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PURPOSE: Therapeutic drug monitoring (TDM) of voriconazole (VCZ) should be mandatory for all pediatric patients with invasive fungal infections (IFIs). The narrow therapeutic index, inter-individual variability in VCZ pharmacokinetics, and genetic polymorphisms cause achieving therapeutic concentration during therapy to be challenging in this population. METHODS: The study included 44 children suffering from IFIs treated with VCZ. Trough concentrations (Ctrough) of VCZ ware determined by the HPLC-FLD method. Identification of the CYP2C19*2 and CYP2C19*17 genetic polymorphisms was performed by PCR-RFLP. The correlation between polymorphisms and VCZ Ctrough was analyzed. Moreover, the effect of factors such as dose, age, sex, route of administration, and drug interactions was investigated. RESULTS: VCZ was administered orally and intravenously at a median maintenance dosage of 14.7 mg/kg/day for a median of 10 days. The VCZ Ctrough was highly variable and ranged from 0.1 to 6.8 mg/L. Only 45% of children reached the therapeutic range. There was no significant association between Ctrough and dosage, age, sex, route of administration, and concomitant medications. The frequencies of variant phenotype normal (NM), intermediate (IM), rapid (RM) and ultrarapid metabolizers (UM) were 41%, 18%, 28%, and 13%, respectively. Ctrough of VCZ were significantly higher in NM and IM groups compared with RM, and UM groups. CONCLUSION: The Ctrough of VCZ is characterized by inter-individual variability and a low rate of patients reaching the therapeutic range. The significant association exists in children between VCZ Ctrough and CYPC19 phenotype. The combination of repeated TDM and genotyping is necessary to ensure effective treatment.
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Cyclosporine A (CsA) is the prevalent immunosuppressive drug for preventing and treating graft-versus-host disease after hematopoietic stem cell transplantation (HSCT) in both children and adults. Population pharmacokinetic studies have identified covariates, owing to their large between-subject variability, facilitating individualized therapy. However, no review has summarized CsA's population pharmacokinetics post-HSCT. This systematic review aims to synthesize population pharmacokinetic studies of CsA therapy in HSCT recipients and explore influencing covariates. Thirteen studies, comprising five involving children, one involving both children and adults and seven involving adults, were included. The median apparent clearance in children surpassed that in adults, influenced notably by hematocrit level and body. While liver function impacted clearance, the effect was insignificant. Co-administration with cytochrome P450 enzyme inhibitors (e.g., fluconazole or itraconazole) decreased drug clearance, whereas inducers (e.g., rifampicin or rifapentine) increased it. Area under the curve analysis is recommended over trough concentration-based monitoring for HSCT recipients on CsA. In cases of insufficient trough concentration, additional sampling points are recommended for improved area under the curve estimation. Further studies are needed to evaluate the optimal sampling points required for the area under the curve estimation in CsA therapy post-HSCT.
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Background: The latest published therapeutic drug monitoring (TDM) guidelines for vancomycin recommend changing trough-based monitoring to area under the concentration-to-time curve (AUC)-based monitoring. This study aimed to evaluate the implementation status and perceptions of vancomycin AUC-based TDM in China and to determine the challenges in performing AUC-based TDM. Methods: A nationwide cross-sectional survey was conducted in China using an online questionnaire. The questionnaire comprised a total of 25 questions with open- and closed-ended answers to collect information about the current implementation of vancomycin TDM and the participants' perceptions of these practices. The questionnaire responses were collected via the Questionnaire Star platform and analyzed. Results: A total of 161 questionnaires were completed by 131 hospitals and were included. Approximately 59.5% (78/131) of the surveyed hospitals conducted vancomycin TDM; however, only 10.7% (14/131) of these hospitals performed AUC-based vancomycin TDM. Of the eligible participants, 58.4% (94/161) had experience with vancomycin TDM, and only 37 participants (37/161, 23.0%) had the ability to estimate the AUC, primarily through Bayesian simulation (33/161, 20.5%). The participants considered the following challenges to implementing AUC-based monitoring: (1) the high cost of AUC-based monitoring; (2) inadequate knowledge among pharmacists and/or physicians; (3) the complexity of AUC calculations; (4) difficulty obtaining AUC software; and (5) unclear benefit of AUC-based monitoring. Conclusion: The majority of surveyed hospitals have not yet implemented AUC-based vancomycin TDM. Multiple challenges should be addressed before wide implementation of AUC-based monitoring, and guidance for trough-based monitoring is still needed.
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Background: Voriconazole is primarily metabolized by CYP2C19 and CYP3A4. Drug interactions that affect this pathway can alter its plasma exposures, resulting in untargeted voriconazole concentrations. Case summary: In this case report, we describe the case of a 64-year-old man who was treated for non-Hodgkin's lymphoma with continuous glucocorticoids co-administrated with voriconazole against invasive pulmonary aspergillosis. A decrease in trough concentration (Cmin) of voriconazole was observed and related with co-administration of dexamethasone in the patient carrying the CYP2C19 *1*2 genotype: voriconazole Cmin/dose ratios of 0.018 (0.1 mg L-1/5.7 mg kg-1 day-1), 0.18 (1 mg L-1/5.7 mg kg-1 day-1), and 0.23 (2 mg L-1/8.6 mg kg-1 day-1) at dexamethasone doses of 20, 12.5, and 2.5 mg, respectively. Sub-therapeutic voriconazole Cmin was associated with high- and moderate-dose dexamethasone (20 and 12.5 mg), leading to failure of antifungal treatment. Conclusion: The extent of voriconazole-dexamethasone interaction was determined by the dose of dexamethasone and associated with the CYP2C19 *1*2 genotype. Therapeutic drug monitoring of voriconazole is necessary to avoid clinically relevant interactions for optimal antifungal therapy.
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AIMS: Although there are various model-based approaches to individualized vancomycin (VCM) administration, few have been reported for adult patients with periprosthetic joint infection (PJI). This work attempted to develop a machine learning (ML)-based model for predicting VCM trough concentration in adult PJI patients. METHODS: The dataset of 287 VCM trough concentrations from 130 adult PJI patients was split into a training set (229) and a testing set (58) at a ratio of 8:2, and an independent external 32 concentrations were collected as a validation set. A total of 13 covariates and the target variable (VCM trough concentration) were included in the dataset. A covariate model was respectively constructed by support vector regression, random forest regression and gradient boosted regression trees and interpreted by SHapley Additive exPlanation (SHAP). RESULTS: The SHAP plots visualized the weight of the covariates in the models, with estimated glomerular filtration rate and VCM daily dose as the 2 most important factors, which were adopted for the model construction. Random forest regression was the optimal ML algorithm with a relative accuracy of 82.8% and absolute accuracy of 67.2% (R2 =.61, mean absolute error = 2.4, mean square error = 10.1), and its prediction performance was verified in the validation set. CONCLUSION: The proposed ML-based model can satisfactorily predict the VCM trough concentration in adult PJI patients. Its construction can be facilitated with only 2 clinical parameters (estimated glomerular filtration rate and VCM daily dose), and prediction accuracy can be rationalized by SHAP values, which highlights a profound practical value for clinical dosing guidance and timely treatment.
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Antibacterianos , Aprendizaje Automático , Infecciones Relacionadas con Prótesis , Vancomicina , Humanos , Femenino , Masculino , Vancomicina/farmacocinética , Vancomicina/administración & dosificación , Vancomicina/sangre , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Antibacterianos/sangre , Persona de Mediana Edad , Anciano , Infecciones Relacionadas con Prótesis/tratamiento farmacológico , Adulto , Tasa de Filtración Glomerular , Estudios Retrospectivos , Modelos Biológicos , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Vancomycin trough concentration is closely associated with clinical efficacy and toxicity. Predicting vancomycin trough concentrations in pediatric patients is challenging due to significant inter-individual variability and rapid physiological changes during maturation. AIM: This study aimed to develop a machine learning model to predict vancomycin trough concentrations and determine optimal dosing regimens for pediatric patients < 4 years of age using ML algorithms. METHOD: A single-center retrospective observational study was conducted from January 2017 to March 2020. Pediatric patients who received intravenous vancomycin and underwent therapeutic drug monitoring were enrolled. Seven ML models [linear regression, gradient boosted decision trees, support vector machine, decision tree, random forest, Bagging, and extreme gradient boosting (XGBoost)] were developed using 31 variables. Performance metrics including R-squared (R2), mean square error (MSE), root mean square error (RMSE), and mean absolute error (MAE) were compared, and important features were ranked. RESULTS: The study included 120 eligible trough concentration measurements from 112 patients. Of these, 84 measurements were used for training and 36 for testing. Among the seven algorithms tested, XGBoost showed the best performance, with a low prediction error and high goodness of fit (MAE = 2.55, RMSE = 4.13, MSE = 17.12, and R2 = 0.59). Blood urea nitrogen, serum creatinine, and creatinine clearance rate were identified as the most important predictors of vancomycin trough concentration. CONCLUSION: An XGBoost ML model was developed to predict vancomycin trough concentrations and aid in drug treatment predictions as a decision-support technology.
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Antibacterianos , Monitoreo de Drogas , Aprendizaje Automático , Vancomicina , Humanos , Vancomicina/administración & dosificación , Vancomicina/farmacocinética , Vancomicina/sangre , Estudios Retrospectivos , Preescolar , Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Antibacterianos/sangre , Femenino , Lactante , Masculino , Monitoreo de Drogas/métodos , Relación Dosis-Respuesta a DrogaRESUMEN
This study conducted a quantitative meta-analysis to investigate the association of vancomycin indicators, particularly area under the curve over 24 h (AUC24) and trough concentrations (Ctrough), and their relationship with both nephrotoxicity and efficacy. Literature research was performed in PubMed and Web of Science on vancomycin nephrotoxicity and efficacy in adult inpatients. Vancomycin Ctrough, AUC24, AUC24/minimum inhibitory concentration (MIC), nephrotoxicity evaluation and treatment outcomes were extracted. Logistic regression and Emax models were conducted, stratified by evaluation criterion for nephrotoxicity and primary outcomes for efficacy. Among 100 publications on nephrotoxicity, 29 focused on AUC24 and 97 on Ctrough, while of 74 publications on efficacy, 27 reported AUC24/MIC and 68 reported Ctrough. The logistic regression analysis indicated a significant association between nephrotoxicity and vancomycin Ctrough (odds ratio = 2.193; 95% CI 1.582-3.442, p < 0.001). The receiver operating characteristic curve had an area of 0.90, with a cut-off point of 14.55 mg/L. Additionally, 92.3% of the groups with a mean AUC24 within 400-600 mg·h/L showed a mean Ctrough of 10-20 mg/L. However, a subtle, non-statistically significant association was observed between the AUC24 and nephrotoxicity, as well as between AUC24/MIC and Ctrough concerning treatment outcomes. Our findings suggest that monitoring vancomycin Ctrough remains a beneficial and valuable approach to proactively identifying patients at risk of nephrotoxicity, particularly when Ctrough exceeds 15 mg/L. Ctrough can serve as a surrogate for AUC24 to some extent. However, no definitive cut-off values were identified for AUC24 concerning nephrotoxicity or for Ctrough and AUC24/MIC regarding efficacy.
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INTRODUCTION: Peritoneal dialysis (PD) is an effective renal replacement modality in people with HIV (PWH) with end-stage kidney disease (ESKD), particularly those with residual kidney function. Data on pharmacokinetics (PK) of antiretrovirals in patients on peritoneal dialysis are limited. METHODS: A single-participant study was performed on a 49-year-old gentleman with ESKD on PD and controlled HIV on once daily dolutegravir (DTG) 50 mg + tenofovir alafenamide (TAF) 25 mg / emtricitabine (FTC) 200 mg. He underwent serial blood plasma, peripheral blood mononuclear cell, and urine PK measurements over 24 h after an observed DTG + FTC/TAF dose. RESULTS: Plasma trough (Cmin) concentrations of TAF, tenofovir (TFV), FTC, and DTG were 0.05, 164, 1,006, and 718 ng/mL, respectively. Intracellular trough concentrations of TFV-DP and FTC-TP were 1142 and 11,201 fmol/million cells, respectively. Compared to published mean trough concentrations in PWH with normal kidney function, observed TFV and FTC trough concentrations were 15.5- and 20-fold higher, while intracellular trough concentrations of TFV-DP and FTC-TP were 2.2-fold and 5.4-fold higher, respectively. TFV and FTC urine levels were 20 times lower than in people with normal GFR. CONCLUSIONS: In a single ESKD PWH on PD, daily TAF was associated with plasma TFV and intracellular TFV-DP trough concentrations 15-fold and 2-fold higher than those of people with uncompromised kidney function, potentially contributing to nephrotoxicity. This suggests that TFV accumulates on PD; thus, daily TAF in PD patients may require dose adjustment or regimen change to optimize treatment, minimize toxicity, and preserve residual kidney function.
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Adenina , Alanina , Fármacos Anti-VIH , Emtricitabina , Infecciones por VIH , Compuestos Heterocíclicos con 3 Anillos , Fallo Renal Crónico , Oxazinas , Diálisis Peritoneal , Piperazinas , Piridonas , Tenofovir , Humanos , Masculino , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Oxazinas/farmacocinética , Piridonas/farmacocinética , Persona de Mediana Edad , Tenofovir/farmacocinética , Tenofovir/uso terapéutico , Tenofovir/análogos & derivados , Emtricitabina/farmacocinética , Emtricitabina/uso terapéutico , Piperazinas/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/uso terapéutico , Alanina/farmacocinética , Adenina/análogos & derivados , Adenina/farmacocinética , Adenina/uso terapéutico , Fallo Renal Crónico/terapiaRESUMEN
BACKGROUND: The relationship between plasma tenofovir (TFV) concentration at the beginning of tenofovir disoproxil fumarate (TDF) administration and the development of renal dysfunction during long-term administration of TDF has not been demonstrated yet. The objective of the present study was to determine whether plasma TFV trough concentrations during early TDF administration could serve as an indicator of renal dysfunction when TDF is administered for long periods. METHODS: We included 149 HIV-1 infected Japanese patients who were prescribed TDF. We investigated the relationship between plasma TFV trough concentrations and the rate of discontinuation due to the development of renal dysfunction for up to five years after the start of TDF administration. We also examined how the decrease in renal function over time due to TDF administration was related to factors associated with high TFV levels and plasma TFV trough concentrations. RESULTS: The median TFV trough concentration in the TDF discontinuation group was 88 ng/mL, which was significantly higher (p = 0.0041), than that in the continuation group (72 ng/mL). Further, using an ROC curve, the cut-off value for TFV trough concentration at which TDF discontinuation was significantly high was found to be 98 ng/mL. Logistic multivariate analysis of factors associated with discontinuation of TDF due to renal function-related adverse events showed that being ≥ 50 years old (OR = 2.96; 95% CI, 1.01-8.64), having eGFR < 80 mL/min/1.73m2 at the start of TDF administration (OR = 5.51; 95% CI, 1.83-17.5), and TFV trough concentration ≥ 98 ng/mL (OR = 2.96; 95% CI, 1.16-7.60) were independent factors. CONCLUSIONS: The results suggested that the importance of measuring TFV concentrations to evaluate the risk of developing renal function-related adverse events during long-term TDF administration.
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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.
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Clozapine is characterized by a large within- and between-patient variability in its pharmacokinetics, attributed to non-genetic and genetic factors. A cross-sectional analysis of clozapine trough concentration (Clz C0) issued from Tunisian schizophrenic patients was collected and analysed using a nonparametric modelling approach. We assessed the impact of demographic covariates (age, weight and sex), patient's habits (smoking status, alcohol and caffeine intake) and the genetic factors (CYP1A2*1C, CYP1A2*1F and CYP2C19*2 polymorphisms) on each pharmacokinetic parameter. An external validation of this pharmacokinetic model using an independent data set was performed. Fit goodness between observed- and individual-predicted data was evaluated using the mean prediction error (% MPE), the mean absolute prediction error (% MAPE) as a measure of bias, and the root mean squared error (% RMSE) as a measure of precision. Sixty-three CLz C0 values issued from 51 schizophrenic patients were assessed in this study and divided into building and validation groups. CYP1A2*1F polymorphism and smoking status were the only covariates significantly associated with clozapine clearance. Precision parameters were as follows: 1.02%, 0.95% and 22.4%, respectively, for % MPE, % MAPE and % RMSE. We developed and validated an accurate pharmacokinetic model able to predict Clz C0 in Tunisian schizophrenic patients using the two parameters CYP1A2*1F polymorphism and smoking.
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Antipsicóticos , Clozapina , Citocromo P-450 CYP1A2 , Citocromo P-450 CYP2C19 , Esquizofrenia , Humanos , Clozapina/farmacocinética , Clozapina/sangre , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genética , Masculino , Femenino , Túnez , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP1A2/metabolismo , Adulto , Antipsicóticos/farmacocinética , Estudios Transversales , Persona de Mediana Edad , Citocromo P-450 CYP2C19/genética , Modelos Biológicos , Fumar , Adulto Joven , Polimorfismo GenéticoRESUMEN
Introduction: Brain metastases (BM) are common in patients with advanced EGFR-mutated (EGFRm+) NSCLC. Despite good BM-related outcomes of osimertinib, several patients still experience intracranial progression. A possible explanation is pharmacologic failure due to low plasma trough levels (Cmin,SS) and consequently limited intracranial osimertinib exposure. We investigated the relation between osimertinib Cmin,SS and BM development or progression. Methods: A prospective multicenter cohort study, including patients receiving osimertinib for advanced EGFRm+ NSCLC. At osimertinib start, patients were allocated to the BM or no or unknown BM cohort and were further divided into subgroups based on osimertinib Cmin,SS (low, middle, and high exposure). Cumulative incidence of BM progression or development and overall survival were determined for each group. Results: A total of 173 patients were included, with 49 (28.3%) had baseline BM. Of these patients, 36.7% experienced BM progression, of which 16.7% in the low (<159.3 ng/mL), 40.0% in the middle, and 47.1% in the high (>270.7 ng/mL) Cmin,SS subgroups. After 12 months, the cumulative incidence of BM progression for the BM cohort was 20% (95% confidence interval [CI] 2.6-49.0), 31% (95% CI:10.6-53.9), and 31% (95% CI:10.8-54.5) per Cmin,SS subgroup, respectively. After 20 months, this was 20% (95% CI:2.6-49.0), 52% (95% CI:23.8-74.2), and 57% (95% CI:24.9-79.7), respectively. For the no or unknown BM cohort, 4.0% developed BM without differences within Cmin,SS subgroups. Conclusions: No relation was found between osimertinib Cmin,SS and BM development or progression in patients with advanced EGFRm+ NSCLC. This suggests that systemic osimertinib exposure is not a surrogate marker for BM development or progression.
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BACKGROUND: Vancomycin-associated acute kidney injury (VA-AKI) is the most clinically relevant side effect of vancomycin. The objective of this study was to investigate the association between VTC and VA-AKI as well as 30-day mortality in critically ill elderly adults. METHOD: Elderly patients with trough serum vancomycin concentration records(VTC) in the Medical Information Mart-IV (MIMIC-IV) and eICU databases were retrospectively studied. RESULTS: A total of 3,146 critically ill elderly adults were finally enrolled. The incidence of VA-AKI in the elderly population was 76.5%. Logistic regression analysis revealed significant relationships between VA-AKI and various factors, including VTC, comorbidities, and laboratory indicators, and SOFA, and GCS score. For each mg/L increase, the OR for VA-AKI increased by 2.5%. The association between VTC and 30-day mortality was found to be statistically significant (odds ratio (OR): 1.021, 95% CI: 1.010-1.031), P < 0.001). The Restricted cubic splines (RCS) curves revealed that VTC ranged of 19.67 to 35.72 mg/l for AKI and 19.17 to 42.86 mg/l for 30-day mortality exhibit OR with 95% CI above 1, indicating statistically significant associations with an increased risk of AKI and 30-day mortality, respectively. In the subgroup analysis, VTC was identified as a risk factor for VA-AKI in specific patient groups, including white individuals, female patients, those with shock, patients with SOFA > 6, patients with baseline creatinine > 1.2 mg/dl and patients with or without exposed to other nephrotoxic medications. CONCLUSION: This study found the significant association between VTC and the incidence of VA-AKI and 30-day mortality in critically ill elderly adults. The RCS curves indicated concentration ranges for AKI (19.67-35.72 mg/L) and 30-day mortality (19.17-42.86 mg/L), signifying increased risk.
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Lesión Renal Aguda , Vancomicina , Adulto , Humanos , Femenino , Anciano , Vancomicina/efectos adversos , Antibacterianos/efectos adversos , Estudios Retrospectivos , Enfermedad Crítica , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/epidemiologíaRESUMEN
Antibody-conjugated magnetic immunoassay (ACMIA) for tacrolimus (FK506) may detect falsely elevated tacrolimus trough levels, a commonly underreported event. We report a case of falsely elevated whole-blood tacrolimus levels in a patient post-orthotopic liver transplantation. A 71-year-old male patient underwent liver transplantation in 2012. Post-transplantation, the patient was immediately started on tacrolimus for maintenance immunosuppression. His most recent dose was 0.5 mg four times weekly. During monitoring, trough levels were at 25.9 ng/mL using ACMIA. After this result, a decision was made to hold tacrolimus. After holding tacrolimus for seven days, detected trough levels were still continually greater than 20 ng/mL. Upon suspicion of falsely elevated results, liquid chromatography with mass spectroscopy (LC-MS) was used to check tacrolimus trough levels. Results showed normal trough levels of 7.6 ng/mL. Because of its narrow therapeutic window, tacrolimus levels need to be carefully monitored throughout treatment. When high tacrolimus levels are detected using ACMIA without a correlating clinical scenario, trough levels should be re-confirmed using LC-MS to prevent clinical decisions from being made based on falsely elevated results.
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Therapeutic drug monitoring (TDM) of elexacaftor, tezacaftor, ivacaftor (ETI) could be a useful tool to increase efficacy and decrease the risk of adverse effects in people with Cystic Fibrosis (pwCF). It is however unclear whether drug exposure should be monitored by assessment of trough (Cmin) levels or determination of the area under the curve (AUC). Hence, in this study the correlation between measured Cmin concentration and AUC was evaluated. Serial plasma samples, including Cmin, were drawn after administration of ETI in order to calculate the AUC and assess the correlation between the two parameters. A linear correlation between Cmin and AUC0-24h was found, with Pearson's r correlation coefficients of 0.963, 0.908 and 0.860 for elexacaftor, tezacaftor and ivacaftor, respectively. Exposure of ETI may be monitored by assessment of Cmin levels.
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Aminofenoles , Benzodioxoles , Fibrosis Quística , Monitoreo de Drogas , Indoles , Quinolonas , Humanos , Aminofenoles/farmacocinética , Aminofenoles/uso terapéutico , Quinolonas/farmacocinética , Quinolonas/administración & dosificación , Benzodioxoles/farmacocinética , Benzodioxoles/sangre , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/sangre , Indoles/farmacocinética , Indoles/sangre , Indoles/administración & dosificación , Monitoreo de Drogas/métodos , Masculino , Femenino , Agonistas de los Canales de Cloruro/farmacocinética , Agonistas de los Canales de Cloruro/uso terapéutico , Pirazoles/farmacocinética , Pirazoles/administración & dosificación , Pirazoles/sangre , Adulto , Área Bajo la Curva , Pirroles/farmacocinética , Pirroles/administración & dosificación , Sulfóxidos , Piridinas/farmacocinética , Piridinas/administración & dosificación , PirrolidinasRESUMEN
AIM: Patients with advanced gastrointestinal stromal tumors (GISTs) exhibiting an imatinib plasma trough concentration (IM Cmin) under 1100 ng/ml may show a reduced drug response rate, leading to the suggestion of monitoring for IM Cmin. Consequently, the objective of this research was to create a customized IM Cmin classification model for patients with advanced GISTs from China. METHODS: Initial data and laboratory indicators from patients with advanced GISTs were gathered, and the above information was segmented into a training set, validation set, and testing set in a 6:2:2 ratio. Key variables associated with IM Cmin were identified to construct the classification model using the least absolute shrinkage and selection operator (LASSO) regression and forward stepwise binary logistic regression. Within the training and validation sets, nine ML classification models were constructed via the resampling method and underwent comparison through the Brier scores, the areas under the receiver-operating characteristic curve (AUROC), the decision curve, and the precision-recall (AUPR) curve to determine the most suitable model for this dataset. Two methods of internal validation were used to assess the most suitable model's classification performance: tenfold cross-validation and random split-sample validation (test set), and the value of the test set AUROC was used to evaluate the model's classification performance. RESULTS: Six key variables (gender, daily IM dose, metastatic site, red blood cell count, platelet count, and percentage of neutrophils) were ultimately selected to construct the classification model. In the validation set, it is found by comparison that the Extreme Gradient Boosting (XGBoost) model has the largest AUROC, the lowest Brier score, the largest area under the decision curve, and the largest AUPR value. Furthermore, as evaluated via internal verification, it also performed well in the test set (AUROC = 0.725). CONCLUSION: For patients with advanced GISTs who receive IM, initial data and laboratory indicators could be used to accurately estimate whether the IM Cmin is below 1100 ng/ml. The XGBoost model may stand a chance to assist clinicians in directing the administration of IM.
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Tumores del Estroma Gastrointestinal , Humanos , Área Bajo la Curva , China , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Mesilato de Imatinib/sangre , Aprendizaje Automático , Masculino , FemeninoRESUMEN
OBJECTIVE: To explore independent influencing factors for clinical efficacy of roxadustat in hemodialysis patients. METHODS: Hemodialysis patients treated with roxadustat were enrolled. The plasma trough concentrations of roxadustat were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). A multiple logistic regression model was established to determine the factors that affect clinical efficacy of roxadustat in patients undergoing hemodialysis. RESULTS: A total of 67 hemodialysis patients were enrolled in the study. The results showed that age, blood trough concentration of roxadustat, and baseline hemoglobin (Hb) level were independent factors of clinical efficacy of roxadustat (OR = 1.06, p = .025 for age; OR = 1.001, p = .037 for plasma concentration; and OR = 0.941, p = .003 for baseline Hb), with an AUC score of 0.859. CONCLUSIONS: Age, blood trough concentration of roxadustat, and baseline Hb level were independent influencing factors of the response to roxadustat in hemodialysis patients.
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Insuficiencia Renal Crónica , Espectrometría de Masas en Tándem , Humanos , Cromatografía Liquida , Resultado del Tratamiento , Glicina/uso terapéutico , Diálisis RenalRESUMEN
PURPOSE: To analyze the risk factors influencing the development of cefoperazone-induced coagulopathy in critically ill patients and determine the threshold of serum trough concentration. METHODS: A retrospective case-control study was conducted in the intensive care unit patients treated with cefoperazone, and it was approved by the Ethical Committee of Drum Tower Hospital affiliated with the Medical School of Nanjing University (NO.2023-158-01). Patients were divided into the normal group and coagulopathy group based on prothrombin time. The clinical characteristics of the two groups were compared using univariate analysis. The serum concentration threshold and influencing factors of cefoperazone-induced coagulopathy in critically ill patients were analyzed using the receiver operating characteristic curve and multivariate logistic regression analysis. RESULTS: A total of 113 patients were included, and cefoperazone-induced coagulopathy occurred in 39 patients, with an incidence of 34.5%. These patients experienced significant prothrombin time prolongation around day 6 (median) after cefoperazone application. The serum trough concentration threshold of cefoperazone-induced coagulopathy in critically ill patients was 87.765 mg/l. Multivariate logistic regression analysis revealed that the APACHE II score (p = 0.034), prophylactic use of vitamin K1 (p < 0.001), hepatic impairment (p = 0.014), and Cmin ≥ 87.765 mg/l (p = 0.005) were associated with cefoperazone-induced coagulopathy. CONCLUSION: Cefoperazone-induced coagulopathy usually occurs on the 6th day of cefoperazone use in critically ill patients. The risk will increase in patients with an APACHE II score > 25, hepatic impairment, and cefoperazone Cmin ≥ 87.765 mg/l. Vitamin K1 is effective in preventing this adverse reaction.
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Trastornos de la Coagulación Sanguínea , Hepatopatías , Humanos , Cefoperazona/efectos adversos , Estudios de Casos y Controles , Estudios Retrospectivos , Enfermedad Crítica , Factores de Riesgo , Trastornos de la Coagulación Sanguínea/inducido químicamente , Vitamina K , Unidades de Cuidados IntensivosRESUMEN
Objective To analyze the achievement of target vancomycin concentration and the risk factors affecting the concentration to reach the target,providing a reference for the rational use of vancomycin and the implementation of therapeutic drug monitoring(TDM).Methods Patients who were hospitalized and received vancomycin TDM from January 2016 to June 2019 at Zhongshan Hospital,Fudan University were selected.Clinical data,vancomycin blood concentrations,and occurrences of acute kidney injury(AKI)during the hospitalization were collected.Factors affecting the attainment of target vancomycin concentrations were analyzed using logistic regression and grouped according to whether the target concentrations were attained.The correlation between drug concentration and the occurrence of AKI was analyzed.Results A total of 1 106 patients were included,with 70.7％being males and a median age of 60.0(IQR=20)years.Surgical departments accounted for 76.4％of the distribution.The median duration of vancomycin therapy was 10.8 d(IQR=9.0).A total of 21.6％of patients had their first concentration monitored before administration of doses 4 and 5.The drug concentration monitoring results of 46.8％(518/1 106)of patients were in the range between 10-20 μg·mL-1,reaching the target concentration range.The incidence of vancomycin-associated AKI was 25.9％.The incidence of AKI varied among patients with different vancomycin concentrations:when the concentrations are＜10,10-＜15,15-20,and＞20 μg·mL-1,the AKI rates are 15.8％,20.5％,25.8％,and 39.4％,respectively.Multivariate logistic regression analysis showed that target concentrations were more likely to be reached with a dosing course of＞7-14 d(OR=1.688,P=0.001)and＞14 d(OR=1.744,P=0.002)than with a dosing course of ≤7 d.Patients receiving conventional daily doses were more likely to achieve target concentrations than those receiving the non-conventional daily dose(OR=1.540,P=0.003).Conclusion The current status of vancomycin TDM in China still suffers from deficiencies,such as delayed timing of monitoring and low rate of target concentration attainment.Higher vancomycin concentrations are significantly associated with AKI,and the factors affecting the vancomycin concentration to reach the target mainly include treatment duration and the complexity of the dosing regimen.
RESUMEN
Osimertinib is prescribed to patients with metastatic non-small cell lung cancer (NSCLC) and a sensitizing EGFR mutation. Limited data exists on the impact of patient characteristics or osimertinib exposure on effectiveness outcomes. This was a Dutch, multicenter cohort study. Eligible patients were ≥18 years, with metastatic EGFRm+ NSCLC, receiving osimertinib. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Kaplan-Meier analyses and multivariate Cox proportional hazard models were performed. In total, 294 patients were included. Primary EGFR-mutations were mainly exon 19 deletions (54%) and p.L858R point mutations (30%). Osimertinib was given in first-line (40%), second-line (46%) or beyond (14%), with median PFS 14.4 (95% CI: 9.4-19.3), 13.9 (95% CI: 11.3-16.1) and 8.7 months (95% CI: 4.6-12.7), respectively. Patients with low BMI (<20.0 kg/m2 ) had significantly shorter PFS/OS compared to all other subgroups. Patients with a high plasma trough concentration in steady state (Cmin,SS ; >271 ng/mL) had shorter PFS compared to a low Cmin,SS (<163 ng/mL; aHR 2.29; 95% CI: 1.13-4.63). A significant longer PFS was seen in females (aHR = 0.61, 95% CI: 0.45-0.82) and patients with the exon 19 deletion (aHR = 0.58, 95% CI: 0.36-0.92). A trend towards longer PFS was seen for TP53 wild-type patients, while age did not impact PFS. Patients with a primary EGFR exon 19 deletion had longer PFS, while a low BMI, male sex and a high Cmin,SS were indicative for shorter PFS and/or OS. Age was not associated with effectiveness outcomes of osimertinib.