Therapeutic Drug Monitoring In Oncology Research Articles

Therapeutic drug monitoring in anticancer agents: perspectives of Australian medical oncologists.

In the development of anticancer agents for solid tumours, body surface area continues to be used to personalise dosing despite minimal evidence for its use over other dosing strategies. With the development of tyrosine kinase inhibitors and other oral targeted anticancer agents, dosing using therapeutic drug monitoring (TDM) is now utilised in many health systems but has had limited uptake in Australia. To determine attitudes and barriers to the implementation of TDM among Australian oncologists. A comprehensive questionnaire was developed by the Dutch Pharmacology Oncology Group from semistructured interviews of stakeholders. Seventy-nine questions across seven domains were developed with three free-text responses. This was rationalised to 17 questions with three free-text responses for Australian medical oncologists who identified limited experience with TDM. Fifty-seven responses were received, with 49 clinicians (86%) identifying limited experience of performing TDM in daily practice. Clinicians were positive (62-91% agree/strongly agree across seven questions) about the advantages of TDM. There was a mixed response for cost-effectiveness and scientific evidence being a barrier to implementation, but strong agreement that prospective studies were needed (75% agreed or strongly agreed); that national treatment guidelines would enable practice (80%) and that a 'pharmacology of oncolytics' education programme would be useful (96%) to provide knowledge for dose individualisation. Despite the limited experience of TDM in oncology in Australia, medical oncologists appear positive about the potential benefit to their patients. We have identified three barriers to implementation that could be targeted for increased adoption of TDM in oncology in Australia.

Therapeutic drug monitoring guidelines in oncology: what do we know and how to move forward? Insights from a systematic review.

Compared with anti-infective drugs, immunosuppressants and other fields, the application of therapeutic drug monitoring (TDM) in oncology is somewhat limited. We aimed to provide a comprehensive understanding of TDM guidelines for antineoplastic drugs and to promote the development of individualized drug therapy in oncology. This study type is a systematic review. This study was performed and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 statement. Databases including PubMed, Embase, the official websites of TDM-related associations and Chinese databases were comprehensively searched up to March 2023. Two investigators independently screened the literature and extracted data. The methodological and reporting quality was evaluated using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) and the Reporting Items for Practice Guidelines in Healthcare (RIGHT), respectively. Recommendations and quality evaluation results were presented by visual plots. This study was registered in PROSPERO (No. CRD42022325661). A total of eight studies were included, with publication years ranging from 2014 to 2022. From the perspective of guideline development, two guidelines were developed using evidence-based methods. Among the included guidelines, four guidelines were for cytotoxic antineoplastic drugs, three for small molecule kinase inhibitors, and one for antineoplastic biosimilars. Currently available guidelines and clinical practice provided recommendations of individualized medication in oncology based on TDM, as well as influencing factors. With regard to methodological quality based on AGREE II, the average overall quality score was 55.21%. As for the reporting quality by RIGHT evaluation, the average reporting rate was 53.57%. From the perspective of current guidelines, TDM in oncology is now being expanded from cytotoxic antineoplastic drugs to newer targeted treatments. Whereas, the types of antineoplastic drugs involved are still small, and there is still room for quality improvement. Furthermore, the reflected gaps warrant future studies into the exposure-response relationships and population pharmacokinetics models.

Proposition of a drug score to predict the clinical usefulness of therapeutic dose monitoring of oral molecularly targeted therapies.

3091 Background: Therapeutic drug monitoring (TDM) consists in measuring and interpreting drug concentrations in biological fluids to personalize drug dosage. This method is widely used for drugs with a narrow therapeutic index ( e.g., immunosuppressants or neuroleptics agents). In onco-hematology, current recommendations of TDM for oral molecularly targeted therapies (oMTT) differ among molecules, making it difficult to identify good TDM candidates. This study aims to propose a quantitative approach with a score to predict the clinical usefulness of TDM of oMTT. Methods: We selected the four key parameters needed for an oMTT to be a good candidate for TDM (e.g. interpatient pharmacokinetic variability, feasible dose-adaptation strategy, exposure-efficacy relationship, exposure-safety relationship). We collected each drug’s pharmacokinetic (PK) and pharmacodynamics variables from drug labels, Center for Drug Evaluation and Research reports and early trials data. The score was defined from oMTT’s exposition variability (variability score: coefficient of variation of drug exposition, the impact of food and proton pump inhibitors), technical complexity (PK linearity, active metabolite, half-life), efficacy (Exposure-response relationship (ERR)) and safety (maximum tolerated dose, Exposure-safety relationship (ESR)). The global score ranged from 0 to 100. To assess the relevance of the score, we evaluated molecules from other therapeutic classes with known strong recommendations of TDM (clozapine, everolimus, voriconazole). Results: In September 2021, we collected data from sixty-seven oMTTs. Scores were normally distributed (mean 48.3, standard deviation 15.6) and varies from 15 for acalabrutinib to 80 for sunitinib. Scores of drugs with strong recommendation of TDM were 68, 68 and 64 for clozapine, everolimus as an immunosuppressant, and voriconazole, respectively. We hypothesized that a score above 60 might be associated with relevant indications of TDM. Fifteen molecules had a score above 60 (sunitinib (80), cabozantinib (76.5), nilotinib (76), abemaciclib (76), axitinib (75), sorafenib (69.5) gefitinib (69.5), trametinib (67.5), talazoparib (67), crizotinib (66), pazopanib (65), sonidegib (63.5), neratinib (62.5), panobinostat (62) and imatinib (60.5)). Conclusions: We defined a score to identify good candidates for TDM in onco-hematology. Usefulness of TDM in oncology should be confirmed prospectively prioritizing these molecules.

Therapeutic drug monitoring in oncology - What's out there: A bibliometric evaluation on the topic.

Pharmacological therapy is the mainstay of treatment for cancer patients. Despite wide interpatient variability in systemic drug concentrations for numerous antineoplastics, dosing based on body size remains the predominant approach. Therapeutic drug monitoring (TDM) is used for few antineoplastics in specific scenarios. We conducted a rapid bibliometric evaluation of TDM in oncology to capture a snapshot of research in this area over time and explore topics that reflect development in the field. Reports with the composite, indexed term 'therapeutic drug monitoring' in the title and abstract were extracted from MEDLINE (inception to August 2021). Reports related to applications in cancer were selected for inclusion and were tagged by study design, antineoplastic drugs and concepts related to TDM. We present a timeline from 1980 to the present indicating the year of first report of antineoplastic agents and key terms. The reports in our sample primarily reflected development and validation of analytical methods with few relating to clinical outcomes to support implementation. Our work emphasises evidence gaps that may contribute to poor uptake of TDM in oncology.

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

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.

Comparison of four immunoassays to an HPLC method for the therapeutic drug monitoring of methotrexate: Influence of the hydroxylated metabolite levels and impact on clinical threshold.

Methotrexate requires therapeutic drug monitoring in oncology because of narrow therapeutic index, especially the metabolite 7-hydroxymethotrexate exhibits nephrotoxicity. The goal of this study was to evaluate different assays and their impact on clinical decisions. Following routine measurement with Abbott TDxFLx® assay (MTX-TDX), 62 samples were analysed on Architect®i1000 (MTX-ARCHI), Xpand® (ARK/XPND), Indiko® (ARK/INDI), and HPLC (MTX-HPLC) as the reference method. The influence of 7-hydroxymethotrexate was explored on ARK reagent to document the cause of the observed bias. ROC curves were built to study the impact of the method on the discharge thresholds for the patients at three levels. Total imprecision was below 2.60% for the methotrexate-ARCHI and close to 10% for both ARK assays for plasma pools. The correlation coefficients were 0.93, 0.93, 0.89 and 0.95, the Bland-Altman difference plot revealed a bias of 0.075, 0.037, 0.049 and -0.002, and the number of results exceeding the TE criteria of 0.1 µM was 17 (27%), 13 (21%), 15 (24%) and 15 (24%) for MTX-TDX, ARK/INDI, ARK/XPND and MTX-ARCHI, respectively. Cross reactivity with 7-hydroxymethotrexate was between 1 and 9%. Overestimation of methotrexate concentration was between -4% and +32%. The most robust clinical level was found to be the highest level (0.2 µM) with ROC curves. The authors found the best results for imprecision with chemiluminescent microparticle immunoassay method on methotrexate-ARCHI, with bias below to the RICOS recommendations and best correlation to the reference method. Impact on the threshold values for clinical decision need to be clearly exposed to clinicians.

A comprehensive review of economic evaluations of therapeutic drug monitoring interventions for cancer treatments.

Therapeutic drug monitoring (TDM) of cancer drugs has been shown to improve treatment effectiveness and safety. The aim of this paper was to comprehensively review economic evaluations of TDM interventions for cancer drugs. Searches were conducted in 4 electronic databases, Medline, EMBASE, and Centre for Reviews and Dissemination databases (Database of Abstracts of Reviews of Effects and the NHS Economic Evaluation Database), from their inception to June 2019. Studies were included if they were economic evaluations of TDM interventions for an active cancer treatment. The quality of reporting of economic evaluations was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS checklist). Of the 11 publications identified, imatinib with TDM and 5-fluorouracil with TDM were the most commonly assessed interventions (4 publications each). Overall study quality was good, with publications meeting 61 to 91% (median 80%) of CHEERS checklist criteria. A variety of studies were used to estimate the clinical effectiveness inputs for the cost effectiveness models. All publications considered TDM to be cost-effective based on an incremental cost-effectiveness ratio below the willingness to pay threshold (64%) or being cost-saving (36%). TDM interventions were considered cost-effective across the economic evaluations. Further clinical research assessing the impact of TDM on overall survival or other long-term health outcomes may enhance the evidence base for TDM in oncology. Future economic evaluations of TDM should explicitly consider uncertainty in the underlying clinical evidence and incorporate changes in the use of newer targeted drugs that form the current standard of care.

Barriers and opportunities for the clinical implementation of therapeutic drug monitoring in oncology.

There are few fields of medicine in which the individualisation of medicines is more important than in the area of oncology. Under-dosing can have significant ramifications due to the potential for therapeutic failure and cancer progression; by contrast, over-dosing may lead to severe treatment-limiting side effects, such as agranulocytosis and neutropenia. Both circumstances lead to poor patient prognosis and contribute to the high mortality rates still seen in oncology. The concept of dose individualisation tailors dosing for each individual patient to ensure optimal drug exposure and best clinical outcomes. While the value of this strategy is well recognised, it has seen little translation to clinical application. However, it is important to recognise that the clinical setting of oncology is unlike that for which therapeutic drug monitoring (TDM) is currently the cornerstone of therapy (e.g. antimicrobials). Whilst there is much to learn from these established TDM settings, the challenges presented in the treatment of cancer must be considered to ensure the implementation of TDM in clinical practice. Recent advancements in a range of scientific disciplines have the capacity to address the current system limitations and significantly enhance the use of anticancer medicines to improve patient health. This review examines opportunities presented by these innovative scientific methodologies, specifically sampling strategies, bioanalytics and dosing decision support, to enable optimal practice and facilitate the clinical implementation of TDM in oncology.

Therapeutic Drug Monitoring in Oncology.

Therapeutic Drug Monitoring in Oncology.

Enzyme-Based Electrochemical Biosensor for Therapeutic Drug Monitoring of Anticancer Drug Irinotecan.

Therapeutic drug monitoring (TDM) is the clinical practice of measuring pharmaceutical drug concentrations in patients' biofluids at designated intervals, thus allowing a close and timely control of their dosage. To date, TDM in oncology can only be performed by trained personnel in centralized laboratories and core facilities employing conventional analytical techniques (e.g., MS). CPT-11 is an antineoplastic drug that inhibits topoisomerase type I, causing cell death, and is widely used in the treatment of colorectal cancer. CPT-11 was also found to directly inhibit acetylcholine esterase (AChE), an enzyme involved in neuromuscular junction. In this work, we describe an enzymatic biosensor, based on AChE and choline oxidase (ChOx), which can quantify CPT-11. ACh (acetylcholine) substrate is converted to choline, which is subsequently metabolized by ChOx to give betaine aldehyde and hydrogen peroxide. The latter one is then oxidized at a suitably polarized platinum electrode, providing a current transient proportional to the amount of ACh. Such an enzymatic process is hampered by CPT-11. The biosensor showed a ∼60% maximal inhibition toward AChE activity in the clinically relevant concentration range 10-10 000 ng/mL of CPT-11 in both simple (phosphate buffer) and complex (fetal bovine serum) matrixes, while its metabolites showed negligible effects. These findings could open new routes toward a real-time TDM in oncology, thus improving the therapeutic treatments and lowering the related costs.

Therapeutic Drug Monitoring in Oncology: Does it Have a Future?

Therapeutic Drug Monitoring in Oncology: Does it Have a Future?

Pharmacokinetics and therapeutic drug monitoring of anticancer agents

Treatment individualisation, an old concept renovated by the progress of analytical techniques and the advent of pharmacogenetics, aims at optimizing the usage of existing drugs by adjusting the nature and dose of anticancer agents to each patient, based on genetic, physiological and pathological criteria, on tumour nature, on associated drugs or previous treatment lines, on treatment efficacy and toxicity or on patient's exposure to the active drug form. This article exposes the pre-requisites and clinical trials necessary to demonstrate the usefulness of therapeutic drug monitoring (TDM) for drugs in general and anticancer agents in particular. It also presents the different TDM approaches used in oncology and reviews the current situation of anticancer drugs' TDM. When TDM cannot be expected to optimize efficacy, it may at least contribute to secure high dose regimens in intensification protocols. TDM in oncology is a discipline in progress. Proofs of efficacy are both scarce are difficult to obtain. However, taking this limitation into account and using the benefits of technical progress could lead to better cognitive research on the predictive response factors for a larger number of anticancer agents in the future. When the usefulness of TDM has been clinically demonstrated or strongly suggested, it is essential that as many patients as possible benefit from it. This "technological transfer" is a continuous process that requires periodical reviews of research results for TDM specialists and clinicians.

Dose monitoring of 5-fluorouracil in patients with colorectal or head and neck cancer—status of the art

Anticancer drugs are good candidates for therapeutic drug monitoring (TDM) because of their high toxicity and documented exposure–response relationship for many anticancer drugs. In contrast to this, a few years ago Peterson concluded that in oncology “…plasma concentration monitoring has not proved to be of value to individualize the treatment…”. However, there are several examples where TDM in oncology has been shown to improve safety, and for some drugs, also efficacy. Examples such as 5-fluorouracil, busulfan, asparaginase, or imatinib are discussed below. It appears that there is a lack of interest of TDM and other pharmacokinetic issues in cancer chemotherapy. There is the perception that in case of toxicity or lack of efficacy switching to another drug is better than checking dose intensity of the drug applied. However, dose individualisation based on drug concentration measurements has been shown to be advantegeous for many anticancer agents.

Pharmacodynamics in cancer therapy.

Our understanding of anticancer pharmacodynamics, and the relationships between pharmacologic measurements and clinical effects, has grown markedly in recent years due to advances in analytical and computational technology. Although methotrexate plasma levels have been empirically used to guide leucovorin dosing during high-dose methotrexate therapy, there has been no other standard use of therapeutic drug monitoring in oncology. More recently, investigators have attempted to titrate precisely the dose of antineoplastic agents based on previously derived models and real-time analysis of plasma drug or tissue concentrations. Studies have been completed or are in progress using hexamethylene bisacetamide, etoposide, teniposide, fluorouracil (FUra), and cytarabine (ara-C). Future studies will focus on optimal sampling strategies, analysis of intermediate biochemical end points, combination chemotherapy, modulation by colony-stimulating factors, and more sophisticated pharmacodynamic models.

Therapeutic Drug Monitoring in Oncology

Therapeutic drug monitoring is now used in many areas of medicine and has contributed to individualization of drug therapy. ' In clinical oncology, however, the application of therapeutic drug monitoring has evolved very slowly. Most cancer treatment centers today measure plasma concentrations of a single cytostatic agent, methotrexate, as part of the clinical routine.

Therapeutic drug monitoring in oncology. Problems and potential in antineoplastic therapy.

Therapeutic drug monitoring is now widely used in many areas of medicine. With its proliferation has come an understanding of the clinical situations in which it is likely to be of value. Factors that can limit the usefulness of therapeutic drug monitoring and situations where it is less likely to be of benefit have also been identified. At present, the routine use of therapeutic drug monitoring in antineoplastic therapy is limited to measurement of plasma methotrexate concentrations after high-dose methotrexate therapy. The lack of a more widespread application of therapeutic drug monitoring in oncology has been due to deficiencies in knowledge about the clinical pharmacology of antineoplastic agents and to factors specific to the chemotherapy of neoplasms. These factors include the broad heterogeneity of malignant neoplasms, the complexities of the drug-tumour interaction, difficulties in assessment of this interaction and the use of combinations of antineoplastic agents with cumulative efficacies and toxicities. Despite these problems, there are many areas in antineoplastic therapy where the use of therapeutic drug monitoring could prove of benefit. The prevention of the chronic pulmonary toxicity of bleomycin, the assessment of the bioavailability of oral chemotherapy, and monitoring drug disposition in the presence of hepatic or renal dysfunction are just some of the potential applications. If recent emphasis on dose as a critical factor in the success of cancer chemotherapy is substantiated, then the need to apply therapeutic drug monitoring within oncology will become more pressing.