Nomogram prediction for the risk of venous thromboembolism in patients with lung cancer.

OBJECTIVE: The aim of this study was to establish a nomogram graph model to accurately predict the venous thromboembolism (VTE) risk probability in the general population with lung cancer. METHODS: Based on data from patients with lung cancer in Chongqing University Cancer Hospital of China, the independent risk factors of VTE were identified by the logistic univariable and multivariable analysis and were integrated to construct a nomogram, which was validated internally. The predictive effectiveness of the nomogram was evaluated by the receiver operating characteristic curve (ROC) and calibration curve. RESULTS: A total of 3398 lung cancer patients were included for analysis. The nomogram incorporated eleven independent VTE risk factors including karnofsky performance scale (KPS), stage of cancer, varicosity, chronic obstructive pulmonary disease (COPD), central venous catheter (CVC), albumin, prothrombin time (PT), leukocyte counts, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), dexamethasone, and bevacizumab. The C-index of the nomogram model was 0.843 and 0.791 in the training and validation cohort, respectively, demonstrating good discriminative power. The calibration plots of the nomogram revealed excellent agreement between the predicted and actual probabilities. CONCLUSIONS: We established and validated a novel nomogram for predicting the risk of VTE in patients with lung cancer. The nomogram model could precisely estimate the VTE risk of individual lung cancer patients and identify high-risk patients who are in need of a specific anticoagulation treatment strategy.

Effects of Unsuppressed Endogenous Insulin on Pharmacokinetics and/or Pharmacodynamics of Study Insulin in the Healthy: A Retrospective Study.

C-peptide, a marker of endogenous insulin, should be consistently inhibited during euglycemic clamping, while an elevated postdosing C-peptide (CPpostdosing ) is not an occasional phenomenon. This was a retrospective study that included 33 men who underwent a manual euglycemic clamp with a subcutaneous injection of insulin aspart (IAsp) aiming to describe the effects of insufficient suppression of endogenous insulin on estimates of the pharmacokinetics and pharmacodynamics of injected insulin. The time profiles of whole blood glucose, human insulin, glucose infusion rate (GIR), and C-peptide were recorded. The subjects were divided into 2 groups at a ratio of 2:1: group A ([CPpostdosing ]max >baseline CP [CPbaseline ]), group B ([CPpostdosing ]max ≤ CPbaseline ). The endogenous insulin was approximately equal to the measured value of human insulin or calculated from the C-peptide. The basal glucose, CPbaseline , basal human insulin, homeostatic model assessment of insulin resistance, IAsp dose, and demographic statistics were all comparable between the 2 groups except the "clamped" glucose. The average clamped glucose was 99.7% (group A) and 94.9% (group B) of baseline. After correction for clamped glucose, GIR area under the concentration-time curve from time 0 to 8 hours was higher in group A (P < .05) under comparable IAsp exposure. Endogenous insulin area under the concentration-time curve from time 0 to 8 hours calculated from C-peptide was different from that measured from human insulin in group A (P < .05), whereas no statistical difference between these measures was observed in group B. Hence, blood glucose should be controlled below the baseline to ensure the inhibition of endogenous insulin. Unsuppressed endogenous insulin may contribute to observed GIR, and the endogenous insulin-corrected pharmacokinetics estimated by C-peptide may be inaccurate with insufficient endogenous insulin suppression.

Similar pharmacokinetics and pharmacodynamics of a new biosimilar and reference insulin aspart in healthy Chinese males.

Insulin aspart (IAsp) is one of the main therapies used to control blood glucose after a meal. This study aimed to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of 2 rapid-acting IAsp products: a new IAsp biosimilar (RD10046) and NovoRapid. In a single-center, randomized, single-dose, 2-period, crossover, euglycemic clamp study (registry number: CTR20180517, registration date: 2018-05-30), healthy Chinese males were randomized to receive 0.2 U/kg of the IAsp biosimilar RD10046 and NovoRapid under fasted conditions on two separate occasions. PK and PD were assessed for up to 10 h. Of the 30 randomized subjects, all 30 completed both treatment periods. The PK (area under the curve [AUC] of total IAsp; maximum observed IAsp concentration [Cmax]) and PD (maximum glucose infusion rate [GIRmax]; total glucose infusion during the clamp [AUCGIR,0-10h]) were similar between the new IAsp biosimilar RD10046 and NovoRapid. In all cases, the 90% CIs for the ratios of the geometric means were completely contained in the prespecified acceptance limits of 0.80-1.25. No hypoglycemic events, allergic reactions, or local injection adverse reactions occurred in this trial. We concluded that the studied IAsp biosimilar (RD10046) was bioequivalent to NovoRapid.

Interindividual Variability in the Pharmacodynamic and Pharmacokinetic Characteristics of Recombinant Human Insulin and Insulin Aspart.

PURPOSE: The present study compared the interindividual variability in the pharmacodynamic (PD) and pharmacokinetic (PK) properties of a short-acting recombinant human insulin to those of insulin aspart through manual euglycemic glucose clamp tests. METHODS: Sixty healthy Chinese male volunteers were randomly assigned to receive human insulin or insulin aspart, administered via SC injection (0.2 U/kg). For the evaluation of interindividual variability in PD and PK properties (glucose infusion rate [GIR], insulin concentration [INS]) through euglycemic clamp studies, %CVs were calculated, and PK/PD interindividual variability was compared between the 2 groups. FINDINGS: The differences between the human insulin and insulin aspart groups in interindividual variabilities in total AUCs of the GIR (19% vs 21%) and INS (14% vs 17%) were not significant. The interindividual variabilities in AUCgir0-120min, early Tmax50%, and AUCins0-120min were lower in the insulin aspart group than in the human insulin group (22% vs 44%, 21% vs 35%, and 22% vs 28%, respectively; all, P ˂ 0.05), while the interindividual variabilities in the AUCs of GIR120-600min and INS120-600min were higher with insulin aspart than with human insulin (29% vs 20%, 51% vs 30%; both, P ˂ 0.05). IMPLICATIONS: The overall interindividual variability with insulin aspart was similar to that with recombinant human insulin. Yet insulin concentration and metabolic effect during the declining period were more variable with insulin aspart compared to human insulin in these healthy male subjects.

Oscillations of C-peptide in the euglycemic clamp and their effect on the pharmacodynamic assessment of insulin preparations.

C-peptide should be continuously suppressed. However, increased postdosing C-peptide is not an uncommon phenomenon in euglycemic clamp studies involving healthy participants. This study aimed to determine the extent to which the postdosing C-peptide increases from the baseline that could affect the accuracy of glucodynamics in euglycemic clamp studies involving healthy subjects. First, 10 healthy males underwent a 10-h euglycemic clamp without exogenous insulin administration to obtain a reference interval (RI) for the ratio of C-peptide after 0 min (CPt ) to baseline C-peptide (CP0 ). Then, the data from a pharmacokinetic and pharmacodynamic study of insulin aspart (IAsp) were analyzed, and 70 eligible clamps were grouped by CPt /CP0 : group A ([CPt /CP0 ]max   > upper limit of RI), group B (1<[CPt /CP0 ]max  ≤ upper limit of RI), and group C ([CPt /CP0 ]max  ≤ 1). The differences in basal and clamped blood glucose, CPt /CP0 , and the pharmacokinetics and pharmacodynamics of IAsp were compared, and the relationship between elevated CPt and the accuracy of pharmacodynamics was analyzed. The RI of CPt /CP0 was 22.7%-152.1%; 1.5 × baseline might be a ceiling for the increase in CPt under stable conditions. The maximum glucose infusion rate (GIR) in group A tended to be higher than that in group B or C (Pfor trend  = 0.033). The AUCGIR,0-10h in groups A, B, and C was 1983 ± 650,1682 ± 454, and 1479 ± 440 mg/kg (P = 0.047), respectively, under comparable IAsp exposure. No intergroup difference was detected in clamped glucose, IAsp dose, or body mass index. In conclusion, postdosing C-peptide over 1.5× baseline indicates insufficient inhibition of endogenous insulin secretion, which could compromise the pharmacodynamics of insulin preparations.

Determination of glyphosate in soil/sludge by high performance liquid chromatography.

In order to evaluate the pollution caused due to glyphosate (Glyp) in soils and sludge, it is important to establish a set of standard determination techniques. In this work, the previously reported HPLC analytical method for determination of Glyp has been improved in order to be applied for all kinds of soils/sludge. The soil/sludge samples were extracted using sodium phosphate and trisodium citrate aqueous solutions. The extract was adjusted to pH 9 and contaminations were removed by washing with n-hexane. The method developed in this work further involves derivatization with 9-fluorenylmethylchloroformate (FMOC-Cl) followed by high performance liquid chromatography (HPLC) coupled with fluorescence detection. The method was validated in three soil (red soil, black soil and paddy soil) and two sludge samples (lake and river sludge) from China and verified in six laboratories. A good linear relationship (correlation coefficients ≥0.999) was observed within the range of 0.005-0.5mg/L. The limit of detection (LOD) and the limit of quantitation (LOQ) were determined to be 0.01mg/kg and 0.04mg/kg, respectively. The precision and accuracy were satisfactory with the relative standard deviation (RSD) lower than 15% and the mean recovery values ranging from 75% to 110% (n=6), that spiked at three levels (0.1, 0.5 and 1.0mg/kg).