Therapeutic drug monitoring (TDM) of 5-fluorouracil (5-FU): new preanalytic aspects

2019 ◽  
Vol 57 (7) ◽  
pp. 1012-1016 ◽  
Author(s):  
Sonani Mindt ◽  
Sihem Aida ◽  
Kirsten Merx ◽  
Annette Müller ◽  
Tobias Gutting ◽  
...  
Keyword(s):  
Dose Adjustment ◽  
Area Under The Curve ◽  
Dose Calculation ◽  
Therapeutic Drug ◽  
Individual Dose ◽  
Blood Samples ◽  
Sampling Points ◽  
Port System ◽  
The Right ◽  
Edta Blood

Abstract Background 5-Fluorouracil (5-FU) is frequently used for the treatment of gastrointestinal tumors. The pharmacological effect of 5-FU is influenced by genetic polymorphisms as well as differently dosed regimens. Currently, 5-FU is generally administered as a continuous infusion via an implanted port system using a body surface area (BSA)-based dose calculation. In order to optimize treatment, the area under the curve (AUC) can be estimated to allow for individual dose adjustment. A 5-FU AUC range between 20 and 30 [mg×h×L] is recommended. The aim of the current study was to assess if blood for AUC analysis could also be drawn at the side where the port system had been placed. Methods We collected EDTA blood samples of patients receiving infusional 5-FU simultaneously from different sampling points (right/left cubital vein). 5-FU concentrations were measured in a steady-state equilibrium based on nanoparticle immunoassay (My5-FU; Saladax). Results A total of 39 patients took part in this study. About half of the patients did not reach the target 5-FU concentration window (37% were under- and 16% of the patients were overdosed). Calculated median AUC was 23.3 for the right arm (range 5.8–59.4) and a median of 23.4 for the left arm (range 5.3–61.0). AUC values showed no difference between right compared to left arms (p=0.99). Conclusions In all, these results confirm that a high percentage of patients are not treated with 5-FU doses reaching suggested AUC levels of 20–30. The location of venepuncture, however, had no impact on the results of plasma 5-FU concentration.

scholarly journals P30 Limited sampling strategies to predict valganciclovir exposure in kidney transplanted children

2019 ◽  
Vol 104 (6) ◽  
pp. e29.2-e29
Author(s):  
N Benyoub ◽  
A Facchin ◽  
S Magreault ◽  
E Jacqz-Aigrain ◽  
V Elie
Keyword(s):  
Model Development ◽  
Area Under The Curve ◽  
Sampling Strategy ◽  
Therapeutic Drug ◽  
Pharmacokinetic Data ◽  
Multilinear Regression ◽  
Post Dose ◽  
Blood Samples ◽  
Limited Sampling ◽  
Pharmacokinetic Profiles

BackgroundGanciclovir and its pro-drug, valganciclovir, are anti-viral drugs used in cytomegalovirus infections treatment in kidney transplanted children. Both present a high pharmacokinetic variability requiring dosage individualization and Therapeutic Drug Monitoring to ensure optimal therapeutic exposure. This retrospective monocentric study aimed to develop a Limited Sampling Strategy (LSS) predicting Area Under the Curve (AUC0-24h) reducing the number of blood samples to improve and facilitate kidney transplanted children medical care.MethodsPediatric kidney transplanted children treated with valganciclovir were included. Rich pharmacokinetic data from ganciclovir plasmatic dosages (sampling times at 0h, 1h, 2h, 4h, 8h, 12 h and 24 h) were collected between February 2005 and November 2018. Ganciclovir exposures at steady-state (AUC0-24h) were calculated using the trapezoidal method. The LSS was developed using a multilinear regression approach to predict AUC0-24h. The overall patients population was divided into two groups for model development and validation purposes.Results129 patients were included: 46 girls and 83 boys, mean age at transplantation was 11.3years ± 5.1. Multilinear regression models were developed on 85 pharmacokinetic profiles (85 patients, mean AUC0-24h=64µg.h/mL ± 27, creatinine clearance=72.4 mL/min per 1.73 m2) and validated on an independent group of 73 pharmacokinetic profiles (44 patients). Regressions based on samples collected at 0, 2, 4 h (R=0.946) or 0, 2, 8 h (R=0.968) presented the best AUC0-24h predictive performances (RMSE=7.5 and 6.6, MAE=5.7 and 4.8 respectively) with an average difference between reference and predicted AUC0-24h of -0.52 and 0.67µg.h/mL respectively.ConclusionsTo date, this is the largest cohort of valganciclovir treated pediatric transplanted children used to develop a LSS. This LSS allows to accurately predict ganciclovir AUC0-24h in pediatric transplanted patients using 3 pharmacokinetic blood samples at 0h, 2h, and 4 h post-dose. Beside other Bayesian estimators developed in the literature, this multilinear regression can be easily implemented into daily practice facilitating patients care.Disclosure(s)Nothing to disclose

Therapeutic drug monitoring of 5-fluorouracil (5-FU) in the treatment of patients with colorectal cancer (CRC).

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 563-563 ◽  
Author(s):  
Gaurav Goel ◽  
Rajesh Sehgal ◽  
Dennis James Meisner ◽  
Min Sun ◽  
Gurleen Pasricha ◽  
...  
Keyword(s):  
Combination Chemotherapy ◽  
Dose Adjustment ◽  
Area Under The Curve ◽  
Systemic Exposure ◽  
Stage Iv ◽  
Median Number ◽  
Subsequent Treatment ◽  
Target Range ◽  
Therapeutic Drug ◽  
Dose Modifications

563 Background: 5-FU continues to serve as the backbone of systemic combination chemotherapy for treatment of CRC in the adjuvant and metastatic disease settings. The dosing of 5-FU has traditionally been based on body surface area (BSA). Growing evidence suggests that BSA-based 5-FU dosing has several limitations, and that pharmacokinetic (PK)-guided dosing of 5-FU improves clinical efficacy with reduced toxicity. We conducted a QI study to evaluate the clinical feasibility of PK-guided 5-FU dose adjustment and its impact on clinical outcome. Methods: CRC patients treated with combination chemotherapy regimens containing infusional 5-FU who underwent PK-guided optimization of 5-FU dosing using an antibody-based immunoassay (OnDose or MyCare) were included in the analysis. Results: A total of 58 patients (34 males, 24 females) meeting the entry criteria have been identified to date. The median age was 61 years (range, 27-85). Fifteen patients had stage III disease, and the remaining 43 patients had stage IV disease. The 5-FU infusional regimens included mFOLFOX6 (n=45) and FOLFIRI (n=13). A total of 143 5-FU PK tests were performed for these 58 patients. The median number of tests performed per patient was 2 (range, 1-5). On initial testing, only 36% (n=21) patients had 5-FU systemic exposure, measured as area under the curve (AUC), within the suggested target range of 20-30 mg.hr/L. Fifty-five percent of the patients were below the target AUC while 9% (n=5) patients were above the target range. Of the 32 patients below the target range on 5-FU AUC test, the 5-FU doses were increased in 22 patients for the subsequent treatment cycle. The median number of dose modifications required to achieve the target AUC levels in these patients was 1 (range, 1-2). The majority of these patients (86%, n=19) tolerated the increased 5-FU dose well without worsening of 5-FU related toxicity. Conclusions: Our data provides further evidence that 5-FU dosing based on BSA results in sub-optimal 5-FU exposure levels for the majority of patients (64%). PK-guided dose adjustment of 5-FU appears to be a practical and feasible approach that can be applied in routine clinical practice.

scholarly journals Limited Sampling Strategy for Determination of Ibrutinib Plasma Exposure: Joint Analyses with Metabolite Data

2021 ◽  
Vol 14 (2) ◽  
pp. 162
Author(s):  
Félicien Le Louedec ◽  
Fanny Gallais ◽  
Fabienne Thomas ◽  
Mélanie White-Koning ◽  
Ben Allal ◽  
...  
Keyword(s):  
Area Under The Curve ◽  
Sampling Strategy ◽  
Predictive Performance ◽  
Pharmacokinetic Profile ◽  
Limited Sampling Strategy ◽  
Joint Analysis ◽  
Therapeutic Drug ◽  
Post Dose ◽  
Limited Sampling ◽  
Three Samples

Therapeutic drug monitoring of ibrutinib is based on the area under the curve of concentration vs. time (AUCIBRU) instead of trough concentration (Cmin,ss) because of a limited accumulation in plasma. Our objective was to identify a limited sampling strategy (LSS) to estimate AUCIBRU associated with Bayesian estimation. The actual AUCIBRU of 85 patients was determined by the Bayesian analysis of the full pharmacokinetic profile of ibrutinib concentrations (pre-dose T0 and 0.5, 1, 2, 4 and 6 h post-dose) and experimental AUCIBRU were derived considering combinations of one to four sampling times. The T0–1–2–4 design was the most accurate LSS (root-mean-square error RMSE = 11.0%), and three-point strategies removing the 1 h or 2 h points (RMSE = 22.7% and 14.5%, respectively) also showed good accuracy. The correlation between the actual AUCIBRU and Cmin,ss was poor (r2 = 0.25). The joint analysis of dihydrodiol-ibrutinib metabolite concentrations did not improve the predictive performance of AUCIBRU. These results were confirmed in a prospective validation cohort (n = 27 patients). At least three samples, within the pre-dose and 4 h post-dose period, are necessary to estimate ibrutinib exposure accurately.

Doing More With Less: Pragmatic Implementation of Vancomycin Area-Under-the-Curve (AUC) Monitoring

2021 ◽  
pp. 089719002110272
Author(s):  
Joanne Huang ◽  
Jeannie D. Chan ◽  
Thu Nguyen ◽  
Rupali Jain ◽  
Zahra Kassamali Escobar
Keyword(s):  
Quality Improvement ◽  
High Risk ◽  
Therapeutic Drug Monitoring ◽  
Paradigm Shift ◽  
Area Under The Curve ◽  
Cost Effective ◽  
Practical Method ◽  
Therapeutic Drug ◽  
Short Term ◽  
Quality Improvement Process

Universal area-under-the-curve (AUC) guided vancomycin therapeutic drug monitoring (TDM) is resource-intensive, cost-prohibitive, and presents a paradigm shift that leaves institutions with the quandary of defining the preferred and most practical method for TDM. We report a step-by-step quality improvement process using 4 plan-do-study-act (PDSA) cycles to provide a framework for development of a hybrid model of trough and AUC-based vancomycin monitoring. We found trough-based monitoring a pragmatic strategy as a first-tier approach when anticipated use is short-term. AUC-guided monitoring was most impactful and cost-effective when reserved for patients with high-risk for nephrotoxicity. We encourage others to consider quality improvement tools to locally adopt AUC-based monitoring.

scholarly journals Feasibility of Extrapolating Randomly Taken Plasma Samples to Trough Levels for Therapeutic Drug Monitoring Purposes of Small Molecule Kinase Inhibitors

2021 ◽  
Vol 14 (2) ◽  
pp. 119
Author(s):  
Ruben A. G. van Eerden ◽  
Esther Oomen-de Hoop ◽  
Aad Noordam ◽  
Ron H. J. Mathijssen ◽  
Stijn L. W. Koolen
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Small Molecule ◽  
Trough Concentration ◽  
Drug Monitoring ◽  
Half Life ◽  
Kinase Inhibitors ◽  
Therapeutic Drug ◽  
Blood Samples ◽  
Elimination Half ◽  
Trough Levels

Small molecule kinase inhibitors (SMKIs) are widely used in oncology. Therapeutic drug monitoring (TDM) for SMKIs could reduce underexposure or overexposure. However, logistical issues such as timing of blood withdrawals hamper its implementation into clinical practice. Extrapolating a random concentration to a trough concentration using the elimination half-life could be a simple and easy way to overcome this problem. In our study plasma concentrations observed during 24 h blood sampling were used for extrapolation to trough levels. The objective was to demonstrate that extrapolation of randomly taken blood samples will lead to equivalent estimated trough samples compared to measured Cmin values. In total 2241 blood samples were analyzed. The estimated Ctrough levels of afatinib and sunitinib fulfilled the equivalence criteria if the samples were drawn after Tmax. The calculated Ctrough levels of erlotinib, imatinib and sorafenib met the equivalence criteria if they were taken, respectively, 12 h, 3 h and 10 h after drug intake. For regorafenib extrapolation was not feasible. In conclusion, extrapolation of randomly taken drug concentrations to a trough concentration using the mean elimination half-life is feasible for multiple SMKIs. Therefore, this simple method could positively contribute to the implementation of TDM in oncology.

Serotonin stimulates GH secretion through a direct pituitary action: studies in hypophysectomized autografted animals and in perifused pituitaries

1986 ◽  
Vol 113 (3) ◽  
pp. 317-322 ◽  
Author(s):  
F. López ◽  
D. Gónzalez ◽  
E. Aguilar
Keyword(s):  
Plasma Volume ◽  
Direct Action ◽  
Experimental Models ◽  
Male Rats ◽  
Blood Samples ◽  
Kidney Capsule ◽  
Gh Secretion ◽  
Significant Release ◽  
The Right ◽  
Dose Dependent

Abstract. To analyze a possible direct action of serotonin (5-hydroxytryptamine) at pituitary level in GH secretion, two experimental models were used: hypophysectomized autografted rats and perifused pituitaries. Adult male rats were hypophysectomized and their own pituitaries placed under the right kidney capsule. Ten days later an intra-atrial cannula was inserted. The next day, blood samples were obtained before and every 10 min during a 2 h period after the injection of saline or 5-hydroxytryptamin (1 or 2 mg/kg iv). Plasma volume was replaced with saline. Both doses of 5-hydroxytryptamine elicit a strong release of GH, the effect being dose-dependent. In pituitaries perifused with 5-hydroxytryptamine (100 μm during 115 min or 1, 10 and 100 μm during 15 min), a significant release of GH was also observed. These results suggested that 5-hydroxytryptamine may stimulate GH secretion through a direct pituitary action.

scholarly journals Novel Trends in Electrochemical Biosensors for Early Diagnosis of Alzheimer’s Disease

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Pavla Valkova ◽  
Miroslav Pohanka
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Diagnosis ◽  
Neurodegenerative Disorder ◽  
Electrochemical Biosensors ◽  
Standard Laboratory ◽  
Blood Samples ◽  
Number Of Patients ◽  
Asymptomatic Phase ◽  
The Right

Background. Alzheimer’s disease (AD) is a multifactorial progressive and irreversible neurodegenerative disorder affecting mainly the population over 65 years of age. It is becoming a global health and socioeconomic problem, and the current number of patients reaching 30–50 million people will be three times higher over the next thirty years. Objective. Late diagnosis caused by decades of the asymptomatic phase and invasive and cost-demanding diagnosis are problems that make the whole situation worse. Electrochemical biosensors could be the right tool for less invasive and inexpensive early diagnosis helping to reduce spend sources— both money and time. Method. This review is a survey of the latest advances in the design of electrochemical biosensors for the early diagnosis of Alzheimer’s disease. Biosensors are divided according to target biomarkers. Conclusion. Standard laboratory methodology could be improved by analyzing a combination of currently estimated markers along with neurotransmitters and genetic markers from blood samples, which make the test for AD diagnosis available to the wide public.

scholarly journals Permissible Medicine and Rationalization of Halal Pharma

Halalpshere ◽  
2021 ◽  
Vol 1 (1) ◽  
pp. 43-52
Author(s):  
Jawad Alzeer
Keyword(s):  
Potential Energy ◽  
Production Process ◽  
Placebo Effect ◽  
Therapeutic Drug ◽  
Spiritual Values ◽  
Therapeutic Concept ◽  
Compatible System ◽  
Specific Standard ◽  
The Right

Permissible medicine “Halalopathy” represents a compatible relation between therapeutic drug and human beliefs/lifestyles. Production of permissible drugs is achieved by evaluating ingredients and monitoring the production process to be compatible with a certain specific standard depending on the requirement of the lifestyle or belief of the patient. If drugs and beliefs are compatible, a domino chain effect will be initiated; trust will be developed, and the placebo effect will be activated. Consequently, a compatible system between mind and drug is established, faith in the treatment is intensified, entropy is lowered, potential energy is increased, and self-assurance is enriched. The compatibility concept is based on finding a connection between human’s belief and therapeutic drug where certain genes will be turned off epigenetically. Halalopathic medicine represents a new therapeutic concept in which holistic values - material, human, moral and spiritual values - are used to deliver the right treatment to the right patient.

Population pharmacokinetic modeling and dosing simulations of tobramycin in pediatric patients with cystic fibrosis

2021 ◽  
Author(s):  
Antonin Praet ◽  
Laurent Bourguignon ◽  
Florence Vetele ◽  
Valentine Breant ◽  
Charlotte Genestet ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Dose Adjustment ◽  
Total Body Weight ◽  
Compartment Model ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Population Pharmacokinetic Modeling ◽  
Two Compartment Model ◽  
Total Body

Initial dosing and dose adjustment of intravenous tobramycin in cystic fibrosis children is challenging. The objectives of this study were to develop nonparametric population pharmacokinetic (PK) models of tobramycin in children with CF to be used for dosage design and model-guided therapeutic drug monitoring. We performed a retrospective analysis of tobramycin PK data in our CF children center. The Pmetrics package was used for nonparametric population PK analysis and dosing simulations. Both the maximal concentration over the MIC (Cmax/MIC) and daily area under the concentration-time curve to the MIC (AUC 24 /MIC) ratios were considered as efficacy target. Trough concentration (Cmin) was considered as the safety target. A total of 2884 tobramycin concentrations collected in 195 patients over 9 years were analyzed. A two-compartment model including total body weight, body surface area and creatinine clearance as covariates best described the data. A simpler model was also derived for implementation into the BestDose software to perform Bayesian dose adjustment. Both models were externally validated. PK/PD simulations with the final model suggest that an initial dose of tobramycin of 15 to 17.5 mg/kg/day was necessary to achieve Cmax/MIC ≥ 10 values for MIC values up to 2 mg/L in most patients. The AUC 24 /MIC target was associated with larger dosage requirements and higher Cmin. A daily dose of 12.5 mg/kg would optimize both efficacy and safety target attainment. We recommend to perform tobramycin TDM, model-based dose adjustment, and MIC determination to individualize intravenous tobramycin therapy in children with CF.

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