Unraveling the efficacy network: A network meta-analysis of adjuvant external beam radiation therapy methods after hepatectomy.

BACKGROUND: Primary liver cancer is a malignant tumor with a high recurrence rate that significantly affects patient prognosis. Postoperative adjuvant external radiation therapy (RT) has been shown to effectively prevent recurrence after liver cancer resection. However, there are multiple RT techniques available, and the differential effects of these techniques in preventing postoperative liver cancer recurrence require further investigation. AIM: To assess the advantages and disadvantages of various adjuvant external RT methods after liver resection based on overall survival (OS) and disease-free survival (DFS) and to determine the optimal strategy. METHODS: This study involved network meta-analyses and followed the PRISMA guidelines. The data of qualified studies published before July 10, 2023, were collected from PubMed, Embase, the Web of Science, and the Cochrane Library. We included relevant studies on postoperative external beam RT after liver resection that had OS and DFS as the primary endpoints. The magnitudes of the effects were determined using risk ratios with 95% confidential intervals. The results were analyzed using R software and STATA software. RESULTS: A total of 12 studies, including 1265 patients with hepatocellular carcinoma (HCC) after liver resection, were included in this study. There was no significant heterogeneity in the direct paired comparisons, and there were no significant differences in the inclusion or exclusion criteria, intervention measures, or outcome indicators, meeting the assumptions of heterogeneity and transitivity. OS analysis revealed that patients who underwent stereotactic body radiotherapy (SBRT) after resection had longer OS than those who underwent intensity modulated radiotherapy (IMRT) or 3-dimensional conformal RT (3D-CRT). DFS analysis revealed that patients who underwent 3D-CRT after resection had the longest DFS. Patients who underwent IMRT after resection had longer OS than those who underwent 3D-CRT and longer DFS than those who underwent SBRT. CONCLUSION: HCC patients who undergo liver cancer resection must consider distinct advantages and disadvantages when choosing between SBRT and 3D-CRT. IMRT, a RT technique that is associated with longer OS than 3D-CRT and longer DFS than SBRT, may be a preferred option.

Improved sample treatment for the determination of flavonoids and polyphenols in sweet potato leaves by ultra performance convergence chromatography-tandem mass spectrometry.

This work reports the development and application of a multi-compound analysis method for the determination of 17 flavonoids and polyphenols in sweet potato leaves. Samples were processed by microwave-enhanced accelerated solvent extraction under low pressure at 120 °C for 10 min. Salting-out homogeneous liquid-liquid extraction was used to remove water and water-soluble impurities from the extract before ultra performance convergence chromatography-tandem mass spectrometry analysis. By using the supercritical fluid (CO2 and methanol) as the mobile phase, the 17 components and the internal standard were well separated in 10 min without obvious matrix effect. Method validation was performed and good accuracy (relative error in the range of ±3.6%) and precision (inter- and intra-day relative standard deviations<10.9%) were obtained. The limits of detection were in the range of 0.1-0.6 ng ∙ mL-1. Recoveries were assessed at three concentration levels and acceptable mean values (76.1-101.5%) were found. This method has also been used to analyze ten different samples, and the average concentrations of components were determined in the range of 4.9-218.6 mg/100 g dry weight. The results showed the method could be helpful for the analysis of flavonoids and polyphenols in plant leaves.

Determination of multi-class antibiotic residues in compost by microwave-enhanced accelerated solvent extraction and ultra performance convergence chromatography with tandem mass spectrometry.

This work reports the development and application of a multi-class compound analysis method for the determination of 20 antibiotic residues in compost. Samples were processed by microwave-enhanced accelerated solvent extraction at 120°C for 7.5 min. Salting-out homogeneous liquid-liquid extraction was used to remove water and water-soluble impurities from the extract before ultra performance convergence chromatography with tandem mass spectrometry analysis. By using the supercritical fluid (carbon dioxide) and organic solvent (methanol) as the mobile phase, the 20 antibiotics and the internal standard were well separated in 8.2 min without obvious matrix effect. Method validation was performed and good trueness (relative error in the range of ±5.0%) and precision (inter- and intraday relative standard deviations < 10.8%) were obtained. Method detection and quantitation limits were 0.8-1.9 and 2.7-7.1 ng/g, respectively. Recoveries were assessed at three concentration levels (10, 60, and 400 ng/g) and acceptable mean values (70.4-111.9%) were found. This method has also been used to analyze real samples, and the average concentrations of antibiotics (excepting the concentrations < method quantitation limits) were determined up to 123.6 ng/g. The results showed the method could be helpful for the analysis of multi-class antibiotics in environmental samples.

Antitumor effect of axitinib combined with dopamine and PK-PD modeling in the treatment of human breast cancer xenograft.

Rising evidence has shown the development of resistance to vascular endothelial growth factor receptor (VEGFR) inhibitors in the practices of cancer therapy. It is reported that the efficacy of axitinib (AX), a VEGFR inhibitor, is limited in the treatment of breast cancer as a single agent or in combination with other chemotherapeutic drugs due to the probability of rising population of cancer stem-like cells (CSCs) caused by AX. The present study evaluated the effect of dopamine (DA) improving AX's efficacy on MCF-7/ADR breast cancer in vitro and in vivo, and developed a pharmacokinetic-pharmacodynamic (PK-PD) model describing the in vivo experimental data and characterizing the interaction of effect between AX and DA. The results showed that AX up-regulated the expression of breast CSC (BCSC) markers (CD44+/CD24-/low) in vivo, and DA significantly synergized the inhibitory effect on tumor growth by deducting the BCSC frequency. The PK-PD model quantitatively confirmed the synergistic interaction with the parameter estimate of interaction factor ψ 2.43. The dose regimen was optimized as 60 mg/kg AX i.g. b.i.d. combined with 50 mg/kg DA i.p. q3d in the simulation study on the basis of the PK-PD model. The model where DA synergistically enhances the effect of AX in an all-or-none manner provides a possible solution in modeling the agents like DA. Moreover, the outcome of AX and DA combination therapy in MCF-7/ADR breast cancer provided further insight of co-administering DA in the treatment of the possible CSC-causing AX-resisting breast cancer. And this combination therapy has the prospect of clinical translation.

Determination of fluoroquinolones in cattle manure-based biogas residue by ultrasonic-enhanced microwave-assisted extraction followed by online solid phase extraction-ultra-high performance liquid chromatography-tandem mass spectrometry.

The present work describes the development and application of an ultrasonic-enhanced microwave-assisted extraction (UEMAE) followed by online solid phase extraction (SPE)-ultra-high performance liquid chromatography-tandem mass spectrometry method for the analysis of 14 fluoroquinolones in cattle manure-based biogas residue (CMBBR). The UEMAE was performed using the mixed solution of sodium dihydrogen phosphate and disodium ethylenediamine tetraacetic acid, avoiding use of any organic solvent. The online SPE system employed two solid phase extraction columns in a parallel manner, and the extraction was performed by passing 1 mL of the extract through the column. Quantification was performed using standard spiked samples and structural analogue internal standard, which were indispensable to reduce the matrix effects. Validation parameters were performed and good linearity (R2 > 0.99 in all cases) and precision (inter- and intra-day relative standard deviations were lower than 12.8%) were obtained. Limits of detection were as low as 0.021 ng ∙ g-1 and lower limits of quantification were 0.5 ng ∙ g-1 for all fluoroquinolones. The overall extraction recovery, which was the product of the UEMAE recovery and the online SPE recovery, was assessed for three concentration levels (0.8, 40 and 400 ng ∙ g-1) and acceptable values (74.3-99.3%) were found. As a part of the method validation, the developed method has been used to analyze real CMBBR samples. Nine fluoroquinolones were found in the concentration range of 0.9-74.6 ng ∙ g-1, while five were not detected in the samples. The results showed the method could be adapted for screening the presence or the final fate of fluoroquinolones during fermentation of animal waste.

Integrated pharmacokinetic/viral dynamic model for daclatasvir/asunaprevir in treatment of patients with genotype 1 chronic hepatitis C.

In order to develop an integrated pharmacokinetic/viral dynamic (PK/VD) model to predict long-term virological response rates to daclatasvir (DCV) and asunaprevir (ASV) combination therapy in patients infected with genotype 1 (GT1) chronic hepatitis C virus (HCV), a systematic publication search was conducted for DCV and ASV administered alone and/or in combination in healthy subjects or patients with GT1 HCV infection. On the basis of a constructed meta-database, an integrated PK/VD model was developed, which adequately described both DCV and ASV PK profiles and viral load time curves. The IC50 values of DCV and ASV were estimated to be 0.041 and 2.45 µg/L, respectively, in GT1A patients. A sigmoid Emax function was applied to describe the antiviral effects of DCV and ASV, depending on the drug concentrations in the effect compartment. An empirical exponential function revealed that IC50 changing over time described drug resistance in HCV GT1A patients during DCV or ASV monotherapy. Finally, the PK/VD model was evaluated externally by comparing the expected and observed virological response rates during and post-treatment with DCV and ASV combination therapy in HCV GT1B patients. Both the rates were in general agreement. Our PK/VD model provides a useful platform for the characterization of pharmacokinetic/pharmacodynamic relationships and the prediction of long-term virological response rates to aid future development of direct acting antiviral drugs.

Preclinical PK/PD model for combined administration of erlotinib and sunitinib in the treatment of A549 human NSCLC xenograft mice.

AIM: Combined therapy of EGFR TKI and VEGFR TKI may produce a greater therapeutic benefit and overcome EGFR TKI-induced resistance. However, a previous study shows that a combination of EGFR TKI erlotinib (ER) with VEGFR TKI sunitinib (SU) did not improve the overall survival in patients with non-small-cell lung cancer (NSCLC). In this study we examined the anticancer effect of ER, SU and their combination in the treatment of A549 human NSCLC xenograft mice, and conducted PK/PD modeling and simulations to optimize the dose regimen. METHODS: ER (20, 50 mg·kg(-1)·d(-1)) or SU (5, 10, 20 mg·kg(-1)·d(-1)) alone, or their combination were administered to BALB/c nude mice bearing A549 tumors for 22 days. The tumor size and body weight were recorded daily. The experimental data were used to develop PK/PD models describing the quantitative relationship between the plasma concentrations and tumor suppression in different dose regimens. The models were further evaluated and validated, and used to predict the efficacy of different combination regimens and to select the optimal regimen. RESULTS: The in vivo anticancer efficacy of the combination groups was much stronger than that of either drug administered alone. A PK/PD model was developed with a combination index (φ) of 4.4, revealing a strong synergistic effect between ER and SU. The model simulation predicted the tumor growth in different dosage regimens, and showed that the dose of SU played a decisive role in the combination treatment, and suggested that a lower dose of ER (≤5 mg·kg(-1)·d(-1)) and adjusting the dose of SU might yield a better dosage regimen for clinical research. CONCLUSION: The experimental data and modeling confirm synergistic anticancer effect of ER and SU in the treatment of A549 xenograft mice. The optimal dosage regimen determined by the PK/PD modeling and simulation can be used in future preclinical study and provide a reference for clinical application.

Model-based meta-analysis of the effects of non-selective and α1-selective GABAA receptor agonists in healthy volunteers.

PURPOSE: To quantify pharmacokinetic (PK) and pharmacodynamic (PD) relationships of various classes of GABAA agonists in healthy volunteers, in order to investigate the sensitivity of the biomarker responses due to differing GABAA-subtype selectivity and to explore the correlation between biomarker responses and side effects of these drugs. METHODS: A comprehensive search was conducted for published placebo-controlled clinical studies of non- and α1-selective GABAA drugs in healthy volunteers. PK/PD models were developed for concentrations and biomarker outcomes (saccadic eye movement (SEM), visual analogue scale (VAS), digit symbol substitution task (DSST), and critical flicker fusion test (CFFT)) extracted from included studies. Predicted responses and equivalent doses for biomarkers (based on predicted response) were used to compare drug effects. And the relationship between biomarkers and safety was explored by linear regression. RESULTS: A total of 2237 data from 163 articles were included. Based on PK and placebo effect modeling, linear biomarker-concentration relationships well fit the data. The α1-selective compounds had similar equivalent doses for VAS, DSST, and CFFT (4.7-6.7 mg), which were about three to seven times lower than that for SEM (14.4-35.5 mg), while such difference was less evident for non-selective drugs. DSST had the highest correlations with incidences of somnolence and dizziness. CONCLUSIONS: The integral PK/PD models of GABAA agonists were established in healthy volunteers. SEM was identified as the most sensitive biomarker in differentiating GABAA receptor α1 subtype selective compounds. The exploratory analysis implied that different relationships existed between the drug effects on biomarkers and the adverse event profiles in healthy volunteers.

A population pharmacokinetic study of tacrolimus in healthy Chinese volunteers and liver transplant patients.

AIM: To develop a population pharmacokinetic (PopPK) model of tacrolimus in healthy Chinese volunteers and liver transplant recipients for investigating the difference between the populations, and for potential individualized medication. METHODS: A set of 1100 sparse trough concentration data points from 112 orthotopic liver transplant recipients, as well as 851 dense data points from 40 healthy volunteers receiving a single dose of tacrolimus (2 mg, p.o.) were collected. PopPK model of tacrolimus was constructed using the program NONMEM. Related covariates such as age, hepatic and renal functions that were potentially associated with tacrolimus disposition were evaluated. The final model was validated using bootstrapping and a visual predictive check. RESULTS: A two-compartment model of tacrolimus could best describe the data from the two populations. The final model including two covariates, population (liver transplant recipients or volunteers) and serum ALT (alanine aminotransferase) level, was verified and adequately described the pharmacokinetic characteristics of tacrolimus. The estimates of V2/F, Q/F and V3/F were 22.7 L, 76.3 L/h and 916 L, respectively. The estimated CL/F in the volunteers and liver transplant recipients was 32.8 and 18.4 L/h, respectively. Serum ALT level was inversely related to CL/F, whereas age did not influence CL/F. Thus, the elderly (≥65 years) and adult (<65 years) groups in the liver transplant recipients showed no significant difference in the clearance of tacrolimus. CONCLUSION: Compared with using the sparse data only, the integrating modeling technique combining sparse data from the patients and dense data from the healthy volunteers improved the PopPK analysis of tacrolimus.

Population pharmacokinetic/pharmacodynamic model of clozapine for characterizing the relationship between accumulated exposure and PANSS scores in patients with schizophrenia.

BACKGROUND: The aim of this study was to characterize the relationship between accumulated exposure of clozapine and changes in Positive and Negative Syndrome Scale (PANSS) score in Chinese patients with schizophrenia by pharmacokinetic/pharmacodynamic (PK/PD) modeling. METHODS: Sparse clozapine PK data and PANSS scores were collected from 2 clinical studies of Chinese inpatients with schizophrenia. Two other rich PK data sets were included for more accurate assessment of clozapine PK characteristics. The relationship between clozapine-accumulated exposure and PANSS score was investigated using linear, log-linear, E(max), and sigmoid models, and each model was evaluated using visual predictive condition and normalized prediction distribution error methods. Simulations based on the final PK/PD model were preformed to investigate the effect of clozapine on PANSS scores under different dose regimens. RESULTS: A total of 1391 blood clozapine concentrations from 198 subjects (180 patients and 18 healthy volunteers) and 576 PANSS scores from 137 patients were included for PK and PK/PD analysis. A first-order 2-compartment PK model with covariates gender and smoking status influencing systemic clearance adequately described the PK profile of clozapine. The decrease in total PANSS score during treatment was best characterized using cumulated clozapine area under the curve (AUC) data in the E(max) model. The maximum decrease in PANSS during clozapine treatment (Emax) was 55.4%, and the cumulated AUC(50) (cAUC(50)) required to attain half of E(max) was 296 mg·L(-1)·h(-1)·d(-1). The simulations demonstrated that the accelerated dose titration and constant dose regimens achieved a similar maximum drug response but with a slower relief of symptoms in dose titration regimen. CONCLUSIONS: The PK/PD model can describe the clinical response as measured by decreasing PANSS score during treatment and may be useful for optimizing the dose regimen for individual patients.

Population pharmacokinetics of clozapine and its primary metabolite norclozapine in Chinese patients with schizophrenia.

AIM: To develop a combined population pharmacokinetic model (PPK) to assess the magnitude and variability of exposure to both clozapine and its primary metabolite norclozapine in Chinese patients with refractory schizophrenia via sparse sampling with a focus on the effects of covariates on the pharmacokinetic parameters. METHODS: Relevant patient concentration data (eg, demographic data, medication history, dosage regimen, time of last dose, sampling time, concentrations of clozapine and norclozapine, etc) were collected using a standardized data collection form. The demographic characteristics of the patients, including sex, age, weight, body surface area, smoking status, and information on concomitant medications as well as biochemical and hematological test results were recorded. Persons who had smoked 5 or more cigarettes per day within the last week were defined as smokers. The concentrations of clozapine and norclozapine were measured using a HPLC system equipped with a UV detector. PPK analysis was performed using NONMEM. Age, weight, sex, and smoking status were evaluated as main covariates. The model was internally validated using normalized prediction distribution errors. RESULTS: A total of 809 clozapine concentration data sets and 808 norclozapine concentration data sets from 162 inpatients (74 males, 88 females) at multiple mental health sites in China were included. The one-compartment pharmacokinetic model with mixture error could best describe the concentration-time profiles of clozapine and norclozapine. The population-predicted clearance of clozapine and norclozapine in female nonsmokers were 21.9 and 32.7 L/h, respectively. The population-predicted volumes of distribution for clozapine and norclozapine were 526 and 624 L, respectively. Smoking was significantly associated with increases in the clearance (clozapine by 45%; norclozapine by 54.3%). The clearance was significantly greater in males than in females (clozapine by 20.8%; norclozapine by 24.2%). The clearance of clozapine and norclozapine did not differ significantly between Chinese patients and American patients. CONCLUSION: Smoking and male were significantly associated with a lower exposure to clozapine and norclozapine due to higher clearance. This model can be used in individualized drug dosing and therapeutic drug monitoring.

Pharmacokinetic/pharmacodynamic studies on exenatide in diabetic rats.

AIM: To quantitatively evaluate the blood glucose-lowering effect of exenatide in diabetic rats. METHODS: Male Harlan-Sprague-Dawley rats were treated with high-fat diet/streptozotocin to induce type 2 diabetes. After subcutaneous administration of a single dose of exenatide (4.2, 42, or 210 µg/kg), serum exenatide, insulin concentration and blood glucose were measured. The pharmacokinetics of exenatide was characterized by a two-compartment model with first-order absorption. Insulin turnover was characterized by an effect compartment and indirect response combined model. Glucose turnover was described using an indirect response model with insulin (in effect compartment) stimulating glucose disposition and insulin (in insulin compartment) inhibiting glucose production simultaneously. The model parameters were estimated using nonlinear mixed-effects model program. Visual predictive check and model evaluation were used to make assessments. RESULTS: Exenatide exhibited rapid absorption with k(a)=4.45 h(-1), and the two-compartment model well described its pharmacokinetic profile. For the pharmacodynamic model, exenatide increased insulin release with the estimated S(m1) of 0.822 and SC(50) of 4.02 µg/L. It was demonstrated that insulin stimulated glucose dissipation (S(m2)=0.0513) and inhibited the production of glucose (I(m)=0.0381). Visual predictive check and model evaluation study indicated that a credible model was developed. CONCLUSION: The glucose-lowering effect of exenatide in diabetic rats is reliably described and predicted by the combined effect compartment/indirect response model.

[Comparison study of model evaluation methods: normalized prediction distribution errors vs. visual predictive check].

The objective of this study is to compare the normalized prediction distribution errors (NPDE) and the visual predictive check (VPC) on model evaluation under different study designs. In this study, simulation method was utilized to investigate the capability of NPDE and VPC to evaluate the models. Data from the false models were generated by biased parameter typical value or inaccurate parameter inter-individual variability after single or multiple doses with the same sampling time or multiple doses with varied sampling time, respectively. The results showed that there was no clear statistic test for VPC and it was difficult to make sense of VPC under the multiple doses with varied sampling time. However, there were corresponding statistic tests for NPDE and the factor of study design did not affect NPDE significantly. It suggested that the clinical data and model which VPC was not fit for could be evaluated by NPDE.