Pharmacokinetics of Voriconazole in Peritoneal Fluid of Critically Ill Patients.

Data on the distribution of voriconazole (VRC) in the human peritoneal cavity are sparse. This prospective study aimed to describe the pharmacokinetics of intravenous VRC in the peritoneal fluid of critically ill patients. A total of 19 patients were included. Individual pharmacokinetic curves, drawn after single (first dose on day 1) and multiple (steady-state) doses, displayed a slower rise and lower fluctuation of VRC concentrations in peritoneal fluid than in plasma. Good but variable penetration of VRC into the peritoneal cavity was observed, and the median (range) peritoneal fluid/plasma ratios of the area under the concentration-time curve (AUC) were 0.54 (0.34 to 0.73) and 0.67 (0.63 to 0.94) for single and multiple doses, respectively. Approximately 81% (13/16) of the VRC steady-state trough concentrations (Cmin,ss) in plasma were within the therapeutic range (1 to 5.5 µg/mL), and the corresponding Cmin,ss (median [range]) in peritoneal fluid was 2.12 (1.39 to 3.72) µg/mL. Based on the recent 3-year (2019 to 2021) surveillance of the antifungal susceptibilities for Candida species isolated from peritoneal fluid in our center, the aforementioned 13 Cmin,ss in peritoneal fluid exceeded the MIC90 of C. albicans, C. glabrata, and C. parapsilosis (0.06, 1.00, and 0.25 µg/mL, respectively), which supported VRC as a reasonable choice for initial empirical therapies against intraabdominal candidiasis caused by these three Candida species, prior to the receipt of susceptibility testing results.

Population pharmacokinetics and limited sampling strategies of polymyxin B in critically ill patients.

OBJECTIVES: To characterize the pharmacokinetics (PK) of polymyxin B in Chinese critically ill patients. The factors significantly affecting PK parameters are identified, and a limited sampling strategy for therapeutic drug monitoring of polymyxin B is explored. METHODS: Thirty patients (212 samples) were included in a population PK analysis. A limited sampling strategy was developed using Bayesian estimation, multiple linear regression and modified integral equations. Non-linear mixed-effects models were developed using Phoenix NLME software. RESULTS: A two-compartment population PK model was used to describe polymyxin B PK. Population estimates of the volumes of central compartment distribution (V) and peripheral compartment distribution (V2), central compartment clearance (CL) and intercompartmental clearance (Q) were 7.857 L, 12.668 L, 1.672 L/h and 7.009 L/h. Continuous renal replacement therapy (CRRT) significantly affected CL, and body weight significantly affected CL and Q. The AUC0-12h of polymyxin B in patients with CRRT was significantly lower than in patients without CRRT. CL and Q increased with increasing body weight. A limited sampling strategy was suggested using a two-sample scheme with plasma at 0.5h and 8h after the end of infusion (C0.5 and C8) for therapeutic drug monitoring in the clinic. CONCLUSIONS: A dosing regimen should be based on body weight and the application of CRRT. A two-sample strategy for therapeutic drug monitoring could facilitate individualized treatment with polymyxin B in critically ill patients.

The Nazeris fauna of the Leigong Mountain, Guizhou, China (Coleoptera, Staphylinidae, Paederinae).

Seven species of Nazeris Fauvel, 1873 are reported for Guizhou, China. All of them are described as new: N. ingentis Lin, Yu Hu, sp. n., N. resimus Lin, Yu Hu, sp. n., N. leigongensis Lin, Yu Hu, sp. n., N. yujiei Lin, Yu Hu, sp. n., N. muricatus Lin, Yu Hu, sp. n., N. excertus Lin, Yu Hu, sp. n. and N. serratus Lin, Yu Hu, sp. n.

A new species and additional records of Lobrathium Mulsant amp; Rey (Coleoptera: Staphylinidae: Paederinae) from southern China.

Lobrathium chengzhifeii Lin Peng sp. n. (Yunnan: Mengsong) is described and illustrated. The female sexual characters of L. anatinum W.-R. Li and L.-Z. Li, 2013 are described and illustrated for the first time. Additional records of L. ablectum Assing, 2012, L. biaculeatum Assing, 2012, L. demptum Assing, 2012, L. diaoluoense W.-R. Li and L.-Z. Li, 2013, L. excisissimum Assing, 2012, L. hongkongense Bernhauer, 1931 and L. tortile F.-K. Zheng, 1988 are reported. Including the new taxa, 66 Lobrathium species are currently known from China.

Organic chromium derived from the chelation of Ganoderma lucidum polysaccharide and chromium (III) alleviates metabolic syndromes and intestinal microbiota dysbiosis induced by high-fat and high-fructose diet.

Organic chromium is of great interest and has become an important chromium supplement resource in recent years because of its low toxicity and easy absorption. In our previous study, we synthesized a novel organic chromium [GLP-Cr] through the chelation of Ganoderma lucidum polysaccharide and chromium (III). The purpose of this study was to investigate the beneficial effects of GLP-Cr on the improvement of metabolic syndromes (MetS) in mice fed with a high-fat and high-fructose diet (HFHFD) and its mechanism of action. The results indicated that oral administration of GLP-Cr inhibited the excessive exaltation of body weight, glucose tolerance, fasting blood glucose and lipid levels, hepatic total cholesterol (TC), triglyceride (TG) levels caused by HFHFD. Besides, 16S rRNA amplicon sequencing showed that GLP-Cr intervention evidently ameliorated intestinal microbiota dysbiosis by changing the proportions of some intestinal microbial phylotypes. In addition, correlation network-based analysis indicated that the key intestinal microbial phylotypes were closely related to biochemical parameters associated with MetS under GLP-Cr intervention. Liver metabolomics analysis suggested that GLP-Cr intervention significantly regulated the levels of some biomarkers involved in alpha-linolenic acid metabolism, fatty acid biosynthesis, steroid hormone biosynthesis, glycerophospholipid metabolism, glycerolipid metabolism, steroid hormone biosynthesis, primary bile acid biosynthesis, and so on. Moreover, GLP-Cr intervention regulated liver mRNA levels of key genes associated with glucose and lipid metabolism. The mRNA level of glucose transporter type 4 (Glut4) was markedly increased by GLP-Cr intervention, and the mRNA levels of phosphoenolpyruvate carboxykinase (Pepck) and glucose-6-phosphatase (G6Pase) in the liver were significantly decreased. Meanwhile, GLP-Cr intervention significantly decreased hepatic mRNA levels of cluster of differentiation 36 (Cd36), acetyl-CoA carboxylase 1 (Acc1) and sterol regulatory element binding protein-1c (Srebp-1c), indicating that GLP-Cr intervention inhibited the excessive accumulation of free fatty acids in the liver. These findings suggest that the prevention of hyperglycemia and dyslipidemia by GLP-Cr may be closely related to the regulation of gut microbial composition and hepatic metabolic pathways, thus GLP-Cr can be serving as a functional component in the prevention of MetS.

New data on the genus Lathrobium Gravenhorst (Coleoptera: Staphylinidae: Paederinae) of Guangxi, South China.

Lathrobium caiyujiei Lin Peng sp. n. (Guangxi: Jinwanshan N. R.), L. jiuwanshanense Lin Peng sp. n. (Guangxi: Jinwanshan N. R.) and L. zhusha Lin Peng sp. n. (Guangxi: Jinwanshan N. R.) are described and illustrated. Additional records of L. damingense Peng Li, 2013, L. dayaoshanense Peng Li, 2012, L. hujiayaoi Peng Li, 2013, L. maoershanense Peng Li, 2012 and L. zhujianqingi Peng Li, 2012 are reported. Including the new taxa, 227 Lathrobium species are currently known from mainland China.

Evaluation of quality and readability of over-the-counter medication package inserts.

BACKGROUND: Over-the-counter (OTC) medication package inserts are vital references for healthcare professionals to make drug recommendations and influential education materials that patients commonly refer to when self-caring. However, little is known about the quality and readability of the OTC medication package inserts in China. OBJECTIVES: This study aimed at evaluating the quality and readability of OTC medication package inserts. METHODS: Package inserts of OTC medication were selected based on the market share and pharmacological category. The quality of the package inserts was evaluated based on standards adapted separately from the Chinese National Medical Products Administration (NMPA) and European Medicines Agency's (EMA) Working Group. The readability was assessed using the Patient Education Materials Assessment Tool (PEMAT) in conjunction with the Chinese Readability Index Explorer (CRIE). RESULTS: A total of 29 OTC medication package inserts consisting of 12 Western Medicine (WM) and 17 Chinese Tradition Patent Medicine (CTPM) package inserts were included. Overall, the OTC package inserts met 92% of the NMPA standards and 54% of the EMA standards. In terms of readability assessment using PEMAT, the overall median (interquartile range) understandability score was 38% (38-45%) and for actionability score was 40% (40-55%). The overall text reading level of package inserts measured by the CRIE, after removing some medical jargon, is equivalent to the median reading level for the 12th (9.5-12th) grade reading level. CONCLUSIONS: The quality of OTC medication package inserts was satisfactory under internal standards but poor under international standards. Some OTC pharmacological information is not provided due to lack of research, especially for CTPM. A more informative and comprehensive package insert may be needed to guide drug use decisions. OTC medication package inserts are not appropriate patient education materials in terms of readability. Additional materials may be developed to supplement package inserts for patient education for OTC medications.

Population pharmacokinetic model-guided optimization of intravenous voriconazole dosing regimens in critically ill patients with liver dysfunction.

STUDY OBJECTIVES: This study aimed to establish a population pharmacokinetic (PPK) model of intravenous voriconazole (VRC) in critically ill patients with liver dysfunction and to explore the optimal dosing strategies in specific clinical scenarios for invasive fungal infections (IFIs) caused by common Aspergillus and Candida species. DESIGN: Prospective pharmacokinetics study. SETTING: The intensive care unit in a tertiary-care medical center. PATIENTS: A total of 297 plasma VRC concentrations from 26 critically ill patients with liver dysfunction were included in the PPK analysis. METHODS: Model-based simulations with therapeutic range of 2-6 mg/L as the plasma trough concentration (Cmin ) target and the free area under the concentration-time curve from 0 to 24 h (ƒAUC24 ) divided by the minimum inhibitory concentration (MIC) (ie, ƒAUC24 /MIC) ≥25 as the effective target were performed to optimize VRC dosing regimens for Child-Pugh class A and B (CP-A/B) and Child-Pugh class C (CP-C) patients. RESULTS: A two-compartment model with first-order elimination adequately described the data. Significant covariates in the final model were body weight on both central and peripheral distribution volume and Child-Pugh class on clearance. Intravenous VRC loading dose of 5 mg/kg every 12 h (q12h) for the first day was adequate for CP-A/B and CP-C patients to attain the Cmin target at 24 h. The maintenance dose regimens of 100 mg q12h or 200 mg q24h for CP-A/B patients and 50 mg q12h or 100 mg q24h for CP-C patients could obtain the probability of effective target attainment of >90% at an MIC ≤0.5 mg/L and achieve the cumulative fraction of response of >90% against C. albicans, C. parapsilosis, C. glabrata, C. krusei, A. fumigatus, and A. flavus. Additionally, the daily VRC doses could be increased by 50 mg for CP-A/B and CP-C patients at an MIC of 1 mg/L, with plasma Cmin monitored closely to avoid serious adverse events. It is recommended that an appropriate alternative antifungal agent or a combination therapy could be adopted when an MIC ≥2 mg/L is reported, or when the infection is caused by C. tropicalis but the MIC value is not available. CONCLUSIONS: For critically ill patients with liver dysfunction, the loading dose of intravenous VRC should be reduced to 5 mg/kg q12h. Additionally, based on the types of fungal pathogens and their susceptibility to VRC, the adjusted maintenance dose regimens with lower doses or longer dosing intervals should be considered for CP-A/B and CP-C patients.

Voriconazole pharmacokinetics in a critically ill patient during extracorporeal membrane oxygenation.

The pharmacokinetics (PK) of several drugs including antimicrobials might be highly altered during extracorporeal membrane oxygenation (ECMO) therapy. We present the change of voriconazole (VRC) PK during ECMO in a critically ill patient who received intravenous VRC at a maintenance dose of 200 mg every 12 h for empirical antifungal therapy. Two PK profiles were drawn before and after the initiation of ECMO therapy. Though the trough levels (both C0 and C12) with ECMO were slightly lower than that without ECMO (12.58 and 12.84 vs. 14.02 µg/mL), the peak levels and the area under the concentration-time curve from 0 h to 6 h (AUC0-6) were comparable (16.36 vs. 16.06 µg/mL and 90.78 vs. 91.45 µg·h/mL, respectively), indicating that VRC plasma exposure during ECMO therapy did not greatly decrease in our patient. The circuit factors including the type of membrane should be taken into account to further identify the effects of ECMO on the PK of VRC.

New species and records of Anchocerus Fauvel in China (Coleoptera: Staphylinidae: Staphylininae).

Two species of Anchocerus Fauvel are reported from China, one of them described as new: A. wenxuani Lin Hu, sp. n. (Guangxi). Anchocerus giganteus Hu, Li Zhao, 2010 is newly recorded from Shanghai, Jiangxi, Guangxi and Guangdong. A map showing the distribution of all Chinese species is provided.

The Nazeris fauna of the Nanling Mountain Range, China (Coleoptera, Staphylinidae, Paederinae).

Fourteen species of Nazeris Fauvel, 1873 are reported for the Nanling Mountain Range, China. Four of them are described as new: N.xingmini Lin & Hu, sp. nov. (Guangdong, Jiangxi), N.huaiweni Lin & Hu, sp. nov. (Guangdong), N.meihuaae Lin & Hu, sp. nov. (Guangdong, Jiangxi) and N.lichongi Lin & Hu, sp. nov. (Hunan). An identification key to the Nazeris species reported for the Nanling Mountains, and a map showing their distribution are provided.

On the Lathrobium fauna of the Nanling National Nature Reserve, southern China (Coleoptera, Staphylinidae, Paederinae).

Material of the paederine genus Lathrobium Gravenhorst, 1802 from the Nanling National Nature Reserve, southern China, is examined. Four species are identified, one of them described previously. Three species are described and illustrated for the first time, all of them micropterous and locally endemic: L.yangyihani Lin & Peng sp. nov., L.jiaxingyangi Lin & Peng sp. nov., and L.wangxingmini Lin & Peng sp. nov. The female sexual characters of L.guangdongense Peng & Li, 2014 are described and illustrated for the first time. Including the new taxa, 224 Lathrobium species are currently known from mainland China.

Two new species and additional records of mainland Chinese Domene (Coleoptera: Staphylinidae: Paederinae).

Material of the genus Domene Fauvel, 1873 from the Chinese provinces Heilongjiang, Gansu, Hunan, Guangdong, Guangxi, Sichuan and Guizhou is examined. Eight species were identified, six of them described previously and two are newly described: D. hui sp. n. (Guangdong: Shimentai); D. leigongensis sp. n. (Guizhou: Leigong Shan). The genus is now represented in mainland China by 23 species.

Predictors of Adverse Events and Determinants of the Voriconazole Trough Concentration in Kidney Transplantation Recipients.

Voriconazole is the mainstay for the treatment of invasive fungal infections in patients who underwent a kidney transplant. Variant CYP2C19 alleles, hepatic function, and concomitant medications are directly involved in the metabolism of voriconazole. However, the drug is also associated with numerous adverse events. The purpose of this study was to identify predictors of adverse events using binary logistic regression and to measure its trough concentration using multiple linear modeling. We conducted a prospective analysis of 93 kidney recipients cotreated with voriconazole and recorded 213 trough concentrations of it. Predictors of the adverse events were voriconazole trough concentration with the odds ratios (OR) of 2.614 (P = 0.016), cytochrome P450 2C19 (CYP2C19), and hemoglobin (OR 0.181, P = 0.005). The predictive power of these three factors was 91.30%. We also found that CYP2C19 phenotypes, hemoglobin, platelet count, and concomitant use of ilaprazole had quantitative relationships with voriconazole trough concentration. The fit coefficient of this regression equation was R2  = 0.336, demonstrating that the model explained 33.60% of interindividual variability in the disposition of voriconazole. In conclusion, predictors of adverse events are CYP2C19 phenotypes, hemoglobin, and voriconazole trough concentration. Determinants of the voriconazole trough concentration were CYP2C19 phenotypes, platelet count, hemoglobin, concomitant use of ilaprazole. If we consider these factors during voriconazole use, we are likely to maximize the treatment effect and minimize adverse events.

Pharmacokinetics of intravenous voriconazole in patients with liver dysfunction: A prospective study in the intensive care unit.

OBJECTIVES: To characterize the pharmacokinetics (PK) of intravenous voriconazole (VRC) in critically ill patients with liver dysfunction. METHODS: Patients with liver dysfunction in the intensive care unit (ICU) were included prospectively. The Child-Pugh score was used to categorize the degree of liver dysfunction. The initial intravenous VRC dosing regimen comprised a loading dose of 300 mg every 12 h for the first 24 h, followed by 200 mg every 12 h. The first PK curves (PK curve 1) were drawn within one dosing interval of the first dose for 17 patients; the second PK curves (PK curve 2) were drawn within one dosing interval after a minimum of seven doses for 12 patients. PK parameters were estimated by non-compartmental analysis. RESULTS: There were good correlations between the area under the curve (AUC0-12) of PK curve 2 and the corresponding trough concentration (C0) and peak concentration (Cmax) (r2 = 0.951 and 0.963, respectively; both p < 0.001). The median half-life (t1/2) and clearance (CL) of patients in Child-Pugh class A (n = 3), B (n = 5), and C (n = 4) of PK curve 2 were 24.4 h and 3.31 l/h, 29.1 h and 2.54 l/h, and 60.7 h and 2.04 l/h, respectively. In the different Child-Pugh classes, the CL (median) of PK curve 2 were all lower than those of PK curve 1. The apparent steady-state volume of distribution (Vss) of PK curve 1 was positively correlated with actual body weight (r2 = 0.450, p = 0.004). The median first C0 of 17 patients determined on day 5 was 5.27 (2.61) µg/ml, and 29.4% of C0 exceeded the upper limit of the therapeutic window (2-6 µg/ml). CONCLUSIONS: The CL of VRC decreased with increasing severity of liver dysfunction according to the Child-Pugh classification, along with an increased t1/2, which resulted in high plasma exposure of VRC. Adjusted dosing regimens of intravenous VRC should be established based on Child-Pugh classes for these ICU patients, and plasma concentrations should be monitored closely to avoid serious adverse events.

Population pharmacokinetics of voriconazole and CYP2C19 polymorphisms for optimizing dosing regimens in renal transplant recipients.

AIMS: The aims of the present study were to characterize the pharmacokinetics of voriconazole in renal transplant recipients and to identify factors significantly affecting pharmacokinetic parameters. We also aimed to explore the optimal dosing regimens for patients who developed invasive fungal infections. METHODS: A total of 105 patients (342 concentrations) were included prospectively in a population pharmacokinetic analysis. Nonlinear mixed-effects models were developed using Phoenix NLME software. Dosing simulations were performed based on the final model. RESULTS: A one-compartment model with first-order absorption and elimination was used to characterize voriconazole pharmacokinetics. Population estimates of clearance, volume of distribution and oral bioavailability were 2.88 l·h-1 , 169.3 l and 58%, respectively. The allele frequencies of cytochrome P450 gene (CYP) 2C19*2, *3 and *17 variants were 29.2%, 5.2% and 0.5%, respectively. CYP2C19 genotype had a significant effect on the clearance. Voriconazole trough concentrations in poor metabolizers were significantly higher than in intermediate metabolizers and extensive metabolizers alike. The volume of distribution increased with increased body weight. The oral bioavailability was substantially lower within 1 month after transplantation but increased with postoperative time. Dosing simulations indicated that during the early postoperative period, poor metabolizers could be treated with 150 mg intravenously or 250 mg orally twice daily; intermediate metabolizers with 200 mg intravenously or 350 mg orally twice daily; and extensive metabolizers with 300 mg intravenously twice daily. CONCLUSIONS: Using a combination of CYP2C19 genotype and postoperative time to determine the initial voriconazole dosing regimens followed by therapeutic drug monitoring could help to advance individualized treatment in renal transplantation patients with invasive fungal infections.

Impact of CYP2C19 Genotype and Liver Function on Voriconazole Pharmacokinetics in Renal Transplant Recipients.

BACKGROUND: Invasive fungal infection (IFI) is one of the leading causes of early death after renal transplantation. Voriconazole (VRC) is the first-line drug of IFI. Because of the large inter- and intraindividual variability in VRC plasma concentrations and the narrow therapeutic window for treating patients with IFIs, it is crucial to study the factors which could influence pharmacokinetic variability. We performed a population pharmacokinetics (PPK) study of VRC for personalized medicine. METHODS: A total of 125 trough concentrations (Cmin) from 56 patients were evaluated, retrospectively. Nonlinear mixed effect model was used to describe a PPK model that was internally validated by bootstrap method. Potential covariates included demographic characteristics, physiological and pathological data, concomitant medications, and CYP2C19 genotype. RESULTS: A 1-compartment model with first-order absorption and elimination was fit to characterize the VRC pharmacokinetics in renal transplant recipients (RTRs). Aspartate aminotransferase (AST) had a significant influence on clearance (CL) while CYP2C19 genotype had a major impact on the volume of distribution (V). The parameters of CL and V were 4.76 L/h and 22.47 L, respectively. The final model was V (L) = 22.47 × [1 + 2.21 × (EM = 1)] × [1 + 4.67 × (IM = 1)] × [1 + 3.30 × (PM = 1)] × exp (0.96); CL (L/h) = 4.76 × (AST/33)^(-0.23) × exp (0.14). VRC Cmin in intermediate metabolizers was significantly higher than in extensive metabolizers. CONCLUSIONS: Liver function and CYP2C19 polymorphism are major determinants of VRC pharmacokinetic variability in RTRs. Genotypes and clinical biomarkers can determine the initial scheme. Subsequently, therapeutic drug monitoring can optimize clinical efficacy and minimize toxicity. Hence, this is a feasible way to facilitate personalized medicine in RTRs. In addition, it is the first report about PPK of VRC in RTRs.