in healthy individuals and patients with ankylosing spondylitis (AS). Materials and methods. The PK data for HS016 and adalimumab were obtained in a randomized, doubleblind, phase 1 clinical study in Chinese healthy subjects after a single-dose subcutaneous administration (136 healthy subjects), and in a randomized, double-blind, phase 3 trial of AS patients who received subcutaneous injection of HS016 or adalimumab once every 2 weeks for 24 weeks (366 AS patients). Results. The time course of HS016 and adalimumab was characterized by a one-compartment model with firstorder absorption and elimination kinetics. Age, body weight, creatinine clearance (CLcr) and anti-drug antibody were covariates for the apparent clearance (CL/F); body weight and subject type were significant covariates for the apparent volume of distribution (V/F). The V/F and CL/F were estimated at 11.3 L and 0.0102 L/h. The ratios of the geometric least square (LS) means (HS016 compared to the adalimumab treatment group after multiple doses) in healthy subjects were 97.14 (87.70, 107.59) for the concentration-time curve from time zero to the last measurable concentration (AUC(0-t)) and 99.14 (90.03, 109.16) for the maximum serum drug concentration within a steady-state dosing interval (C-max,C-ss); the ratios (90% confidence interval (90% CI)) in AS patients were 97.03 [84.10; 111.96] for the AUC within the steady-state dose intervals (AUC(0-tau)) and 99.62 [88.09; 112.68] for C-max,C- ss. Conclusions. The systemic exposure of HS016 was similar to that of adalimumab in healthy subjects and AS patients, demonstrating PK similarity.

Background: pGX9501 is a prophylactic DNA vaccine encoding the spike protein of SARS-CoV-2 and can induce immune response in the human body so as to prevent COVID-19. With respect to non-clinical studies, pGX9501 has been demonstrated to induce both cellular and humoral immune responses in various animal models. It was found that the level of antibody titers following a two-dose regimen was higher than that following a single-dose regimen in nonhuman primate challenge model. Methods: In China, a phase I, randomized, double-blind, placebo-controlled clinical trial has been conducted in Huashan Hospital, Shanghai, China to evaluate the safety, tolerability, and immunogenicity of DNA vaccine pGX9501 administered intradermally (ID) followed by electroporation (EP) in 45 Chinese healthy volunteers aged 18 to 59 years old. Results: No adverse events of special interest (AESIs), death, or treatment-related SAEs occurred in this study. All the treatment-related (vaccine or EP) adverse events (TRAEs) were of grade 1 and 2 in severity. The solicited AEs were reported in thirty-two (32/36, 88.9%) and nine (9/9, 100.0%) subjects, respectively, in the DNA vaccine and placebo group. The frequency of solicited AEs did not increase with vaccine dose level and frequency. The DNA vaccine pGX9501 effectively enhanced both humoral and cellular immune responses in a dose-dependent manner, with increased antibody GMTs and peak seroconversion rates observed on day 42. The significant rise in IFN-γ levels confirmed the vaccine’s ability to induce cellular immune responses. Variations in the microbiome structure suggested a tangible impact of the gut microbiota on vaccine immunogenicity. Conclusions: The findings from this study confirm the immunogenicity and safety of the DNA vaccine pGX9501 and point to the potential role of the gut microbiota in vaccine immune responses. These insights provide practical references for the future design and development of DNA vaccines.

Mesalazine is a well-established treatment for ulcerative colitis by oral or topical administration. However, the pharmacokinetic (PK) and safety profiles of mesalazine administered by an enema has not been clarified in Chinese population. We conducted an open-label study to assess the PK and safety profiles of mesalazine in 11 healthy Chinese subjects after receiving mesalazine enema (1 g/100 mL) once daily for 7 consecutive days. Blood and urine samples were collected for assay of mesalazine and N-acetyl mesalazine by liquid chromatography-tandem mass spectrometry. The PK and safety data were summarized using descriptive statistics. The mean (standard deviation) maximum plasma concentration (C_max), area under plasma drug concentration-time curve from time 0 to the last measurable plasma concentration time point (AUC_0-t) and elimination half-life (t_1/2) of mesalazine were 1007.64 (369.00) ng/mL, 9608.59 (3533.08) h·ng/mL and 3.33 (1.99) h, respectively after the first dose administration. In multiple-dose study, the estimated accumulation factor of mesalazine was 1.09. The cumulative urinary excretion rate of parent and major metabolite of mesalazine was 27.77%. After the last doe administration, 2.21% of the administered dose was excreted as mesalazine and 24.47% as N-acetyl mesalazine in urine within 24 h. Overall, 9 adverse events (AEs) were reported in 4 of the 11 subjects (36.4%), including oral ulcer, toothache, upper respiratory tract infection (1 each) and laboratory abnormalities (6 cases). All AEs were mild and recovered spontaneously without treatment, and were not considered as related to mesalazine. Mesalazine enema (1 g/100 mL) was safe and well tolerated in healthy Chinese subjects. These findings support further clinical trials in Chinese patients. Trial registration: This trial was registered to Chinese Clinical Trial Registry (ChiCTR) at https://www.chictr.org.cn (registration number: ChiCTR2300073148).