Manual Therapeutic Drug Monitoring: Newer Drugs and Biomarkers

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Detection of other potentially useful markers falls in analytically challenging concentration ranges, or relies upon detection and read-out technologies that are technically challenging to be re-designed for miniaturization Cheng et al. A textbook example is the blood glucose meter Newman and Turner, ; Wang, The patient can easily monitor glucose concentration in blood through a fingerprick, and adjust therapy or refer to the physician. In addition, a variety of glucose meter of few centimeters in size is available to the end user for few tens of dollars plus test strips costs that devolve the display of results to smartphones Lillehoj et al.

Finally, the extensive knowledge of the pharmacokinetics PK and the pharmacodynamics PD of insulin drove the design of automatized closed loop system integrating blood measurements, evaluation, and dosage adjustment and administration in a small, wearable and soon implantable lab-on-a-chip LoC devices Hirsch et al.

However, blood glucose concentrations in diabetic patients are in the millimolar range, easily achievable technically compared to the 10 8 times smaller concentration of most biomarkers Craighead, ; Chin et al. The readout is usually an electrochemical determination most commonly amperometry of enzyme activity induced by the presence of glucose Wang, , that can be easily implemented with cheap consumer electronic components.

In addition, the frequency and amount of measurements performed daily likely exceed that of any other parameter to be monitored, making the market very appealing Newman and Turner, Similarly, PoC clotting tests are also widely used as companion monitoring during anticoagulant therapy Chin et al.

Therapeutic drug monitoring newer drugs and biomarkers – Health Sciences Library E-Book Database

Recent publications offer detailed reviews of the most recent PoC and LoC devices under development or already available on the market Toner and Irimia, ; Soper et al. As perspicuously detailed by Chin et al.

Indeed, a plethora of different high-sensitivity techniques emerged in the literature. However, despite the high-performance of the individual parts, the final fully integrated device may not be feasible at all due to poor compatibility of its single components, poor understanding of the end-use settings, and of the critical step in the clinical pipeline.

Therapeutic drug monitoring: When, why, and how

Eventually, they also may demonstrate limited improvement of quality of care compared to the cost reduction or easiness of use. Trends in the development of PoC devices are different depending on the end-use settings, like high- or low-income countries Martinez et al. The ideal PoC device, however, has to provide rapid TAT sample to answer with no human intervention besides adding the sample and collecting the data.

Conventional hematological markers like the ones mentioned earlier that are routinely monitored and quantified in clinical laboratory can be evaluated through small bench-top instruments, usually equipped with a series of disposable cartridges for each panel of parameters, which permits the creation of easily accessible diagnostics sites Pollock et al.

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Quantitative PoC system based on microfluidics and implementing separation and sample pretreatment are gaining increased space in the market Luppa et al. Indeed, additional research goes in the direction of systems able to incorporate or to waive specimen pretreatment, in particular blood separation Toner and Irimia, ; Songjaroen et al. Parameters like coagulation indices or glycemia are examples of easily accessible surrogate response pharmacodynamic biomarkers that monitor the therapeutic effect Gross, ; Touw et al.

For many other therapies, the pharmacodynamic effect is not readily measurable, and large inter-individual variation and narrow therapeutic index make it very difficult to adjust dosage without high risk of toxicity for the patients Gross, ; Buclin et al. Variability arises in the different absorption and distribution pharmacokinetic rates in different patients, that is, the same dosage may translate into different drug concentrations and different pharmacodynamic response to the same drug concentration in different patients Gross, ; Touw et al. When the population variability is larger than the therapeutic range that is the difference between the minimum efficacy dose and the lowest dose at which adverse effects arise , monitoring of therapy is crucial.

A long known companion of personalized medicine in these situations is therapeutic drug monitoring TDM Lesko and Schmidt, Commonly the measurement is in a biological matrix of a prescribed xenobiotic, but it may also be of an endogenous compound prescribed as replacement therapy in an individual who is physiologically or pathologically deficient in that compound.

Consensus is reached on the rational prescription of TDM, which is — despite recent advancements — a demanding procedure with non-negligible costs for the healthcare systems, both in high- Schumacher and Barr, ; Ghiculescu, ; Kang and Lee, ; Buclin et al. Drug monitoring of therapy is helpful in intensive care situations i. As their therapeutic index is known to be narrow, administration of these drugs is often accompanied with TDM.

The list of most commonly monitored drugs Gross, ; Schumacher and Barr, ; Dasgupta and Wahed, that meet the aforementioned criteria include — but is not limited to — antiretrovirals Acosta et al. Drug monitoring helps to identify the onset response at the beginning of therapy, and to adjust the dose in critical patient with renal, hepatic, or cardiac impairment, etc. Then, it can be performed at wider time interval to assess efficacy of the therapy, to build a reference range for the patient under evaluation Patsalos et al.

TDM is an exceptional tool to better understand why patients do not respond satisfactorily to a particular dose, and to assess and monitor compliance and ultimately to study the variation in PK that occurs in different individuals and the factors involved Muller and Milton, Anti-epileptic drugs are a very representative case of TDM application to clinical practice Neels et al.

These drugs treat and prevent the clinical manifestations, like seizures, only if an effective drug concentration is reached, and present serious side effects when reaching toxic concentration. Most of these drugs have narrow therapeutic index and large inter-individual variability Eadie, ; Johannessen et al. Historically, the old generation anti epileptic drug phenytoin was one of the first drug for which a TDM test was developed Eadie, ; Patsalos and Berry, Phenytoin presents both a non-linear PK that is, there is a non-linear relation between the administered dose and the blood drug concentration and high-inter-individual variability.

Other old generation anticonvulsants like carbamazepine, valproic acid, ethosuximide, and phenobarbital are still used and monitored Jannuzzi et al. Second generation AEDs were marketed as safer because of a wider therapeutic index, though practice revealed that achieving proper dosage is challenging and TDM could be useful Perucca, ; Johannessen et al. Many recent analyses tried to assess the cost—benefit for TDM of different classes of drugs, and only a few were able to clearly assess the superior clinical performance — in terms of cost-effectiveness — of routine TDM Eadie, ; Touw et al.

AEDs TDM is usually perceived as cost-effective, because of the high risks associated with improper dosage and the successes achieved in managing therapy with the proper interpretation of TDM analysis Glauser and Pippenger, ; Buclin et al. In addition, for AEDs and many other drugs, TDM studies would provide invaluable information on the PK of drugs in subpopulation not well represented in the pharmacokinetic studies during trials, such as gender Morrell, ; Tomson, , pregnancy and newborns Adab, , children Momper and Wagner, , and elderly people Steinman et al.

While the contribution of TDM to the effective management of therapy is substantiated by practice, properly designed studies are missing, or evaluate too different clinical outcome variables that prevent proper comparison Touw et al. As health-care systems aim at providing services at reduced cost whenever possible, rationalization of costly TDM analysis prescription is everywhere highly recommended Touw et al. Unfortunately, the lack of consensus on a clear-cut quantitative analysis in favor of distributed, decentralized TDM procedures is slowing down the investment and applications of PoC system in the field.

Therapeutic Drug Monitoring: Newer Drugs And Biomarkers By Dasgupta

Besides different analytical methodologies, and different specimen analyzed, there are differences in the kind of information that is provided to the treating physician. For the value to be informative, drug measurements need to be accompanied by proper detailed information about dosing schedule, last dose administered timing, and sample timing Aronson and Hardman, Anyhow rarely, TDM service may provide the drug concentration value per se , but more often it is accompanied at least by a reference range validated for the sample and technique employed and with suggestion for clinical interpretation to be translated in therapeutic management.

This reference range is — as the name suggests — just a reference interval, statistically defined, that encompasses the spread of the concentrations in a population of patients addressed during clinical studies.

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It may change for different therapeutic uses of the same drug, and exact values of the boundary limits may change depending on the analytical technique involved. Other critical details are co-medications and demographics, like age, gender, and eventually ethnicity [as pharmacogenomics studies distinguished specific, in distinct subpopulations, in metabolic enzymes responsible for altered metabolism and toxicity risks of certain drugs Gurwitz et al.

Unfortunately, as Phase II and Phase III of drug development clinical trials require dose tolerance and dose response exploration only, PK investigations are often a secondary objective Touw et al. Most of the drugs reaches Phase IV the post-marketing phase with very little information on the PK and PD behavior of the drug, and rarely with estimation on the appropriateness of accompanying TDM, which is left to the responsibility of practitioners Gross, ; Neef et al. Moreover, for most drugs, the need for TDM in proper management of therapy was discovered only in clinical practice.

However, in principle, having the PK and PD data available for the monitored drug, current computational techniques would allow full integration of these calculations in portable devices to provide a proper reference range delivered with the analytical answer, and would allow for fast results during the visit at the physician office for example , and for direct communication of the results to the centralized lab for continuous therapy surveillance. Many groups call for mandatory TDM in drug development clinical trials Neef et al. Besides the burden of additional blood sampling to the enrolled patients, the main hurdle to TDM inclusion in drug development and investigational trials and practice is cost Neef et al.

Indeed, incorporation of TDM in drug development requires additional investments from the industry in the development of a robust, validated bioanalytical assay. In addition, TDM is somehow also perceived by companies as a potential barrier for the subsequent effortless adoption of the drug in the clinical practice Neef et al. Both the increase in costs for drug developments along with a lack of awareness of the regulatory authorities and hence the obligation for companying TDM during drug development and approval led to the fact that little investment and research effort is made in the field, even so the new developments in terms of nanotechnology for sensor techniques are promising.

The main points where improvements need to be made and can be gained with nanotechnologies are to increase the sensitivity in order to work with smaller sample volumes allowing for a repeated sampling or even more non-invasive sampling such as tears or sweat. Smaller volumes also mean that the time of reaction with the sensor system decreases and hence the time-to-result. The most commonly employed technologies for TDM so far have been extensively revised for the different classes of drugs [see, for example, Dasgupta and Wahed ].

Usually, drug concentration is monitored from a plasma sample, though whole blood could also be analyzed Aronson and Hardman, ; Reynolds and Aronson, Sample treatments extract the total drug available in plasma that is the sum of the protein-bound and free drug in circulation. Depending on the assay chosen, the analytical protocol has to be validated at each step from the pre-analytical phases to result communication and storage. The pre-analytical phase includes patient preparation, sample collection, sample treatment, and is often unique to the drug to be analyzed.

For example, lithium therapy monitoring cannot be performed on sample collected in standard lithium heparin blood tubes, and colorimetric tests may suffer the interference of a poorly drawn blood sample from hemoglobin interference Aronson and Hardman, ; Reynolds and Aronson, ; Dasgupta and Wahed, Analytical separation techniques are widely established methodologies for TDM.

Appropriate sample pretreatment is required. It involves solvent or solid-phase extraction Bugamelli et al. These techniques rely upon sophisticated and expensive equipment that has to be operated by technically skilled personnel and are usually more common in large clinical research laboratory. In large laboratory hospitals, immunoassays with different read-out technologies, ranging from nephelometry, chemiluminescence, to colorimetry and fluorescence see Figure 1 for a survey of these techniques , are available for a panel of drugs in multi-well plate assays with ready-made proprietary reagents compatible with automatized commercial system already in use for other analyses.

These commercial systems often include automatized sample pretreatment.

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Protocols may differ among centers, and each center performs a proper analytical validation of the methodological protocol and the entire process, as guidelines require ensuring accurate and robust analyses Shipkova et al. Some immunoassays fall short of simultaneous determination of a drug and its active metabolite Mikel et al. Different commercial assays present different or none cross-reactivity patterns, for many of which the literature offers details Kang et al.

Figure 1.