Clinical Pharmacology and Utility of Contezolid in Chinese Patients with Complicated Skin and Soft-Tissue 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.

Polymyxin B Combined with Minocycline: A Potentially Effective Combination against blaOXA-23-harboring CRAB in In Vitro PK/PD Model.

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.

Nemonoxacin dosage adjustment in patients with severe renal impairment based on population pharmacokinetic and pharmacodynamic analysis.

AIMS: To optimize the dosing regimen in patients with severe renal impairment based on population pharmacokinetic (PPK)/pharmacodynamic analysis. METHODS: The pharmacokinetics and safety of nemonoxacin was evaluated in a single-dose, open-label, nonrandomized, parallel-group study after single oral dose of a 0.5-g nemonoxacin capsule in 10 patients with severe renal impairment and 10 healthy controls. Both blood and urine samples were collected within 72 hours after admission and determined the concentrations. A PPK model was built using nonlinear mixed effects modelling. The probability of target attainment and the cumulative fraction of response against Streptococcus pneumoniae and Staphylococcus aureus was calculated by Monte Carlo simulation. RESULTS: The data best fitted a 2-compartment model, from which the PPK parameters were estimated, including clearance (8.55 L/h), central compartment volume (80.8 L) and peripheral compartment volume (50.6 L). The accumulative urinary excretion was 23.4 ± 6.5% in severe renal impairment patients and 66.1 ± 16.8% in healthy controls. PPK/pharmacodynamic modelling and simulation of 4 dosage regimens found that nemonoxacin 0.5 g every 48 hours (q48h) was the optimal dosing regimen in severe renal impairment patients, evidenced by higher probability of target attainment (92.7%) and cumulative fraction of response (>99%) at nemonoxacin minimum inhibitory concentration ≤ 1 mg/L against S. pneumoniae and S. aureus. The alternative regimens (0.25 g q24h; loading dose 0.5 g on Day 1 followed by 0.25 g q24h) were insufficient to cover the pathogens even if minimum inhibitory concentration = 1 mg/L. CONCLUSION: An extended dosing interval (0.5 g q48h) may be appropriate for optimal efficacy of nemonoxacin in case of severe renal impairment.

Effects of Different Component Contents of Colistin Methanesulfonate on the Pharmacokinetics of Prodrug and Formed Colistin in Human.

PURPOSES: To evaluate the effects of component contents in different colistin methanesulfonate (CMS) formulas on their clinical pharmacokinetics of the prodrug CMS and the formed colistin. METHODS: Two CMS formulas (CTTQ and Parkedale) were investigated in a single dose, randomized, open-label, crossover study conducted in 18 healthy Chinese subjects. Both CMS formulas met the requirements of European Pharmacopoeia 9.2 with 12.1% difference in the two major active components (CMS A and CMS B). The PK parameters after a single intravenous infusion of CMS at 2.5 mg/kg were calculated and the steady-state plasma colistin concentrations (Css,avg) following multiple dosing, once every 12 h for 7 days, were simulated with the non-compartment model. RESULTS: The systemic exposure (AUC0-inf) of CMS were 59.49 ± 5.90 h·µg/mL and 51.09 ± 4.70 h·µg/mL, and the AUC0-inf of colistin were 15.39 ± 2.63 h·µg/mL and 12.36 ± 2.10 h·µg/mL for CTTQ and Parkedale, respectively. The ratios (90% CI) of geometric mean of AUC0-inf of CTTQ to Parkedale were 116.38% (112.95%, 119.91%) and 124.49% (120.76%, 128.35%) for CMS and colistin, respectively. The predicted Css,avg (95% CI) were 0.92 (0.85, 0.99) µg/mL and 0.74 (0.69, 0.79) µg/mL for CTTQ and Parkedale, respectively. CONCLUSION: The difference in component content in the two CMS formulas had a significant (P < 0.001) impact on the systemic exposure of colistin in human, thus, warranted essential considerations in clinical applications.

[Effect of muscle relaxants on the prognosis of neonates with congenital esophageal atresia-tracheoesophageal fistula after surgery].

OBJECTIVE: To summarize the experience in the application of muscle relaxants in the perioperative period in neonates with congenital esophageal atresia-tracheoesophageal fistula (EA-TEF). METHODS: A retrospective analysis was performed on the medical data of 58 previously untreated neonates with EA-TEF who were treated in the Neonatal Center of Beijing Children's Hospital, Capital Medical University from 2017 to 2019. The incidence rate of anastomotic leak was compared between the neonates receiving muscle relaxants for different durations after surgery (≤ 5 days and > 5 days). The correlation between the duration of postoperative use of muscle relaxants and the duration of mechanical ventilation was evaluated. RESULTS: Among the 58 neonates with EA-TEF, 44 underwent surgery, among whom 35 with type III EA-TEF underwent thoracoscopic surgery. Among these 35 neonates, 30 (86%) received muscle relaxants after surgery, with a median duration of 4.75 days, and 6 (18%) experienced anastomotic leak. There was no significant difference in the incidence rate of anastomosis leak between the ≤ 5 days and > 5 days groups (P > 0.05). The duration of postoperative invasive mechanical ventilation was positively correlated with the duration of the use of muscle relaxants (rs=0.548, P < 0.05). CONCLUSIONS: Prolonged use of muscle relaxants after surgery cannot significantly reduce the incidence of anastomotic leak, but can prolong the duration of invasive mechanical ventilation in neonates with EA-TEF. Therefore, prolonged use of muscle relaxants is not recommended after surgery.

Evaluation of the Effect of Contezolid (MRX-I) on the Corrected QT Interval in a Randomized, Double-Blind, Placebo- and Positive-Controlled Crossover Study in Healthy Chinese Volunteers.

Contezolid (MRX-I), a new oxazolidinone, is an antibiotic in development for treating complicated skin and soft tissue infections caused by resistant Gram-positive bacteria. This was a thorough QT study conducted in 52 healthy subjects who were administered oral contezolid at a therapeutic (800 mg) dose, a supratherapeutic (1,600 mg) dose, placebo, and oral moxifloxacin at 400 mg in four separate treatment periods. The pharmacokinetic profile of contezolid was also evaluated. Time point analysis indicated that the upper bounds of the two-sided 90% confidence interval (CI) for placebo-corrected change-from-baseline QTc (ΔΔQTc) were <10 ms for the contezolid therapeutic dose at each time point. The upper bound of the 90% CI for ΔΔQTc was slightly more than 10 ms with the contezolid supratherapeutic dose at 3 and 4 h postdose, and the prolongation effect on the QT/QTc interval was less than that of the positive control, moxifloxacin, at 400 mg. At 3 and 4 h after the moxifloxacin dose, the moxifloxacin group met the assay sensitivity criteria outlined in ICH Guidance E14 by having a lower confidence bound of ≥5 ms. The results of a linear exposure-response model which were similar to that of a time point analysis demonstrated a slightly positive relationship between contezolid plasma levels and ΔQTcF interval with a slope of 0.227 ms per mg/liter (90% CI, 0.188 to 0.266). In summary, contezolid did not prolong the QT interval at a therapeutic dose and may have a slight effect on QT interval prolongation at a supratherapeutic dose.

Simultaneous separation and determination of vancomycin and its crystalline degradation products in human serum by ultra high performance liquid chromatography tandem mass spectrometry method and its application in therapeutic drug monitoring.

A rapid and simple ultra high performance liquid chromatography with tandem mass spectrometry method was developed and validated for the simultaneous separation and determination of vancomycin and its crystalline degradation products in human serum. Vancomycin and two isomers of the degradants were extracted from human serum with a protein precipitation method. The compounds were separated on an Acquity BEH C18 column (2.1 × 50 mm, 1.7 µm) eluted with a gradient mixture of acetonitrile and 0.1% formic acid as the mobile phase. Norvancomycin was used as the internal standard. The linear ranges of vancomycin and two degradant isomers were 1.057-105.7, 0.1437-14.37, and 0.2540-25.40 µg/mL, respectively. The established methods were validated and successfully applied to a therapeutic drug monitoring study of vancomycin in patients with renal insufficiency.

High mobility group box 1 protein (HMGB1) as biomarker in hypoxia-induced persistent pulmonary hypertension of the newborn: a clinical and in vivo pilot study.

Background: Inflammation plays an important role in neonatal hypoxia-induced organ damage. Newborns with perinatal asphyxia often develop persistent pulmonary hypertension of the newborn (PPHN). The objective of this study was to explore changes in the pro-inflammatory high mobility group box-l (HMGB1) protein during hypoxia-induced PPHN clinically and in vivo. Methods: Serum samples were collected from full-term newborns at PPHN onset and remission. As controls, blood serum samples were collected from the umbilical arteries of healthy full-term newborns born in our hospital during the same period. Clinical data for neonates were collected and serum levels of HMGB1, IL-6, and TNF-α were detected by enzyme-linked immunosorbent assay (ELISA). An animal study compared a PPHN Sprague-Dawley rat model to healthy newborn control rats. Histopathology was used to evaluate changes in the pulmonary artery wall. ELISA and western blot analyses were used to examine HMGB1 levels in the serum and lungs. Results: Serum HMGB1 levels were significantly elevated in newborns with PPHN, compared to those in healthy controls, and decreased dramatically after PPHN resolution. HMGB1 changes were positively correlated with serum tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels. Histopathological analysis demonstrated that the median wall thickness of pulmonary arterioles accounting for the percentage of pulmonary arteriole diameter (MT%) was not significantly different between PPHN and control groups 3 d after PPHN, although thickness of the small pulmonary arterial wall middle membrane and stenosis of the small pulmonary arteries. ELISA and western blot analyses showed similar trends between serum HMGB1 levels and HMGB1 protein expression in the lungs. Serum and lung HMGB1 levels were significantly elevated soon after PPHN onset, peaked after 24 h, and then decreased after 3 d, although they remained elevated compared to those in the control group. Conclusions: This study indicates that HMGB1 is related to hypoxia-induced PPHN pathogenesis. HMGB1 changes might thus be used as an early indicator to diagnose hypoxia-induced PPHN and evaluate its improvement. We also provide important evidence for the involvement of inflammation in the progression of hypoxia-induced PPHN.

Hsp60 in caudal fin regeneration from Paramisgurnus dabryanus: molecular cloning and expression characterization.

Heat shock protein 60 (Hsp60) is a kind of highly conserved immunogenic molecule involved in a wide range of biochemical processes in response to external stressors. Its multifunction in regulating immune responses and modulating signal pathway interests us in investigating its role in fin regeneration that has become an excellent and interesting model for studying the molecular basis of morphogenesis. We firstly clarified basical process and crucial period of caudal fins regeneration in Paramisgurnus dabryanus by histological analysis. Then we cloned full-length cDNA of hsp60 from P. dabryanus (designated as PdHsp60) by RACE method. The cDNA contains a 124 bp 5'UTR, a 1731 bp open reading frame (ORF) encoding 576 amino acids and a 510 bp 3'UTR (Accession no.: KF544774). The phylogenetic tree shows that the PdHsp60 fits within the hsp60 clade. And quantitative RT-PCR detected the PdHsp60 began to increase rapidly its expression at 1 dpa and reached its peak at 2 dpa. Next, spatial distribution analysis of PdHsp60 in fins showed that PdHsp60 located mainly in the deeper lay of regenerated epidermis when PdHsp60 expressed most. After the PdHsp60 had been cloned into the pET-32a vector, SDS-PAGE and Western blotting analysis confirmed that the PdHsp60 protein was efficiently expressed in Escherichia coli BL21. These findings have revealed that PdHsp60, a highly conserved gene related to the innate immune system and stress response during vertebrate evolution, is involved in response to wounding stimulation--in the formation of wound epidermis which occurs as the first phase of fin regeneration after fin amputation in caudal fin regeneration.

The Diagnostic Value of Ultrasound-guided Attenuation Parameter (UGAP) in metabolic fatty liver disease.

OBJECTIVES: To evaluate the diagnostic value of ultrasound-guided attenuation parameter (UGAP) in metabolic fatty liver disease (MAFLD) and to explore the correlation between the attenuation coefficient (AC) value of UGAP and commonly used clinical obesity indicators. METHODS: A total of 121 subjects who had physical examinations from November 2021 to March 2022 were prospectively selected; the height, weight, and waist circumference (WC) of all subjects were collected, and conventional ultrasound and UGAP examinations for all subjects. RESULTS: Under the standard of conventional ultrasound, among the 121 subjects, 53 had normal liver, 42 had mild fatty liver, 21 had moderate fatty liver, and 5 had severe fatty liver. The mean AC value of 121 patients was 0.66 ± 0.13 dB/cm/MHz. The best cut-off values for diagnosing mild, moderate, and severe fatty liver were 0.65dB/cm/MHz, 0.72dB/cm/MHz, and 0.83dB/cm/MHz, respectively. The area under the curve (AUC) values were 0.891, 0.929, and 0.914, respectively. When grouped by WC, there was a statistically significant difference in AC value between the normal group and the obese group (t=-4.675, P<0.001). Overall WC and within group WC were moderately correlated with the AC value of UGAP (P<0.001). CONCLUSIONS: UGAP has a good diagnostic value in the quantitative evaluation of liver steatosis in MAFLD, and the change of WC can reflect the occurrence of liver steatosis to a certain extent.

Quorum-Sensing Signal DSF Inhibits the Proliferation of Intestinal Pathogenic Bacteria and Alleviates Inflammatory Response to Suppress DSS-Induced Colitis in Zebrafish.

The imbalance of gut microbiota is an important factor leading to inflammatory bowel disease (IBD). Diffusible signal factor (DSF) is a novel quorum-sensing signal that regulates bacterial growth, metabolism, pathogenicity, and host immune response. This study aimed to explore the therapeutic effect and underlying mechanisms of DSF in a zebrafish colitis model induced by sodium dextran sulfate (DSS). The results showed that intake of DSF can significantly improve intestinal symptoms in the zebrafish colitis model, including ameliorating the shortening of the intestine, reducing the increase in the goblet cell number, and restoring intestinal pathological damage. DSF inhibited the upregulation of inflammation-related genes and promoted the expression of claudin1 and occludin1 to protect the tightness of intestinal tissue. The gut microbiome analysis demonstrated that DSF treatment helped the gut microbiota of the zebrafish colitis model recover to normal at the phylum and genus levels, especially in terms of pathogenic bacteria; DSF treatment downregulated the relative abundance of Aeromonas hydrophila and Staphylococcus aureus, and it was confirmed in microbiological experiments that DSF could effectively inhibit the colonization and infection of these two pathogens in the intestine. This study suggests that DSF can alleviate colitis by inhibiting the proliferation of intestinal pathogens and inflammatory responses in the intestine. Therefore, DSF has the potential to become a dietary supplement that assists in the antibiotic and nutritional treatment of IBD.

Age-Related Differences in Vancomycin-Associated Nephrotoxicity and Efficacy in Methicillin-Resistant Staphylococcus aureus Infection: A Comparative Study between Elderly and Adult Patients.

Elderly patients (age ≥ 65 years) are susceptible to methicillin-resistant Staphylococcus aureus (MRSA) infections, with potential for more adverse treatment outcomes or complications compared to younger adults (18-64 years). This study compared vancomycin-associated nephrotoxicity and efficacy in elderly and adult patients and investigated the correlation between vancomycin pharmacokinetic/pharmacodynamic (PK/PD) indices and clinical outcomes. A prospective study was conducted in 10 hospitals in Shanghai from October 2012 to November 2019. A total of 164 patients with MRSA infections were enrolled, including 83 elderly and 81 adult patients. Vancomycin therapeutic drug monitoring (TDM) was performed in all patients, indicating significantly higher vancomycin trough concentrations (Ctrough), 24-h area under the curve (AUC24) values, and AUC24/minimum inhibitory concentration (AUC24/MIC) values in elderly patients compared to adult patients. The incidence of vancomycin-associated nephrotoxicity was nearly three times higher in elderly patients (18.1% vs. 6.2%, p = 0.020), despite similar clinical and microbiological efficacy. Of particular importance, a Ctrough > 20 mg/L was found as an independent factor of nephrotoxicity in elderly patients. Further analysis of patients with an estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m2 also revealed that elderly patients had significantly higher vancomycin-related PK/PD indices and more nephrotoxicity than adult patients. In conclusion, elderly patients receiving vancomycin therapy face a higher risk of nephrotoxicity, which requires close vancomycin TDM, especially when the Ctrough exceeds 20 mg/L.

A randomised, double-blind, placebo-controlled, first-in-human phase I study to characterise the safety, pharmacokinetics and immunogenicity of 9MW1411 in healthy Chinese subjects.

INTRODUCTION: 9MW1411 is a humanised monoclonal antibody against Staphylococcus aureus alpha-toxin. The safety, pharmacokinetics (PK) and immunogenicity of 9MW1411 should be characterised in humans before further clinical development. METHODS: A single-centre, randomised, double-blind, placebo-controlled phase I clinical study was conducted in humans for the first time. A total of 42 healthy Chinese subjects were randomised to receive a single ascending dose of 9MW1411 (200, 600, 1500, 3000 or 5000 mg) or placebo. Safety, PK parameters and anti-drug antibody (ADA) were analysed. Monte Carlo simulations (MCS) were performed to predict the probability of target attainment (PTA) after single dose IV administration of 1500, 3000 and 5000 mg of 9MW1411. RESULTS: Thirty-four subjects received 9MW1411, completed the study and were included in data analysis. Five cases of drug-related AEs occurred in four subjects. All the adverse events (AEs) were mild or moderate. The Cmax, AUC0-t and AUC0-∞ of 9MW1411 increased with dose after IV administration of 200 to 5000 mg 9MW1411. The mean Cmax increased from 85.40 ± 5.43 to 2082.11 ± 343.10 µg/mL and AUC0-∞ from 29,511.68 ± 5550.91 to 729,985.49 ± 124,932.18 h·µg/mL. The elimination half-life (T1/2) was 19-23 days. 9MW1411 ADA was positive in three subjects. MCS indicated that a single dose of 3000 or 5000 mg 9MW1411 could achieve PTA > 90% for S. aureus. CONCLUSIONS: 9MW1411 has shown a good safety profile in healthy Chinese subjects after a single dose up to 5000 mg. A single dose of 3000 mg 9MW1411 is appropriate for use in subsequent studies.

Contrast-enhanced Ultrasound of Xanthogranulomatous Endometritis: A Case Report and Literature Review.

Xanthogranulomatous endometritis (XGE) is a rare inflammatory disease, which can easily misdiagnose as cancer in imaging diagnosis. Diagnosis of XGE relies on histopathological examination and immunohistochemistry. In this study, a case of a 72-year-old female with XGE and elevated CA125 is presented, which was misdiagnosed as endometrial cancer in transvaginal ultrasonography and ovarian cystadenocarcinoma in CT. However, the features of XGE on the contrast-enhanced ultrasound (CEUS) were different from that of endometrial cancer. The patient finally underwent laparoscopic hysterectomy and bilateral adnexectomy. The histopathological examination and immunohistochemistry suggested xanthogranulomatous endometritis (histiocytic endometritis). This case report manifests that CEUS may be a new noninvasive diagnostic method for XGE, which may reduce extensive tissue sampling and unnecessary hysterectomies for patients.

Population pharmacokinetics of levornidazole in healthy subjects and patients, and sequential dosing regimen proposal using pharmacokinetic/pharmacodynamic analysis.

Although sequential treatment with levornidazole has been used for anaerobic infection in clinical practice, there is no evidence-based dosing regimen. This study aimed to evaluate the pharmacokinetics (PK) of levornidazole in healthy subjects and patients, and to propose an evidence-based sequential dosing regimen by pharmacokinetic/pharmacodynamic (PK/PD) analysis. A population PK model was built using the data of 116 Chinese subjects, including 88 healthy young subjects, 12 healthy elderly subjects, and 16 patients with intra-abdominal anaerobic infection. PK/PD analysis was performed combining the minimum inhibitory concentration (MIC) values of levornidazole against 375 anaerobic strains. Four sequential dosing regimens (500 mg q12h, 1000 mg loading dose followed by 500 mg q12h, 750 mg q24h, and 1000 mg q24h) were evaluated in terms of cumulative fraction of response (CFR) and probability of target attainment (PTA) by Monte Carlo simulation. The concentration data of levornidazole and its active metabolites were described adequately by two- and one-compartment models, respectively. Body weight was identified as a significant covariate of levornidazole clearance. Simulations showed that satisfactory PTA (>90%) was achieved for the four dosing regimens when MIC ≤1 mg/L. Considering the simulation results, patients' safety and compliance, levornidazole 750 mg intravenous infusion q24h for 2 days followed by 750 mg oral dose q24h for 5 days was optimal for Bacteroides spp. with an identified MIC ≤1 mg/L.

Dose adjustment not required for contezolid in patients with moderate hepatic impairment based on pharmacokinetic/pharmacodynamic analysis.

Objective: Contezolid is an oxazolidinone antimicrobial agent newly approved for treatment of Gram-positive bacterial infections. It is primarily metabolized by the liver. This study aimed to assess whether it is required to adjust the dose of contezolid in patients with moderate hepatic impairment for clinicians to use the drug more rationally. Methods: A single-center, open-label, parallel-group study was conducted to compare the pharmacokinetic (PK) parameters of contezolid and its metabolite M2 between the patients with moderate hepatic impairment and healthy controls with normal liver function after oral administration of 800 mg contezolid tablets. Monte Carlo simulation was performed to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) of contezolid based on the PK and pharmacodynamic data. Results: Oral treatment with 800 mg contezolid tablets was safe and well tolerated in both the patients with moderate hepatic impairment and healthy controls. Moderate hepatic impairment did not result in substantial difference in the area under the concentration-time curve from 0 to 24 h (AUC0-24h, 106.79 vs. 97.07 h µg/mL) of contezolid even though lower maximum concentration (Cmax, 19.03 vs. 34.49 µg/mL) compared with healthy controls. The mean cumulative amount excreted in urine from 0 to 48 h (Ae0-48h) and renal clearance (CLR) of contezolid did not show significant difference between the two groups. Moderate hepatic impairment was associated with lower Cmax, slightly lower AUC and Ae0-48h of M2 compared to the healthy controls. fAUC/MIC was the best PK/PD index to predict the clinical efficacy of contezolid. Monte Carlo simulation results indicated that at the proposed fAUC/MIC target value of 2.3, the dosing regimen of oral contezolid 800 mg q12h could achieve satisfactory PTA and CFR (both >90%) for the target pathogen (methicillin-resistant S. aureus, MIC ≤4 mg/L) in patients with moderate hepatic impairment. Conclusion: Our preliminary data suggest that dose adjustment is not required for contezolid in patients with moderate hepatic impairment. Clinical Trial Registration: https://chinadrugtrials.org.cn, identifier: CTR20171377.

A simple and rapid HPLC-MS/MS method for therapeutic drug monitoring of amikacin in dried matrix spots.

Individualized treatment of amikacin under the guidance of therapeutic drug monitoring (TDM) is important to reduce the occurrence of toxicity and improve clinical efficacy. In the present study, we developed and validated a simple and high-throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to determine the concentration of amikacin in dried matrix spots (DMS) which the matrix is serum. DMS samples were obtained by spotting volumetric blood onto Whatman 903® cards. Samples were punched into 3 mm diameter discs and extracted with 0.2 % formic acid in water. The HILIC column (2.1 mm × 100 mm, 3.0 µm) under gradient elution was applied, and the analysis time was 3 min per injection. The mass spectrometry transitions were m/z 586.3 → 163.0 for amikacin and m/z 591.4 → 163.1 for D5-amikacin. Full validation was conducted for DMS method, and the method was applied for the amikacin TDM and compared with serum method. The linearity was ranged from 0.5 to 100 mg/L. Both within-run and between-run accuracy and precision of DMS ranged from 91.8 % to 109.6 % and 3.6 % to 14.2 %, respectively. The matrix effect was 100.5 %-106.5 % of DMS method. Amikacin remained stable in DMS for at least 6 days at room temperature, 16 days at 4 °C, 86 days at -20 °C and -70 °C. A good agreement between the DMS method and serum method has been shown in Bland-Altman plots and Passing-Bablok regression. All of the results demonstrated that the DMS methods can be a favorable replacement for amikacin TDM.

Safety, Tolerability and Pharmacokinetics of Single and Multiple Doses of Mirogabalin in Healthy Chinese Participants: A Randomized, Double-Blind, Placebo-Controlled Study.

INTRODUCTION: Mirogabalin is a treatment option for patients with neuropathic pain; however, safety, tolerability, and pharmacokinetics (PK) data specifically for Chinese individuals are limited to a single-dose study. We aimed to assess these for both single- and multiple-dose mirogabalin in healthy Chinese participants. METHODS: In this randomized, double-blind, placebo-controlled, phase I study, 54 healthy Chinese men and women aged 18-45 years were randomly allocated to receive single- (5, 10, or 15 mg, daily) or multiple-dose (5 mg titrated to 15 mg, twice-daily, over 22 days) oral mirogabalin or placebo. In each of three single-dose groups, 10 participants received mirogabalin and 2 received placebo; in the multiple-dose group, 14 participants received mirogabalin and 4 received placebo. The primary endpoints were PK, safety, and tolerability variables, including treatment-emergent adverse events (TEAEs), laboratory tests, and vital signs. PK data were collected for both single- and multiple-dose cohorts and evaluated by non-compartmental analysis. RESULTS: Single- and multiple-dose mirogabalin was generally well tolerated with no deaths, serious TEAEs, or TEAEs leading to treatment discontinuation. Frequently reported TEAEs included dizziness, nystagmus, increased blood triglycerides, headache, and increased blood uric acid and creatine phosphokinase. Single-dose mirogabalin was rapidly absorbed (median time to maximum plasma concentration, 1.00 h) and eliminated (mean terminal elimination half-life, 2.57-3.08 h). The exposure was approximately dose-proportional. In the multiple-dose cohort, the trough plasma concentration increased dose-proportionally, and exposure and clearance were comparable to that following a single 15-mg dose. The mean cumulative amount excreted into urine up to 48 h post-dose increased in a dose-proportional manner, the mean cumulative percentage excreted into urine was 61.9%-74.3%, and renal clearance remained relatively constant. CONCLUSION: Consistent with previous phase I studies in other populations, mirogabalin was safe and well tolerated in healthy Chinese participants at single and multiple doses of up to 15 mg twice-daily.

Safety and clinical efficacy of linezolid in children: a systematic review and meta-analysis.

BACKGROUND: We aimed to evaluate the tolerability and efficacy of linezolid in children for treating suspected and diagnosed Gram-positive bacterial infections. METHODS: A systematic literature search was conducted up to April 23, 2021, using linezolid and its synonyms as search terms. Two reviewers independently identified and extracted relevant randomized controlled trials and prospective cohort studies. The extracted studies were included in a single-rate meta-analysis of adverse events and clinical outcomes using random-effects models. RESULTS: A total of 1082 articles were identified, and nine studies involving 758 children were included in the meta-analysis. The overall proportion of adverse events was 8.91% [95% confidence interval (CI) = 1.64%-36.52%], with diarrhea (2.24%), vomiting (2.05%), and rash (1.72%) being the most common. The incidences of thrombocytopenia and anemia were 0.68% and 0.16%, respectively. Some specific adverse events, including rash and gastrointestinal events, were more frequent in the oral administration subgroup. In terms of efficacy, the overall proportion of clinical improvement was 88.80% (95% CI = 81.31%-93.52%). Children with a history of specific bacteriological diagnosis or concomitant antibiotic therapy had a 1.13-fold higher clinical improvement than children without such histories. The proportion of microbial eradication was 92.68% (95% CI = 84.66%-96.68%). The proportion of all-cause mortality was 0.16% (95% CI = 0.00%-7.75%). CONCLUSIONS: Linezolid was well-tolerated in pediatric patients and was associated with a low frequency of adverse events, such as anemia, thrombocytopenia, and neutropenia. Moreover, linezolid was effective in children with diagnosed and suspected Gram-positive infections.

Population pharmacokinetics and exposure-safety of lipophilic conjugates prodrug DP-VPA in healthy Chinese subjects for dose regime exploring.

Phospholipid-valproic acid (DP-VPA)is a prodrug for treating epilepsy. The present study explored the pharmacokinetics (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 Weibull 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.