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.

Therapeutic Drug Monitoring of Targeted Anticancer Protein Kinase Inhibitors in Routine Clinical Use

2020 ◽  
Vol 42 (1) ◽  
pp. 33-44 ◽  
Author(s):  
Evelina Cardoso ◽  
Monia Guidi ◽  
Benoît Blanchet ◽  
Marie Paule Schneider ◽  
Laurent A. Decosterd ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Therapeutic Drug ◽  
Clinical Use

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.

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.

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