Individualised cancer chemotherapy: strategies and performance of prospective studies on therapeutic drug monitoring with dose adaptation: a review

Therapeutic drug monitoring (TDM) is increasingly used in clinical practice for the optimisation of drug treatment. Although pharmacokinetic variability is an established factor involved in the variation of therapeutic outcome of many chemotherapeutic agents, the use of TDM in the field of oncology has been limited thus far. An important reason for this is that a therapeutic index for most anticancer agents has not been established; however, in the last 20 years, relationships between plasma drug concentrations and clinical outcome have been defined for various chemotherapeutic agents. Several attempts have been made to use these relationships for optimising the administration of chemotherapeutics by applying pharmacokinetically guided dosage. These prospective studies, individualising chemotherapy dose during therapy based on measured drug concentrations, are discussed in this review. We focus on the way a target value is defined, the methodologies used for dose adaptation and the way the performance of the dose-adaptation approach is evaluated. Furthermore, attention is paid to the results of the studies and the applicability of the strategies in clinical practice. It can be concluded that TDM may contribute to improving cancer chemotherapy in terms of patient outcome and survival and should therefore be further investigated.     

Target concentration intervention in oncology: where are we at?

Therapeutic drug monitoring (TDM) and more recently target concentration intervention (TCI) have been widely used in clinical practice for the optimization of drug treatment. TDM and TCI have been applied most frequently in the cardiovascular, respiratory, neurology, and infectious disease areas because the medications used here have both narrow therapeutic indices and a clear relationship between concentration and effect. However, apart from drugs such as methotrexate and 5-fluorouracil, the clinical application of TDM/TCI in oncology is minimal. An important reason for this is that a therapeutic index for most anticancer agents has not been established. However, in the last 20 years, relationships between plasma drug concentrations and clinical outcome have been defined for various chemotherapeutic agents. Defining concentration-effect relationships is also complicated by the fact that cancer is almost always treated with multiple drugs given in combination making the precise definition of the pharmacodynamics of individual agents difficult. The increase in patients with obesity and also those underweight adds to the complexity of effective oncology treatment. This review describes some of the evidence that supports the use of TDM/TCI in oncology. It is proposed that as more patients previously ineligible for chemotherapy become eligible, TDM/TCI may play a critical role in optimizing chemotherapy outcomes. However, pharmacokinetic-pharmacodynamic research to investigate both therapeutic benefit and feasibility in daily clinical practice is required.     

Therapeutic drug monitoring of cytotoxic drugs

Therapeutic drug monitoring is not routinely used for cytotoxic agents. There are several reasons, but one major drawback is the lack of established therapeutic concentration ranges. Combination chemotherapy makes the establishment of therapeutic ranges for individual drugs difficult, the concentration-effect relationship for a single drug may not be the same as when that drug is used in a drug combination. Pharmacokinetic optimization protocols for many classes of cytotoxic compounds exist in specialized centres, and some of these protocols are now part of large multicentre trials. Nonetheless, methotrexate is the only agent which is routinely monitored in most treatment centres. An additional factor, especially in antimetabolite therapy, is the existence of pharmacogenetic enzymes which play a major role in drug metabolism. Monitoring of therapy could include assay of phenotypic enzyme activities or genotype in addition to, or instead, the more traditional measurement of parent drug or drug metabolites. The cytotoxic activities of mercaptopurine and fluorouracil are regulated by thiopurine methyltransferase (TPMT) and dihydropyrimidine dehydrogenase (DPD), respectively. Lack of TPMT functional activity produces life-threatening mercaptopurine myelotoxicity. Very low DPD activity reduces fluorouracil breakdown producing severe cytotoxicity. These pharmacogenetic enzymes can influence the bioavailability, pharmacokinetics, toxicity and efficacy of their substrate drugs.     

Therapeutic drug monitoring of antimetabolic cytotoxic drugs

Therapeutic drug monitoring is not routinely used for cytotoxic agents. There are several reasons, but one major drawback is the lack of established therapeutic concentration ranges. Combination chemotherapy makes the establishment of therapeutic ranges for individual drugs difficult, the concentration-effect relationship for a single drug may not be the same as that when the drug is used in a drug combination. Pharmacokinetic optimization protocols for many classes of cytotoxic compounds exist in specialized centres, and some of these protocols are now part of large multicentre trials. Nonetheless, methotrexate is the only agent which is routinely monitored in most treatment centres. An additional factor, especially in antimetabolite therapy, is the existence of pharmacogenetic enzymes which play a major role in drug metabolism. Monitoring of therapy could include assay of phenotypic enzyme activities or genotype in addition to, or instead of, the more traditional measurement of parent drug or drug metabolites. The cytotoxic activities of mercaptopurine and fluorouracil are regulated by thiopurine methyltransferase (TPMT) and dihydropyrimidine dehydrogenase (DPD), respectively. Lack of TPMT functional activity produces life-threatening mercaptopurine myelotoxicity. Very low DPD activity reduces fluorouracil breakdown producing severe cytotoxicity. These pharmacogenetic enzymes can influence the bioavailability, pharmacokinetics, toxicity and efficacy of their substrate drugs.     

Clinical utility of drug measurement and pharmacokinetics – therapeutic drug monitoring in psychiatry

Based on the assumption that a relationship between blood levels and clinical effects (therapeutic effects, adverse events and toxicity) can be defined and considering that after equal doses plasma concentrations vary markedly between individual patients, therapeutic drug monitoring (TDM) can assist to personalize dose adjustment. Taken together, drug levels and a knowledge of the pharmacological profile of the administered drugs can enable the optimal dosage to be tailored according to the need of the individual patient. Therapeutic drug monitoring has been established for a limited number of drugs. In psychiatry, it has a 40-year-long history, which started with nortriptyline. Evidence has accumulated which shows that TDM is a valid tool for the optimization of psychopharmacotherapy. When used adequately, TDM is helpful for many patients and in many situations. Combined with pharmacogenetic tests, the metabolic status of a patient can be well characterized. Several new observations have been made during routine TDM that have stimulated clinical pharmacological research, such as investigations on inherited differences in drug metabolism that are closely linked to TDM in psychiatry. The contributions of individual forms of cytochrome P450 (CYP) to the metabolism of drugs was elicited by clinical observations on pharmacokinetic drug interactions. Therapeutic drug monitoring requires a close collaboration between the prescribing physician, the laboratory specialist, the clinical pharmacologist and the patient. This complexity may result in errors which can be detected by analysing the appropriate use of TDM in clinical practice. More education has to be provided to the prescribing clinicians on the pharmacology of the drugs and the algorithm of TDM. Moreover, clinical trials should include measurements of blood concentrations during drug development to generate valid data on the relationships between drug concentrations and clinical outcomes under well-controlled conditions. This would merely increase the amount of work and costs, as high-throughput methods are now available in many laboratories. Any progress in TDM has direct benefits for the treatment of many individual patients.     

Therapeutic drug monitoring in pregnancy

ABSTRACT:: Therapeutic drug monitoring (TDM) is commonly recommended to optimize drug dosing regimens of various medications. It has been proposed to guide therapy in pregnant women, in whom physiological changes may lead to altered pharmacokinetics resulting in difficulty in predicting the appropriate drug dosage. Ideally, TDM may play a role in enhancing the effectiveness of treatment while minimizing toxicity of both the mother and fetus. Monitoring of drug levels may also be helpful in assessing adherence to prescribed therapy in selected cases. Limitations exist as therapeutic ranges have only been defined for a limited number of drugs and are based on data obtained in nonpregnant patients. TDM has been suggested for anticonvulsants, antidepressants, and antiretroviral drugs, based on pharmacokinetic studies that have shown reduced drug concentrations. However, there is only relatively limited (and sometimes inconsistent) information regarding the clinical impact of these pharmacokinetic changes during pregnancy and the effect of subsequent dose adjustments. Further studies are required to determine whether implementation of TDM during pregnancy improves outcome and is associated with any benefit beyond that achieved by clinical judgment alone. The cost effectiveness of TDM programs during pregnancy also remains to be examined.     

Therapeutic drug monitoring of busulfan in transplantation

Busulfan is the only agent used in myeloablative regimens for hematopoietic stem cell transplantation for which therapeutic drug monitoring (TDM) has been widely used. Studies of oral busulfan (Bu) indicate wide intrapatient and interpatient variations in pharmacokinetic (PK) behavior, particularly in children. Dose adjustments of oral Bu based on TDM to bring exposures within established therapeutic ranges have been shown to reduce toxicity and improve outcomes. Intravenous (IV) Bu is becoming more widely used and has much more predictable PK. Outcomes with IV Bu appear to be superior to those achieved using oral Bu without TDM. However there is still at least a threefold variation in exposures achieved by the same dose of IV Bu in different individuals and a small proportion of patients will experience toxic exposures with current dosing regimens. Therapeutic monitoring with appropriate dose adjustment is therefore recommended for all patients treated with regimens containing high doses of Bu. Giving IV Bu at a fixed rate to adults will narrow the range of exposures but more work is needed to establish the best dosing regimen to bring as many exposures as possible within the target range. Studies of test dosing of IV Bu show that this strategy is more accurate when test and treatment doses are infused at the same rate. Finally, targeting exposures to the upper end of the therapeutic range may provide a safe approach to exploiting dose-intensity for the treatment of some malignancies.     

Drug monitoring in systemic lupus erythematosus

Therapeutic drug monitoring (TDM) is not yet accepted by systemic lupus erythematosus (SLE) treatment guidelines. Studies in SLE, however, have proven benefit in three areas: identification of non-adherence or poor adherence; targets for clinical benefit; and ranges of toxicity. This review covers the data on three medications commonly used for SLE, drawing on studies from both the SLE and non-SLE literature.     

Therapeutic drug monitoring of psychotropic medications

Therapeutic drug monitoring (TDM) of a number of psychotropic medications has proven to be of value, enabling minimization of the limitations of considerable genetic variability in their metabolism and the high rates of poor compliance with many psychiatric disorders. Therapeutic ranges have been established for lithium, some of the tricyclic antidepressants, and clozapine. TDM has also been shown to be useful in avoiding toxicity (as many psychotropics have narrow therapeutic indices), particularly that due to interactions with other compounds.     

Therapeutic drug monitoring of psychotropic medications

Therapeutic drug monitoring (TDM) of a number of psychotropic medications has proven to be of value, enabling minimization of the limitations of considerable genetic variability in their metabolism and the high rates of poor compliance with many psychiatric disorders. Therapeutic ranges have been established for lithium, some of the tricyclic antidepressants, and clozapine. TDM has also been shown to be useful in avoiding toxicity (as many psychotropics have narrow therapeutic indices), particularly that due to interactions with other compounds.     

Therapeutic and toxic blood concentrations of more than 800 drugs and other xenobiotics

In order to assess the significance of drug levels measured in clinical and forensic toxicology as well as for Therapeutic Drug Monitoring (TDM) it is essential that good collections of data are readily available. For more than 800 substances, therapeutic ('normal') and, if data was available, toxic, and fatal plasma concentrations as well as elimination half-lives were compiled in a table. The compilation includes data for hypnotics, benzodiazepines, neuroleptics, antidepressants, sedatives, analgesics, anti-inflammatory agents (e.g., NSAIDs), antihistamines, antiepileptics, betaadrenergic antagonists, antibiotics (penicillins, cephalosporins, aminoglycosides, gyrase inhibitors), diuretics, calcium-channel blockers, cardiac glycosides, antiarrhythmics, antiasthmatics, ACE-inhibitors, opiate agonists, and local anesthetics, among others. In addition, toxicologically relevant xenobiotics were listed. Data have been abstracted from published information, both compilations and primary sources and have been completed with data collected in our own forensic and clinical toxicology laboratories. Wherever possible, ranges for therapeutic plasma concentrations are expressed as trough concentration at steady state. The half-life values given for each drug are chosen to represent the terminal log-linear phase at most. It is the purpose to rapidly assess the significance of drug levels for the therapeutic monitoring of patients, and to facilitate the diagnostic and clinical assessment in case of intoxications.     

A validated HPLC method for the monitoring of thiopurine metabolites in whole blood in paediatric patients with inflammatory bowel disease

Therapeutic drug monitoring (TDM) of major metabolites of thiopurine drugs is a widely used tool for assessing treatment efficacy and toxicity in patients with inflammatory bowel disease (IBD). We report the laboratory and clinical validation of a simple and reliable high performance liquid chromatography (HPLC) method for the measurement of 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP) on paediatric patients with IBD. The aim of this paper is to develop and validate a method for the measurement of 6-TGN and 6-MMP applicable to routine practice and to evaluate the usefulness of the TDM of thiopurine drugs in children with IBD attending our Gastroenterology Unit. The HPLC method was validated following international guidelines starting from red blood cells (RBC) and whole blood (WB). A comparison between RBC and WB was assessed. The usefulness of TDM was then evaluated using the new method from WB in 47 paediatric patients with IBD treated with thiopurine drugs. WB and RBC resulted in interchangeable matrices. The majority of patients had the metabolite levels inside the therapeutic ranges. A moderate correlation was found between 6-MMP concentration and the dose of thiopurines. A higher percentage of non responders was found among patients with lower levels of 6-TGN. Toxicity was found in eight patients and was evaluated in respect to the metabolite concentration. The described HPLC method is applicable to routine practice and it is suitable for its use in multicentric studies. Our results of TDM on paediatric IBD patients can contribute to clarify its role in their therapeutic management.     

Therapeutic drug monitoring of antidepressants: cost implications and relevance to clinical practice.

Despite evidence to support its potential benefit in clinical practice, therapeutic drug monitoring (TDM) is under-utilised and underdeveloped in the field of psychiatry. In antidepressant pharmacotherapy drug dose is emphasised as the critical treatment variable. However, dose in, and of, itself can be a strikingly misleading predictor of drug concentration and, hence, treatment effect. For antidepressant drugs, plasma concentrations at a given dose have been shown to vary in excess of 40-fold. The clinical relevance of this variability is that at a standard antidepressant dosage only some patients will have tissue drug concentrations associated with an optimal response whereas others will have either low, ineffective drug concentrations or unnecessarily high concentrations which may be poorly tolerated. Among clinicians and healthcare agencies there is an under-appreciation of the degree of pharmacokinetic variability found in patients and how that might impact on the patients response to pharmacotherapy. Hence there is a perception that TDM is an unnecessary, complicated and costly procedure. This is actually unfounded. There are data to suggest that TDM can favourably affect the outcome of antidepressant treatment by providing a rational alternative to the inherently slower, trial and error practice of dosage titration based on clinical response. It is unlikely that TDM will become a standard of care for all antidepressant agents and all patients. Therefore the question becomes for which antidepressant agents, for which patients and under what circumstances, is TDM more cost-effective than traditional dose titration. The use of TDM to optimise the efficient use of selected antidepressant agents could potentially free up healthcare resources to fund other equally deserving treatments. This article provides a discussion of the major classes of antidepressant drugs with regard to their pharmacological features that predict the utility of TDM in clinical practice. Recommendations are made for the practical application of TDM and the directions for further research.     

Therapeutic drug monitoring in cancer chemotherapy

For a select number of drugs, proper management of patients includes monitoring serum or plasma concentrations of the drugs and adjusting the doses accordingly - this practice is referred to as therapeutic drug monitoring (TDM). The need for TDM arises when pharmacokinetic variability of drugs is not easily accounted for by common clinical parameters. Many chemotherapeutic drugs have large interindividual variability, yet TDM is not commonplace in chemotherapy management. This review will discuss pharmacokinetics in the context of chemotherapeutic drugs, examine the few instances where TDM is currently used in the field of oncology and propose other drugs where TDM might be useful for dose adjustments in the management of chemotherapy.     

Best practice in therapeutic drug monitoring

It is the goal of Therapeutic Drug Monitoring (TDM) to use drug concentrations to manage a patient's medication regime and optimise outcome. Limited resources require that drug assays should only be performed when they do contribute to patient management. For this to be the case a therapeutic drug monitoring service has a far greater role than just therapeutic drug measuring . This article describes the roles and functions of a Best Practice TDM service. The features which can and should be strived for in each step of the TDM process—the decision to request a drug level, the biological sample, the request, laboratory measurement, communication of results by the laboratory, clinical interpretation and therapeutic management—are discussed.     

Best practice in therapeutic drug monitoring

It is the goal of Therapeutic Drug Monitoring (TDM) to use drug concentrations to manage a patient's medication regimen and optimise outcome. Limited resources require that drug assays should only be performed when they do contribute to patient management. For this to be the case a therapeutic drug monitoring service has a far greater role than just therapeutic drug measuring. This article describes the roles and functions of a Best Practice TDM service. The features which can and should be strived for in each step of the TDM process—the decision to request a drug level, the biological sample, the request, laboratory measurement, communication of results by the laboratory, clinical interpretation and therapeutic management—are discussed.     

Recent advances in analytical methods for the therapeutic drug monitoring of immunosuppressive drugs

Therapeutic drug monitoring (TDM) of immunosuppressive drugs (ISDs) with a narrow therapeutic index is an increasingly popular tool for minimizing drug toxicity while maximizing the prevention of graft loss and organ rejection. This review focuses on trends regarding analytical methods for the TDM of ISDs since 2011. The five most commonly prescribed immunosuppressive medications are critically reviewed: cyclosporine A, tacrolimus, sirolimus (rapamycin), everolimus, and mycophenolic acid. This review introduces the general background of TDM and ISDs and presents the recent developments in using liquid chromatography–tandem mass spectrometry (LC–MS/MS) and immunoassays for the TDM of ISDs. Finally, a future perspective for these analytical methods is briefly discussed.     

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.     

Therapeutic drug monitoring of antiarrhythmic drugs

Most antiarrhythmic drugs fulfil the formal requirements for rational use of therapeutic drug monitoring, as they show highly variable plasma concentration profiles at a given dose and a direct concentration-effect relationship. Therapeutic ranges for antiarrhythmic drugs are, however, often very poorly defined. Effective drug concentrations are based on small studies or studies not designed to establish a therapeutic range, with varying dosage regimens and unstandardised sampling procedures. There are large numbers of nonresponders and considerable overlap between therapeutic and toxic concentrations. Furthermore, no study has ever shown that therapeutic drug monitoring makes a significant difference in clinical outcome.Therapeutic concentration ranges for antiarrhythmic drugs as they exist today can give an overall impression about the drug concentrations required in the majority of patients. They may also be helpful for dosage adjustment in patients with renal or hepatic failure or in patients with possible toxicological or compliance problems. Their use in optimising individual antiarrhythmic therapy, however, is very limited.