ABSTRACT Contezolid is a novel oxazolidinone antibiotic for the treatment of gram-positive bacteria, which are one of the most common pathogens of pneumonia. We conducted a prospective, single-center, open-label study to evaluate the clinical and microbiological efficacy, safety profile, and pulmonary epithelial lining fluid (ELF) penetration characteristics of contezolid in adult pneumonia patients. Sparse blood samples and bronchoalveolar lavage fluid samples were collected from patients after multiple oral doses of 800 mg of contezolid twice a day. Pharmacokinetic parameters were calculated by developing population pharmacokinetic (PopPK) modeling, and probability of target attainment was evaluated by Monte Carlo simulations. The study enrolled 15 patients (mean age 55 years) with primarily community-acquired pneumonia. Contezolid achieved a clinical cure rate of 80.0% and a bacterial clearance rate of 71.4%. Oral contezolid was well tolerated, and no drug-related adverse effects were observed in any of the subjects. The mean area under the concentration-time curve (AUC ₀–₁₂,ss ) was estimated by the PopPK model to be 33.06 mg·h/L in ELF and 71.95 mg·h/L in plasma. Assuming a plasma protein binding rate of 90% based on literature data, the ELF-to-free plasma AUC 0–12,ss ratio was 4.50. When the minimum inhibitory concentration was ≤4 mg/L, 800 mg of contezolid q12h could achieve the optimal therapeutic target in the plasma of patients with pneumonia. This study demonstrates that contezolid achieved excellent pulmonary penetration in adult patients with pneumonia.

OBJECTIVES:Cefoperazone-sulbactam, a β-lactam/β-lactamase inhibitor combination, is widely used against ESBL-producing Gram-negative pathogens. This study investigated the in vivo pharmacokinetics/pharmacodynamics (PK/PD) of 1:1 and 2:1 cefoperazone-sulbactam formulations in neutropenic murine thigh and lung infection models. METHODS:Eleven ESBL-producing Gram-negative isolates with varying MICs were used to establish murine thigh and lung infection models. The plasma and epithelial lining fluid (ELF) pharmacokinetics of cefoperazone and sulbactam were evaluated over a wide dose range. Five dose-fractionation experiments were conducted to identify the PK/PD index most correlated with efficacy, and dose-escalation to determine PK/PD targets. RESULTS:All isolates exhibited cefoperazone MICs ≥ 64 mg/L, reduced by 8- to 16-fold by sulbactam at a 1:1 or 2:1 ratio. Cefoperazone and sulbactam showed linear pharmacokinetics across the dose range, well described by a two-compartmental model. Plasma protein binding was 57% for cefoperazone and 3% for sulbactam. ELF penetration was 0.12 for cefoperazone and 0.21 for sulbactam, which were used to determine the ELF-based targets. PK/PD targets reflecting the primary active component against each pathogen were reported. Cefoperazone %fT > MIC was used as the PK/PD index for E. coli and K. pneumoniae, the magnitude for 1-log10 cfu bacterial reduction was 50.3% (1:1) and 51.3% (2:1) in the thigh infection model, 52.4% (1:1) and 75.6% (2:1) in the lung infection model. For A. baumannii, sulbactam was identified as the primary active component, and the 1-log10 cfu %fT > MIC target for sulbactam was 68.7%. CONCLUSIONS:Cefoperazone-sulbactam demonstrated strong in vivo antibacterial activity against the 11 tested isolates. This study established PK/PD targets under varied conditions, providing a valuable foundation for optimizing the clinical application of cefoperazone-sulbactam.

BackgroundMeropenem-vaborbactam is a fixed-dose β-lactam/β-lactamase inhibitor combination active against carbapenem-resistant Enterobacterales (CRE), especially Klebsiella pneumoniae carbapenemase (KPC)-producing CRE. This study evaluated its pharmacokinetics (PK), safety, and tolerability in Chinese participants, and performed population pharmacokinetics/pharmacodynamics (PK/PD) analysis using in vitro data to assess the suitability of the standard dosing regimen for treating CRE infections in China.MethodsThis single-center, open-label study included 20 healthy participants divided into two groups receiving meropenem-vaborbactam (1:1) at 1 g/1 g or 2 g/2 g via 3-h infusion. Plasma and urine concentrations of meropenem, its open-ring metabolite, and vaborbactam were analyzed using a validated liquid chromatography-tandem mass spectrometry method. PK analysis was conducted using WinNonlin. Monte Carlo simulations were used to evaluate the 1 g/1 g and 2 g/2 g regimens administered every 8 h as 3-h intravenous infusions. For the standard 2 g/2 g regimen, the impact of extending the infusion duration from 3 to 4 h was further evaluated based on the FDA-recommended PK/PD target.ResultsPlasma concentrations of meropenem, its open-ring metabolite, and vaborbactam peaked immediately after infusion, with rapid distribution and elimination. Exposure increased proportionally with dose, and almost no accumulation was observed after repeated 8-hourly dosing. Most meropenem (68.5%–77.0%) and nearly all vaborbactam were excreted unchanged in urine. Both single and multiple doses were well tolerated, with no severe or serious adverse events. In addition, PK/PD analysis showed that, for CRE isolates, the standard 2 g/2 g every 8 h regimen with a 3-h intravenous infusion achieved ≥90% probability of target attainment for meropenem (45% fT > MIC) at MIC values up to 8 mg/L. The corresponding cumulative fraction of response ranged from 98.67 to 100% across ESBL-producing and KPC-producing Enterobacterales, including blaKPC variants resistant to ceftazidime-avibactam.ConclusionThe standard meropenem-vaborbactam regimen (2 g/2 g every 8 h, 3-h intravenous infusion) demonstrated favorable PK and safety profiles, with PK/PD analyses supporting the appropriateness of the standard regimen in Chinese participants, consistent with global findings. These results provide PK/PD support for the standard regimen and warrant further evaluation in Chinese patients with CRE infections.

OBJECTIVES:To characterize the pulmonary pharmacokinetics (PK), safety, and exploratory efficacy of eravacycline in critically ill patients with hospital-acquired or ventilator-associated pneumonia (HAP/VAP) caused by carbapenem-resistant pathogens. METHODS:In this prospective, single-center, open-label study, 16 critically ill adults with HAP/VAP caused by carbapenem-resistant Acinetobacter baumannii (CRAB) or carbapenem-resistant Enterobacterales (CRE) received intravenous eravacycline (1 mg/kg every 12 h) for 7-14 days. Plasma and epithelial lining fluid (ELF) PK were assessed at steady state. Pulmonary penetration was evaluated using the ELF-to-plasma AUC0-12h ratio. Safety and exploratory efficacy were assessed at end of therapy (EOT). RESULTS:Sixteen patients were included (13/16 VAP, 3/16 HAP), with a median APACHE II score of 23 (IQR 18-25). Mean plasma AUC0-12h and fAUC0-12h were 2.35 ± 0.84 and 1.48 ± 0.54 µg·h/mL, respectively. ELF exposure was higher than plasma, with ELF-to-free plasma AUC0-12h ratios of 4.0. Eravacycline was well tolerated; treatment-related adverse events (TRAEs) occurred in 7/16 (43.8%) patients and were all mild to moderate, including rash (2/16, 12.5%), prolonged activated partial thromboplastin time (APTT, 2/16, 12.5%), prolonged thrombin time (TT, 1/16, 6.3%), diarrhea (1/16, 6.3%), and vomiting (1/16, 6.3%). All patients received eravacycline-based combination therapy. Clinical response at EOT was observed in 13/16 (81.2%, 95% CI: 54.4-95.9%) patients, and microbiological eradication in 10/16 (62.5%, 95% CI: 35.4-84.8%). CONCLUSIONS:Eravacycline achieved substantial pulmonary exposure in critically ill patients with HAP/VAP despite reduced plasma exposure, with acceptable safety and encouraging clinical responses. Notably, eravacycline's independent contribution to clinical outcomes cannot be determined due to concurrent antimicrobial use.

BackgroundVancomycin, primarily excreted through the urine, is used for complicated urinary tract infections (cUTIs) caused by Gram-positive bacteria. Although serum therapeutic drug monitoring (TDM) is usually performed in vancomycin therapy, its benefits and risk factors in patients with cUTIs remain unclear.MethodsAdults with Gram-positive bacterial cUTIs receiving serum vancomycin TDM were enrolled from three prospective, multicenter trials. Minimal inhibitory concentration (MIC) was measured by agar dilution for pathogens collected from all patients. Clinical characteristics and pharmacokinetic/pharmacodynamic (PK/PD) indices were analyzed between the vancomycin treatment success and failure groups.ResultsA total of 74 adult patients with cUTIs were enrolled. Median initial daily dose of vancomycin was 1.0 g (interquartile range [IQR], 1.0–2.0 g), given in divided doses every 12 h or as a once-daily regimen. Most concomitant antibiotics targeted Gram-negative bacteria or fungi, with very limited anti-Gram-positive co-therapy. The median serum trough concentration (Cmin) of vancomycin was 9.22 mg/L (IQR, 4.36–14.33 mg/L) and 24-h area under the concentration-time curve to MIC (AUC24/MIC) was 455 (IQR, 268–627). Despite low attainment of the AUC24/MIC 400–600 target (27/74, 36.5%), the treatment success rate was 86.5% (64/74) and the nephrotoxicity rate was 4.1% (3/74). Urinary pathogens isolated included Enterococcus spp (55/74), Streptococcus spp (10/74), and Staphylococcus aureus (9/74), including eight methicillin-resistant S. aureus [MRSA]). Both solid tumor and S. aureus infection showed exploratory associations with vancomycin treatment failure. Patients with solid tumor had a lower probability of attaining the target AUC24/MIC, likely due to the elevated MIC of the predominant Enterococcus strains in this population. In contrast, patients with S. aureus-induced cUTIs achieved higher AUC24/MIC levels. All isolates exhibited low MICs (≤1 mg/L), no heteroresistance was detected, and the predominant molecular type was clone complex 5 (CC5).ConclusionVancomycin was effective in Enterococcus-dominant cUTIs and had a modest response in a few MRSA cases, despite low PK/PD target attainment. Serum Cmin and AUC24/MIC showed limited association with clinical outcomes, whereas solid tumor and S. aureus infection showed exploratory associations with treatment failure. However, TDM remains valuable for safety monitoring and individualized dosing. These findings should be validated in larger cohorts.

Development of neutralizing monoclonal antibodies (nAbs) is a strategy for treatment of infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of HFB30132A, a fully human nAb targeting the SARSCoV-2 spike protein receptor binding domain in healthy subjects. A randomized, double-blind, placebo- controlled phase I trial was performed in healthy Chinese and US subjects. The subjects ( n = 44) received a single ascending dose (40 0, 10 0 0, 20 0 0 mg) or placebo. Safety and PK data were analysed. PD were evaluated with a pseudovirus neutralization test in vitro using serum samples of Chinese subjects. A population PK/PD model was developed using non-linear mixed effects modelling. The effects of covariates were evaluated via covariate screening, Monte Carlo simulation and randomization tests. The PK profile was consistent with a three-compartment model. Clearance and V1 were 0.38 mL/h and 2.9 L, respectively. Ethnicity and body weight were factors affecting PK. Compared with subjects who were not Hispanic or Latino, area under the curve increased by 64% in subjects of Han nationality. PD were consistent with the effect-compartment model when 50% of neutralization dilution titre was used as the PD index. Maximal effect (Emax) reduced with time, consistent with the exponential model. The concentration of HFB30132A exerting 50% of Emax was 4590 mg/L. The half-life for reduction of Emax was 133 days. Albumin, lymphocytes, neutrophils and monocytes affected PD. Ethnic differences in PK and tolerance of PD were found for HFB30132A. The population PK/PD model characterized the dose-exposure-response relationship of HFB30132A in healthy subjects. These findings are useful for drug development in the future. Clinical trial registration: ClinicalTrial.gov NCT04590430, NCT05275660. (c) 2024 Published by Elsevier Ltd.

Eravacycline is a tetracycline used for the treatment of complicated intra-abdominal infections (cIAI) and has the potential to treat community-acquired bacterial pneumonia (CABP). The approved regimen for cIAI is 1 mg/kg (Q12h). However, studies have reported the inconvenience of drug preparation based on body weight (BW) and wastage of the drug, because the specification is 50 mg per vial. A fixed-dose regimen based on population pharmacokinetic/pharmacodynamic (PK/PD) modeling and simulations may address these limitations. Three clinical trials were performed in healthy Chinese participants and patients with cIAI and CABP. A PopPK model was developed using nonlinear mixed-effects modeling. A fixed-dose regimen in patients with a BW of 40-175 kg was recommended by the Monte Carlo simulation. The probability of target attainment and the cumulative fraction of response (CFR) were calculated. Overall, 79 participants were included in the study. BW, sex, albumin level, and subject type were covariates on PK. When patients received a fixed-dose, AUC0-12h,ss was 80-125% in patients with BW 60 kg receiving 1 mg/kg eravacycline. The PK/PD cutoff and CFR for the fixed-dose regimens were close to those of 1 mg/kg. The recommended fixed-doses (body weight range) were 50 mg (40-60 kg), 75 mg (60-100 kg), 100 mg (100-125 kg), 125 mg (125-150 kg), and 150 mg (150-175 kg). This should be used with caution in patients with BW >137 kg because the actual PK data were not collected. Nonetheless, fixed dosing is more convenient for drug preparation, avoids drug waste, and reduces medical costs compared with weight-based dosing. Trial Registration Number: ChiCTR1900022906, ChiCTR1900022060, and ChiCTR2200055666.

PURPOSE:This study aimed to examine the pharmacokinetic (PK) characteristics and penetration of contezolid into bone tissues and body fluids in patients undergoing artificial hip or knee replacement surgery. METHODS:In a prospective, single center, open label, cohort study, patients received 800 mg contezolid tablets orally, twice a day, for at least two days before surgery. The steady-state PK parameters of contezolid in plasma, body fluids and bone tissues were determined using both noncompartmental analysis (NCA) and population pharmacokinetic (PopPK) modeling. RESULTS:The plasma peak concentration (Cmax) of contezolid was 7.25 ± 5.27 mg/L in 6 patients undergoing hip replacement surgery, while the corresponding value was 11.46 ± 6.48 mg/L in 15 patients undergoing knee replacement. The median time to maximum plasma concentration (Tmax) was 1 hour after multiple oral doses of 800 mg contezolid. The ratio of the area under the concentration-time curve of contezolid from 0-12 h (AUC0-12h,ss) in tissue to the AUC0-12h,ss in plasma was 0.39 to 1.34 in patients undergoing hip replacement surgery, with body fluid-to-plasma AUC0-12h,ss ratio was 0.69. In patients undergoing knee replacement, the tissue-to-plasma AUC0-12h,ss ratio was 0.12-0.56 and body fluid-to-plasma AUC0-12h,ss ratio was 0.51. CONCLUSIONS:The penetration of contezolid into bone and joint tissues can justify the utility of contezolid in managing infections during joint replacement surgery. TRIAL REGISTRATION:http://www.chinadrugtrials.org.cn/ (identifier: CTR20230232）.

OBJECTIVES:The pharmacokinetics of renally cleared vancomycin are significantly altered in critically ill patients undergoing renal replacement therapy (RRT), affecting the achievement of therapeutic targets. We evaluated the predictive performance of RRT patient-based PopPK models for model-informed precision dosing and subsequently simulated optimal dosing regimens for this population. METHODS:Six adult PopPK models were systematically identified and evaluated using a dataset of 226 concentrations from 23 adult patients on RRT from two study centers. Predictive performance was assessed using simulation and prediction-based diagnostics for a priori dosing based on patient characteristics and Bayesian dosing incorporating more than one measured trough concentration. RESULTS:The Oda model showed the best performance in prediction-based evaluation, with a median prediction error of -8.4%. Bayesian forecasting incorporating at least one measured trough concentration improved predictive capability, and the inclusion of dialysis filter characteristics in the model may further enhance its performance. For a 70 kg patient under this scenario: A 1 g loading dose during the first dialysis session achieves target concentrations within 24-48 h. Subsequent 0.5 g maintenance dose should be administered post-dialysis. Dose escalation is required for extended dialysis sessions (≥12 h). CONCLUSION:The Oda model demonstrated the best predictive capability for dose prediction among the tested models in Chinese adult patients receiving RRT. However, its F20 and F30 values were undershot compared to the standard external evaluation criteria of F20 ≥35% and F30 ≥50%, highlighting the need for further study to optimize the model or collect additional data to validate its performance.

Objective·To evaluate the clearance and pharmacokinetics/pharmacodynamics (PK/PD) of antibiotics from the perspective of protein binding rates in critically ill patients undergoing intermittent hemodialysis (IHD), in order to explore the association between protein binding rate and dialysis clearance of antibiotics, and to provide theoretical basis for developing antibiotic dosing regimens during hemodialysis.Methods·Nineteen patients undergone low-flux hemodialysis and received antibiotic therapy at the Department of Nephrology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, were enrolled and divided into the meropenem group (n=7), the vancomycin group (n=5) and the ceftriaxone group (n=7) according to the type of antibiotics. A liquid chromatography with tandem mass spectrometry (LC-MS/MS) method was established to detect meropenem, vancomycin, and ceftriaxone in human plasma/serum and dialysate. A two-compartment pharmacokinetic model was established using MATLAB. Instantaneous and total dialysis clearance rates were calculated, and PK/PD parameters were analyzed.Results·No significant differences were found in the clinical characteristics of subjects among the three groups. The dialysis clearance rates were as follows: meropenem group (5.14‒5.97 L/h) > vancomycin group (2.87‒3.77 L/h)> ceftriaxone group (1.21‒1.90 L/h), with statistically significant differences (P<0.001). All three antibiotics showed good fit in the two-compartment pharmacokinetic model with a dialysate chamber (fval%<2), and the calculated PK/PD parameters were consistent with previous literature. For meropenem, the fraction of time that the free drug concentration remained above the minimal inhibitory concentration (%fT>MIC) values were 95.2%, 60.8% and 32.4% at minimal inhibitory concentration (MIC) values of 2, 8 and 16 μg/mL, respectively. For ceftriaxone (free concentration), the %fT>MIC values were all above 45.0% at MICs of 0.25, 4 and 16 μg/mL. For vancomycin, only 14.0% of the trough concentrations reached the target range of 15‒20 mg/L.Conclusion·The three antibiotics are well described by the two-compartment model. The plasma protein binding rate has a significant effect on the dialysis clearance of antibiotics in low-flux IHD, with higher protein binding associated with lower clearance. The regimens of meropenem (0.5 g/d) and ceftriaxone (2.0 g/d) are generally effective among patients undergoing low-flux IHD, while the vancomycin regimen with a loading dose of 1.0 g and a maintenance dose of 0.5 g/2 d carries a risk of treatment failure.

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 (Cmax), area under plasma drug concentration-time curve from time 0 to the last measurable plasma concentration time point (AUC0-t) and elimination half-life (t1/2) 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).

This study conducted a quantitative meta-analysis to investigate the association of vancomycin indicators, particularly area under the curve over 24 h (AUC24) and trough concentrations (Ctrough), and their relationship with both nephrotoxicity and efficacy. Literature research was performed in PubMed and Web of Science on vancomycin nephrotoxicity and efficacy in adult inpatients. Vancomycin Ctrough, AUC24, AUC24/minimum inhibitory concentration (MIC), nephrotoxicity evaluation and treatment outcomes were extracted. Logistic regression and Emax models were conducted, stratified by evaluation criterion for nephrotoxicity and primary outcomes for efficacy. Among 100 publications on nephrotoxicity, 29 focused on AUC24 and 97 on Ctrough, while of 74 publications on efficacy, 27 reported AUC24/MIC and 68 reported Ctrough. The logistic regression analysis indicated a significant association between nephrotoxicity and vancomycin Ctrough (odds ratio = 2.193; 95% CI 1.582–3.442, p < 0.001). The receiver operating characteristic curve had an area of 0.90, with a cut-off point of 14.55 mg/L. Additionally, 92.3% of the groups with a mean AUC24 within 400–600 mg·h/L showed a mean Ctrough of 10–20 mg/L. However, a subtle, non-statistically significant association was observed between the AUC24 and nephrotoxicity, as well as between AUC24/MIC and Ctrough concerning treatment outcomes. Our findings suggest that monitoring vancomycin Ctrough remains a beneficial and valuable approach to proactively identifying patients at risk of nephrotoxicity, particularly when Ctrough exceeds 15 mg/L. Ctrough can serve as a surrogate for AUC24 to some extent. However, no definitive cut-off values were identified for AUC24 concerning nephrotoxicity or for Ctrough and AUC24/MIC regarding efficacy.

INTRODUCTION:Neuromyelitis optica spectrum disorder (NMOSD) is a rare debilitating autoimmune disease of the central nervous system (CNS). This is the first-in-human dose-escalation Phase I clinical study of BAT4406F, an antibody-dependent cell-mediated cytotoxicity (ADCC)-enhanced fully humanized anti-CD20 monoclonal antibody, in Chinese NMOSD patients. PATIENTS AND METHODS:Using a "3 + 3" design and based on the planned algorithm of dose escalation, the enrolled NMOSD patients were sequentially assigned to one of the five dose-escalation cohorts of BAT4406F with a single intravenous dose, and were then followed for a 6-month observation period. The maximum tolerated dose (MTD) and dose-limiting toxicity (DLT), safety, pharmacokinetics (PK), pharmacodynamics, and immunogenicity of BAT4406F were investigated, and the efficacy of BAT4406F in NMOSD was also preliminarily explored. RESULTS:Fifteen Chinese NMOSD patients were enrolled to receive BAT4406F of escalated doses ranging from 20 to 750 mg. No subjects experienced DLT at the studied doses. BAT4406F injection exhibited favorable safety, with most of the adverse events (AE) of CTCAE Grade 1 or 2 in severity, and no Grade ≥ 3 adverse drug reactions (ADR) or serious adverse reactions occurred in any subjects. With the dose increase of BAT4406F, the maximum plasma concentration (Cmax), area under concentration-time curve from 0 to the last measurable timepoint (AUC0-t) and area under concentration-time curve from 0 to infinity (AUC0-inf) showed an increasing trend, whereas the mean clearance (CLt), terminal elimination rate (λZ), and apparent volume of distribution (Vd) decreased. The mean elimination half-life (T1/2) was ranged from 9.0-16.4 days. PK profile of BAT4406F was generally nonlinear. BAT4406F led to a rapid and significant B-cell depletion in all dose groups. Single administration of 500 mg or 750 mg maintains the CD19+ B lymphocyte count below 10/μL within the whole 6-month observation period. Three subjects were antidrug antibody (ADA) positive and all of them were neutralizing antibody (NAb)-negative. On day 99/180 postdose, several groups had decreased expanded disability status scale (EDSS) scores compared to baseline. During the observation period, NMOSD relapse occurred in two patients (13.3%) and the other 13 (86.7%) subjects remained relapse free. CONCLUSION:BAT4406F was well tolerated at doses up to 750 mg and showed an expected pharmacodynamic effect of significant and long-term depletion of CD19+ B lymphocytes. It has also shown preliminary evidence of activity in NMOSD maintenance treatment, warranting further investigations. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT04146285.

ABSTRACT Mycoplasma pneumoniae is the causative agent of respiratory infections in children and adults. Macrolide still plays a significant role in treating infections by M. pneumoniae. However, macrolide-resistant M. pneumoniae (MRMP) was encountered, causing more severe or prolonged disease worldwide from the early 2000s. Nemonoxacin is a newly developed C-8-methoxy non-fluorinated quinolone having broad-spectrum activity against gram-positive, gram-negative, and atypical pathogens in vitro, as well as general safety and well tolerance in vivo. This study aimed to assess the killing kinetics of nemonoxacin and other antimicrobial agents against MRMP and macrolide susceptible M. pneumoniae (MSMP) by static time-kill curves. In addition, the pharmacodynamic analyses of these drugs were determined by the sigmoid E max model. The static time-kill curves indicated that nemonoxacin had good mycoplasmacidal activity against both MSMP and MRMP strains. The pharmacodynamic analysis demonstrated that the mycoplasmacidal effect of nemonoxacin was greater than those of moxifloxacin and levofloxacin based on the K max, displaying a dualism of concentration dependency in low minimum inhibitory concentrations (MICs) and time dependency in high MICs. Therefore, nemonoxacin demonstrated efficacy against M. pneumoniae in vitro and is a potential candidate for clinical studies for assessing its therapeutic effects against M. pneumoniae infections. The killing pattern or PK/PD characteristics of nemonoxacin against M. pneumoniae from in vitro data, animal studies, or clinical studies merit further evaluation for treating infections caused by the organism. IMPORTANCE This study first reported the in vitro effector kinetics of the new non-fluorinated quinolone, nemonoxacin, against macrolide-resistant M. pneumoniae (MRMP) and macrolide susceptible M. pneumoniae (MSMP) strains along with other antimicrobial agents. The time-kill assays and pharmacodynamic analysis showed that nemonoxacin has significant mycoplasmacidal activity against MRMP and MSMP. This study paves the road to establish appropriate dosing protocols of a new antimicrobial drug for children infected with M. pneumoniae.

Phospholipid-valproic acid (DP-VPA) is a prodrug for treating epilepsy. The present study explored the phar-macokinetics (PK) and exposure safety of DP-VPA to provide a basis for future studies exploring the safe dosage and therapeutic strategies for epilepsy. The study included a randomized placebo-controlled dose-escalation tolerance evaluation trial and a randomized triple crossover food-effect trial in healthy Chinese volunteers. A population pharmacokinetic (PopPK) model was established to analyze the PK of DP-VPA and active metabolite VPA. The exposure safety was assessed with the adverse drug reaction (ADR) in CNS. The PopPK of DP-VPA and metabolite VPA fitted a two-compartment model coupling one-compartment with Michaelis-Menten metabolite kinetics and first-order elimination. The absorption processes after single oral administration of DP-VPA tablet demonstrated nonlinear characteristics, including 0-order kinetic phase and time-dependent phase fitting Wei-bull distribution. The final model indicated that the DP-VPA PK was significantly affected by dosage and food. The exposure-safety relationship demonstrated a generalized linear regression; mild/moderate ADRs occurred in some subjects with 600 mg and all subjects with 1500 mg of DP-VPA, and no severe ADRs were reported up to 2400 mg. In conclusion, the study established a PopPK model describing the processing of DP-VPA and VPA in healthy Chinese subjects. DP-VPA showed good tolerance after a single dose of 600-2400 mg with nonlinear PK and was affected by dosage and food. Based on the association between neurological ADRs and higher exposure to DP-VPA by exposure-safety analysis, 900-1200 mg was recommended for subsequent study of safety and clinical effectiveness.

BACKGROUND:Interleukin (IL) 23p19 monoclonal antibodies were efficacious and safe in the treatment of psoriasis. A first-in-human (FIH) study was conducted to evaluate the safety, tolerability, pharmacokinetics (PK) and immunogenicity of IBI112, a novel IL-23p19 monoclonal antibody. METHODS:In this FIH, randomized, double-blind, placebo-controlled, single-ascending-dose study, a subcutaneous (SC, 5-600 mg) or intravenous (IV, 100 and 600 mg) or placebo was administered to eligible healthy subjects. Safety was assessed by physical examinations, vital signs, laboratory tests, and electrocardiograms. Furthermore, non-compartment analysis and population PK modeling were conducted to characterize PK, and model-based simulation was applied to justify dose selection for psoriasis patients. RESULTS:A total of 46 subjects were enrolled, with 35 receiving IBI112 and 11 receiving placebo. No serious adverse events (SAEs) and no clinically significant adverse events were identified. After a single SC of IBI112, the median Tmax was 4-10.5 days, and the half-life (t1/2) ranged from 21.8 to 35.8 days. IBI112 exposures (Cmax and AUCinf) approached dose proportionality across 5-300 mg range. CONCLUSION:IBI112 was well tolerated and safe at SC or IV dose up to 600 mg and showed a linear PK characteristics at SC dose from 5 to 300 mg. CLINICAL TRIAL REGISTRATION:ClinicalTrial.gov NCT04511624.

Objective: The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) still protracts worldwide. HFB30132A is an anti- SARS-CoV-2 monoclonal antibody purposely engineered for an extended half-life with neutralizing activity against majority of the virus variants identified so far. The aim of this study was to evaluate the safety, tolerability, pharmacokinetics (PK), and immunogenicity of HFB30132A in healthy Chinese subjects.Methods: A phase 1, randomized, double-blind, placebo-controlled, single ascending dose clinical trial was designed. Twenty subjects were enrolled to Cohort 1 (1,000 mg dose level, 10 subjects) or Cohort 2 (2,000 mg dose level, 10 subjects). Subjects in each cohort were assigned randomly to receive a single intravenous (IV) dose of HFB30132A or placebo at a ratio of 8:2. Safety was assessed in terms of treatment emergent adverse events (TEAEs), vital signs, physical examination, laboratory tests, and ECG findings. PK parameters were measured and calculated appropriately. Anti-drug antibody (ADA) test was performed to detect anti-HFB30132A antibodies.Results: All subjects completed the study. Overall, 13 (65%) of the 20 subjects experienced TEAEs. The most common TEAEs were laboratory abnormalities (12 subjects [60%]), gastrointestinal disorders (6 subjects [30%]), and dizziness (4 subjects [20%]). All TEAEs were Grade 1 or Grade 2 in severity based on the criteria of Common Terminology Criteria for Adverse Events (CTCAE). Serum exposure (Cmax, AUC0-t, AUC0-∞) of HFB30132A increased with ascending dose. After single dose of 1,000 mg and 2000 mg HFB30132A, the mean Cmax was 570.18 μg/mL and 898.65 μg/mL, the mean AUC0-t value was 644,749.42 h*μg/mL and 1,046,209.06 h*μg/mL, and the mean AUC0-∞ value was 806,127.47 h*μg/mL and 1,299,190.74 h*μg/mL, respectively. HFB30132A showed low clearance ranging from 1.38 to 1.59 mL/h, and a long terminal elimination half-life (t½) of 89–107 days. ADA test did not detect any anti-HFB30132A antibodiesConclusion: HFB30132A was safe and generally well-tolerated after single IV dose of 1,000 mg or 2000 mg in healthy Chinese adults. HFB30132A did not induce immunogenic response in this study. Our data support further clinical development of HFB30132A.Clinical Trial Registration:https://clinicaltrials.gov, identifier: NCT05275660.

Introduction: Nemonoxacin is an innovative quinolone antibiotic for treatment of community-acquired pneumonia (CAP). As more data are available from clinical studies, it is necessary to perform an integrative pharmacokinetic/pharmacodynamic (PK/PD) analysis to support and justify the optimal dosing regimen of nemonoxacin in clinical practice.Methods and Results: We developed a population PK model using non-linear mixed effect model based on the data of 195 Chinese subjects receiving nemonoxacin in phase I to III clinical trials. The base model was a standard two-compartment PK model defined by clearance (12 L/h) and central volume of distribution (86 L). Covariates included creatinine clearance (CLcr), body weight (BW), sex, disease status and food. Compared to the subject with BW 60 kg, Cmax and AUC0‐24, ss reduced by 24% and 19% in the subject with BW 80 kg, respectively. Compared to the subject with CLcr 150 ml/min, AUC0‐24, ss and T1/2 increased by 28% and 24%, respectively in the subject with CLcr 30 ml/min. Compared to the fasted status, Tmax of nemonoxacin increased by 1.2 h in the subject with fed status. Effects of sex and disease status on PK parameters were small (change of PK parameters ≤19%). AUC0–24/MIC and %T > MIC were identified as the optimal PK/PD indices for predicting clinical efficacy. The AUC0-24/MIC target was 63.3, 97.8, and 115.7 against Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae, respectively. The %T > MIC target was 7.96% against Klebsiella pneumoniae. Monte Carlo simulation showed that treatment with nemonoxacin 500 mg q24 h could attain a PK/PD cutoff value higher than the MIC90 against S. pneumoniae and S. aureus. The corresponding cumulative fraction of response (CFR) was greater than 93%, while nemonoxacin 750 mg q24 h would provide higher PK/PD cutoff value against Haemophilus parainfluenzae, and higher CFR (83%) than 500 mg q24 h.Conclusion: Integrative PK/PD analysis justifies the reliable clinical and microbiological efficacy of nemonoxacin 500 mg q24 h in treating CAP caused by S. pneumoniae, S. aureus, and K. pneumoniae, irrespective of patient sex, mild renal impairment, empty stomach or not. However, nemonoxacin 750 mg q24 h would provide better efficacy than 500 mg q24 h for the CAP caused by H. parainfluenzae in terms of CFR.

Polymyxin-based combination therapy is commonly used to treat carbapenem-resistant Acinetobacter baumannii (CRAB) infections. In the present study, the bactericidal effect of polymyxin B and minocycline combination was tested in three CRAB strains containing blaOXA-23 by the checkerboard assay and in vitro dynamic pharmacokinetics/pharmacodynamics (PK/PD) model. The combination showed synergistic or partial synergistic effect (fractional inhibitory concentration index ≤0.56) on the tested strains in checkboard assays. The antibacterial activity was enhanced in the combination group compared with either monotherapy in in vitro PK/PD model. The combination regimen (simultaneous infusion of 0.75 mg/kg polymyxin B and 100 mg minocycline via 2 h infusion) reduced bacterial colony counts by 0.9–3.5 log10 colony forming units per milliliter (CFU/mL) compared with either drug alone at 24 h. In conclusion, 0.75 mg/kg polymyxin B combined with 100 mg minocycline via 2 h infusion could be a promising treatment option for CRAB bloodstream infections.

This study aimed to build a population pharmacokinetic (PopPK) model for contezolid tablet (MRX-I) in healthy subjects and adults with complicated skin and soft-tissue infections (cSSTIs) to further evaluate the efficacy and safety of contezolid and recommend the optimal dosing regimen based on pharmacokinetic/pharmacodynamic (PK/PD) analysis. PopPK analysis was performed using a nonlinear mixed-effects model (NONMEM) to examine the effects of age, body weight, sex, liver and renal functions, albumin, food, dosage strength, and subject type on the PK parameters of contezolid. PK/PD analysis was combined with the MIC of contezolid, clinical/microbiological efficacy, and nonclinical study data. Adverse events (AEs) and study drug-related AEs reported were summarized to examine the relationship between contezolid exposure level and safety measures. A two-compartment model was built. An exponential model was used to describe the interindividual variation. A proportional model was used to describe the intraindividual variation of PK parameters. Good clinical and microbiological efficacy are expected for the infections caused by S. aureus when contezolid is administered at 600 mg or 800 mg every 12 h (q12h). The area under the concentration-time curve from 0 to 24 h at steady state and maximum concentration of drug in serum at steady state of contezolid did not show significant association with the incidence of any AE. The dosing regimen of contezolid at 800 mg q12h administered postprandially for 7 to 14 days is expected to achieve satisfactory clinical and microbiological efficacy in cSSTIs, which is slightly better than that of 600 mg contezolid. This administration has been added to the prescribing information of contezolid tablets.