Applications and challenges in therapeutic drug monitoring of cancer treatment: A review

Salman, Bushra; Al-Khabori, Murtadha

doi:10.1177/1078155220979048

Cited by 14 publications

(12 citation statements)

References 30 publications

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“…This may lead to suboptimal dosing of a drug, potentially increasing failure rates due to suboptimal efficacy or increased toxicity. 15 The lack of agents specifically developed for MDS (especially in LR-MDS), may be explained by the limited availability of preclinical models to evaluate therapeutic agents. Few MDS cell lines are available, and virtually all are derived from HR-MDS patients.…”

Section: Discussionmentioning

confidence: 99%

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The wider perspective: twenty years of clinical trials in myelodysplastic syndromes

et al. 2021

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Summary Most patients with myelodysplastic syndromes (MDS) require therapeutic intervention. However, there are few approved treatments for MDS. To explore reasons, we searched clinicaltrials.gov and clinicaltrialsregister.eu for MDS trials from 2000 to 2020. We assessed which agents were under investigation and analysed clinical trial characteristics and continuation rates from phase I to II to III to approval. As such, we identified 384 unique agents in 426 phase I, 430 phase II and 48 phase III trials. Success rates for phase III trials and agents were low, and MDS trials took markedly longer to complete than the average clinical trial. Although success rates were higher when MDS‐specific phase I trials were conducted, 52% of the agents had not been evaluated in a phase I trial for MDS. MDS trials often failed to include quality of life, an especially important outcome for older MDS patients. Our work identifies factors potentially contributing to the paucity of available agents for MDS. We suggest a framework to improve clinical research in MDS that might ultimately augment the number of available agents.

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Section: Discussionmentioning

confidence: 99%

“…a quantitative measurement of relative safety of the drug for MDS patients. This may lead to suboptimal dosing of a drug, potentially increasing failure rates due to suboptimal efficacy or increased toxicity 15 …”

Section: Discussionmentioning

confidence: 99%

The wider perspective: twenty years of clinical trials in myelodysplastic syndromes

et al. 2021

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“…Rationale for TDM of 5-FU 5-FU therapy meets the most important criteria for TDM, i.e., an established exposure-toxicity and exposure-clinical activity relationship. Currently, body surface area (BSA)-based calculation is used for dosing the fluoropyrimidine 5-FU (84). At typical doses, 5-FU's therapeutic effectiveness is moderate, as the dosing is often limited by the safety profile, with myelosuppression and gastrointestinal toxicity being the most common side effects.…”

Section: Clinical Impact Of Busulfan Precision Therapy Strategiesmentioning

confidence: 99%

“…In fact, reaching steady-state 5-FU levels could take several hours ( 91 – 93 ). Furthermore, as DPD activity and maybe that of other 5-FU metabolizing enzymes exhibit some circadian rhythm ( 94 , 95 ), variations in the timing of samples may further contribute to variability 84 – 88 .…”

Section: Fluorouracilmentioning

confidence: 99%

Therapeutic drug monitoring for cytotoxic anticancer drugs: Principles and evidence-based practices

et al. 2022

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Cytotoxic drugs are highly efficacious and also have low therapeutic index. A great degree of caution needs to be exercised in their usage. To optimize the efficacy these drugs need to be given at maximum tolerated dose which leads to significant amount of toxicity to the patient. The fine balance between efficacy and safety is the key to the success of cytotoxic chemotherapeutics. However, it is possibly more rewarding to obtain that balance for this class drugs as the frequency of drug related toxicities are higher compared to the other therapeutic class and are potentially life threatening and may cause prolonged morbidity. Significant efforts have been invested in last three to four decades in therapeutic drug monitoring (TDM) research to understand the relationship between the drug concentration and the response achieved for therapeutic efficacy as well as drug toxicity for cytotoxic drugs. TDM evolved over this period and the evidence gathered favored its routine use for certain drugs. Since, TDM is an expensive endeavor both from economic and logistic point of view, to justify its use it is necessary to demonstrate that the implementation leads to perceivable improvement in the patient outcomes. It is indeed challenging to prove the utility of TDM in randomized controlled trials and at times may be nearly impossible to generate such data in view of the obvious findings and concern of compromising patient safety. Therefore, good quality data from well-designed observational study do add immense value to the scientific knowledge base, when they are examined in totality, despite the heterogeneity amongst them. This article compiles the summary of the evidence and the best practices for TDM for the three cytotoxic drug, busulfan, 5-FU and methotrexate. Traditional use of TDM or drug concentration data for dose modification has been witnessing a sea change and model informed precision dosing is the future of cytotoxic drug therapeutic management.

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“…While there are certainly challenges in implementing TDM in an oncology setting, including the use of traditional dosing regimens and common use of drug combinations, as highlighted in some excellent reviews on the subject (24)(25)(26), these hurdles are certainly not unsurmountable if the problem is approached in the right way. Indeed, TDM approaches have been shown to be beneficial and are commonly used for the anticancer drugs methotrexate and busulfan across a range of cancer types.…”

Section: Introductionmentioning

confidence: 99%

Perspectives and Expertise in Establishing a Therapeutic Drug Monitoring Programme for Challenging Childhood Cancer Patient Populations

et al. 2022

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The utility of Therapeutic Drug Monitoring (TDM) in the setting of childhood cancer is a largely underused tool, despite the common use of cytotoxic chemotherapeutics. While it is encouraging that modern advances in chemotherapy have transformed outcomes for children diagnosed with cancer, this has come at the cost of an elevated risk of life-changing long-term morbidity and late effects. This concern can limit the intensity at which these drugs are used. Widely used chemotherapeutics exhibit marked inter-patient variability in drug exposures following standard dosing, with fine margins between exposures resulting in toxicity and those resulting in potentially suboptimal efficacy, thereby fulfilling criteria widely accepted as fundamental for TDM approaches. Over the past decade in the UK, the paediatric oncology community has increasingly embraced the potential benefits of utilising TDM for particularly challenging patient groups, including infants, anephric patients and those receiving high dose chemotherapy. This has been driven by a desire from paediatric oncologists to have access to clinical pharmacology information to support dosing decisions being made. This provides the potential to modify doses between treatment cycles based on a comprehensive set of clinical information, with individual patient drug exposures being used alongside clinical response and tolerability data to inform dosing for subsequent cycles. The current article provides an overview of recent experiences of conducting TDM in a childhood cancer setting, from the perspectives of the clinicians, scientists and pharmacists implementing TDM-based dosing recommendations. The ongoing programme of work has facilitated investigations into the validity of current approaches to dosing for some of the most challenging childhood cancer patient groups, with TDM approaches now being expanded from well-established cytotoxic drugs through to newer targeted treatments.

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Applications and challenges in therapeutic drug monitoring of cancer treatment: A review

Cited by 14 publications

References 30 publications

The wider perspective: twenty years of clinical trials in myelodysplastic syndromes

The wider perspective: twenty years of clinical trials in myelodysplastic syndromes

Therapeutic drug monitoring for cytotoxic anticancer drugs: Principles and evidence-based practices

Perspectives and Expertise in Establishing a Therapeutic Drug Monitoring Programme for Challenging Childhood Cancer Patient Populations

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