scholarly journals Influence of model-predicted rivaroxaban exposure and patient characteristics on efficacy and safety outcomes in patients with acute coronary syndrome

2019 ◽  
Vol 13 ◽  
pp. 175394471986364 ◽  
Author(s):  
Liping Zhang ◽  
Xiaoyu Yan ◽  
Partha Nandy ◽  
Stefan Willmann ◽  
Keith A. A. Fox ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Coronary Syndrome ◽  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Patient Characteristics ◽  
Therapeutic Drug ◽  
Efficacy And Safety ◽  
Additional Information ◽  
Coronary Syndrome ◽  
Exposure Response

Background: This analysis aimed to evaluate the impact of rivaroxaban exposure and patient characteristics on efficacy and safety outcomes in patients with acute coronary syndrome (ACS) and to determine whether therapeutic drug monitoring might provide additional information regarding rivaroxaban dose, beyond what patient characteristics provide. Methods: A post hoc exposure–response analysis was conducted using data from the phase III ATLAS ACS 2 Thrombolysis in Myocardial Infarction (TIMI) 51 study, in which 15,526 randomized ACS patients received rivaroxaban (2.5 mg or 5 mg twice daily) or placebo for a mean of 13 months (maximum follow up: 31 months). A multivariate Cox model was used to correlate individual predicted rivaroxaban exposures and patient characteristics with time-to-event clinical outcomes. Results: For the incidence of myocardial infarction (MI), ischemic stroke, or nonhemorrhagic cardiovascular death, hazard ratios (HRs) for steady-state maximum plasma concentration (Cmax) in the 5th and 95th percentiles versus the median were statistically significant but close to 1 for both rivaroxaban doses. For TIMI major bleeding events, a statistically significant association was observed with Cmax [HR, 1.08; 95% CI, 1.06–1.11 (95th percentile versus median, 2.5 mg twice daily)], sex [HR, 0.56; 95% CI, 0.38–0.84 (female versus male)], and previous revascularization [HR, 0.62; 95% CI, 0.44–0.87 (no versus yes)]. Conclusions: The shallow slopes of the exposure–response relationships and the lack of a clear therapeutic window render it unlikely that therapeutic drug monitoring in patients with ACS would provide additional information regarding rivaroxaban dose beyond that provided by patient characteristics.

scholarly journals Implementation and Comparison of Two Pharmacometric Tools for Model-Based Therapeutic Drug Monitoring and Precision Dosing of Daptomycin

Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 114
Author(s):  
Justine Heitzmann ◽  
Yann Thoma ◽  
Romain Bricca ◽  
Marie-Claude Gagnieu ◽  
Vincent Leclerc ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Joint Infection ◽  
Significant Proportion ◽  
Initial Dosage ◽  
Validation Dataset ◽  
Therapeutic Drug ◽  
Efficacy And Safety ◽  
Absolute Percent Error ◽  
Better Than

Daptomycin is a candidate for therapeutic drug monitoring (TDM). The objectives of this work were to implement and compare two pharmacometric tools for daptomycin TDM and precision dosing. A nonparametric population PK model developed from patients with bone and joint infection was implemented into the BestDose software. A published parametric model was imported into Tucuxi. We compared the performance of the two models in a validation dataset based on mean error (ME) and mean absolute percent error (MAPE) of individual predictions, estimated exposure and predicted doses necessary to achieve daptomycin efficacy and safety PK/PD targets. The BestDose model described the data very well in the learning dataset. In the validation dataset (94 patients, 264 concentrations), 21.3% of patients were underexposed (AUC24h < 666 mg.h/L) and 31.9% of patients were overexposed (Cmin > 24.3 mg/L) on the first TDM occasion. The BestDose model performed slightly better than the model in Tucuxi (ME = −0.13 ± 5.16 vs. −1.90 ± 6.99 mg/L, p < 0.001), but overall results were in agreement between the two models. A significant proportion of patients exhibited underexposure or overexposure to daptomycin after the initial dosage, which supports TDM. The two models may be useful for model-informed precision dosing.

scholarly journals The Scottish model of vancomycin dosing and therapeutic drug monitoring improves both efficacy and safety of vancomycin therapy

2018 ◽  
Vol 64 (7-8) ◽  
pp. 717-724
Author(s):  
Kristýna Zahálková ◽  
Aleš Chrdle ◽  
Olga Dvořáčková ◽  
Marie Kašparová ◽  
Magdalena Horníková ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Therapeutic Drug ◽  
Efficacy And Safety ◽  
Vancomycin Therapy

scholarly journals A Moving Target—Vancomycin Therapeutic Monitoring

2020 ◽  
Vol 9 (4) ◽  
pp. 474-478
Author(s):  
Alaina N Burns ◽  
Jennifer L Goldman
Keyword(s):  
Clinical Practice ◽  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Clinical Care ◽  
Area Under The Curve ◽  
Therapeutic Monitoring ◽  
Therapeutic Drug ◽  
Moving Target ◽  
Efficacy And Safety ◽  
Vancomycin Trough

Abstract Therapeutic drug monitoring (TDM) has been a common practice to optimize efficacy and safety of vancomycin. While vancomycin trough-only TDM has widely been integrated into pediatric clinical practice since 2009, recently updated vancomycin TDM guidelines published in March 2020 recommend area under the curve (AUC) based TDM for vancomycin instead of trough-only TDM. In this review, we discuss the rationale behind the change in TDM recommendations, describe two approaches for calculating vancomycin AUC in clinical practice, and address considerations for integrating vancomycin AUC TDM into pediatric clinical practice. Our primary goal is to provide pediatric clinicians with a resource for implementing vancomycin AUC monitoring into clinical care.

scholarly journals Multicenter Study of Posaconazole Therapeutic Drug Monitoring: Exposure-Response Relationship and Factors Affecting Concentration

2012 ◽  
Vol 56 (11) ◽  
pp. 5503-5510 ◽  
Author(s):  
Michael J. Dolton ◽  
John E. Ray ◽  
Sharon C.-A. Chen ◽  
Kingsley Ng ◽  
Lisa Pont ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Interactions ◽  
Fungal Infection ◽  
Drug Monitoring ◽  
Linear Regression Analysis ◽  
Therapeutic Drug ◽  
Cell Transplant ◽  
Clinical Factors ◽  
Hematopoietic Stem ◽  
Exposure Response

ABSTRACTPosaconazole has an important role in the prophylaxis and salvage treatment of invasive fungal infections (IFIs), although poor and variable bioavailability remains an important clinical concern. Therapeutic drug monitoring of posaconazole concentrations has remained contentious, with the use of relatively small patient cohorts in previous studies hindering the assessment of exposure-response relationships. This multicenter retrospective study aimed to investigate relationships between posaconazole concentration and clinical outcomes and adverse events and to assess clinical factors and drug interactions that may affect posaconazole concentrations. Medical records were reviewed for patients who received posaconazole and had ≥1 concentration measured at six hospitals in Australia. Data from 86 patients with 541 posaconazole concentrations were included in the study. Among 72 patients taking posaconazole for prophylaxis against IFIs, 12 patients (17%) developed a breakthrough fungal infection; median posaconazole concentrations were significantly lower than in those who did not develop fungal infection (median [range], 289 [50 to 471] ng/ml versus 485 [0 to 2,035] ng/ml;P< 0.01). The median posaconazole concentration was a significant predictor of breakthrough fungal infection via binary logistic regression (P< 0.05). A multiple linear regression analysis identified a number of significant drug interactions associated with reduced posaconazole exposure, including coadministration with proton pump inhibitors, metoclopramide, phenytoin or rifampin, and the H2antagonist ranitidine (P< 0.01). Clinical factors such as mucositis, diarrhea, and the early posttransplant period in hematopoietic stem cell transplant recipients were also associated with reduced posaconazole exposure (P< 0.01). Low posaconazole concentrations are common and are associated with breakthrough fungal infection, supporting the utility of monitoring posaconazole concentrations to ensure optimal systemic exposure.

scholarly journals Posaconazole Exposure-Response Relationship: Evaluating the Utility of Therapeutic Drug Monitoring

2012 ◽  
Vol 56 (6) ◽  
pp. 2806-2813 ◽  
Author(s):  
Michael J. Dolton ◽  
John E. Ray ◽  
Deborah Marriott ◽  
Andrew J. McLachlan
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Fungal Infections ◽  
Gastrointestinal Disease ◽  
Plasma Concentrations ◽  
Response To Therapy ◽  
Common Finding ◽  
Therapeutic Drug ◽  
Response Relationship ◽  
Exposure Response

ABSTRACTPosaconazole has become an important part of the antifungal armamentarium in the prophylaxis and salvage treatment of invasive fungal infections (IFIs). Structurally related to itraconazole, posaconazole displays low oral bioavailability due to poor solubility, with significant drug interactions and gastrointestinal disease also contributing to the generally low posaconazole plasma concentrations observed in patients. While therapeutic drug monitoring (TDM) of plasma concentrations is widely accepted for other triazole antifungal agents such as voriconazole, the utility of TDM for posaconazole is controversial due to debate over the relationship between posaconazole exposure in plasma and clinical response to therapy. This review examines the available evidence for a relationship between plasma concentration and clinical efficacy for posaconazole, as well as evaluating the utility of TDM and providing provisional target concentrations for posaconazole therapy. Increasing evidence supports an exposure-response relationship for plasma posaconazole concentrations for prophylaxis and treatment of IFIs; a clear relationship has not been identified between posaconazole concentration and toxicity. Intracellular and intrapulmonary concentrations have been studied for posaconazole but have not been correlated to clinical outcomes. In view of the high mortality and cost associated with the treatment of IFIs, increasing evidence of an exposure-response relationship for posaconazole efficacy in the prevention and treatment of IFIs, and the common finding of low posaconazole concentrations in patients, TDM for posaconazole is likely to be of significant clinical utility. In patients with subtherapeutic posaconazole concentrations, increased dose frequency, administration with high-fat meals, and withdrawal of interacting medications from therapy are useful strategies to improve systemic absorption.

scholarly journals Therapeutic Drug Monitoring of Protein Kinase Inhibitors in Breast Cancer Patients

2021 ◽  
Vol 122 (4) ◽  
pp. 243-256
Author(s):  
Jaroslava Roušarová ◽  
Martin Šíma ◽  
Ondřej Slanař
Keyword(s):  
Breast Cancer ◽  
Protein Kinase ◽  
Therapeutic Drug Monitoring ◽  
Cancer Treatment ◽  
Drug Monitoring ◽  
Kinase Inhibitors ◽  
Breast Cancer Treatment ◽  
Protein Kinase Inhibitors ◽  
Therapeutic Drug ◽  
Exposure Response

Protein kinase inhibitors (PKIs) represent up-to-date therapeutic approach in breast cancer treatment. Although cancer is a rapidly progressive disease, many substances, including PKIs, are usually used at fixed doses without regard to each patient’s individuality. Therapeutic drug monitoring (TDM) is a tool that allows individualization of therapy based on drug plasma levels. For TDM conduct, exposure-response relationships of drug substances are required. The pharmacokinetic data and exposure-response evidence supporting the use of TDM for 6 PKIs used in breast cancer treatment, one of the most common female tumour diseases, are discussed in this review.

Population Pharmacokinetic (PK) Modeling of Hydroxyurea for Therapeutic Drug Monitoring Applications in Children and Adolescents with Sickle Cell Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2136-2136
Author(s):  
Pawel Wiczling ◽  
Robert I. Liem ◽  
Julie A. Panepinto ◽  
Uttam Garg ◽  
Susan M. Abdel-Rahman ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Sickle Cell ◽  
Drug Monitoring ◽  
Drug Exposure ◽  
Oral Drug ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Average Dose ◽  
Intersubject Variability ◽  
Exposure Response

Abstract Abstract 2136 Introduction: Sickle cell anemia (SCA) is an inherited disorder of abnormal hemoglobin synthesis. Hydroxyurea (HU) is the only disease modifying agent available for use in patients with SCA. Clinically, HU has been shown to decrease pain, number of transfusions, and development of acute chest syndrome as well as improve life expectancy in adults with SCA. Although HU is increasingly utilized to treat children with SCA, drug exposure-response relationships and therapeutic drug monitoring are not well characterized in the pediatric population. The exposure-response relationships of HU are currently being evaluated as is the potential role of therapeutic drug monitoring. Objective: The objective of this study was to develop a population pharmacokinetic (PK) model sufficient to describe HU disposition in serum and urine following oral drug administration in pediatric patients. Such a model is required for exploring concentration-effect relationships in children with SCA taking HU. Methods: PK was determined in 20 subjects (mean age 10.5 yr, range 5–17 yr) with SCA either as a single dose (SD, n=6, average dose 17.4 mg/kg) or at steady state (SS, n=14, average daily dose 25.5 mg/kg). Blood and urine samples for HU assay were taken throughout the 24 hour period post HU administration. HU was quantitated by a validated gas chromatography–mass spectrometry (GC-MS) method. Population nonlinear mixed-effect modeling was done using NONMEM software. Measured HU concentrations at specific sampling time points were compared to model predicted area under the curves (AUCs) to find the most predictive relationship. Results: A one-compartment model with first-order absorption and two elimination pathways (metabolic and renal) was used. The mean absorption rate constant differed for children < 8.5 years of age (19.5 h−1) as compared to those ≥ 8.5 years of age (2.1 h−1) and demonstrated high intersubject variability (76%). The population apparent volume of distribution (V/F) was 21.3 L (for an average weight patient of 30.7 kg) with an intersubject variability of 24.7%. The apparent renal (CLu/F) and metabolic (CLm/F) clearance was 3.47 L/hr and 3.52 L/hr, respectively, with the same between subject variability of 42%. Significant relationships (p<0.005) between both CL/F and V/F and body weight were found with these parameters increasing by 2.96% and 2.49%, respectively, for every kilogram difference from the median weight. Significant linear correlations were apparent between the plasma HU concentration at 0.75, 1, 1.5, 2, 4, and 6 hours post-dose; the most significant (p<0.01, r2 =0.71) occurring at 1.5 hours. Conclusion: In children with SCA, a population PK model parameterized from a classical PK study of HU was successful in describing HU disposition in plasma and urine. Data from the model also demonstrated that HU plasma concentrations at 1.5 or 2 hours after an oral dose of the drug were especially predictive of systemic drug exposure (as reflected by AUC). Data from this study also suggest that there may be age related differences in absorption rates. Further studies are warranted to confirm this finding. Disclosures: Off Label Use: Hydroxyurea is not labeled for use in children.

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