An Introduction to Therapeutic Drug Monitoring and Possibilities With DBS

Therapeutic drug monitoring (TDM) is a clinical practice of measuring the concentration of a specific drug(s) in an individual’s bloodstream at set time intervals. The overall goal of TDM is to maintain a constant blood concentration at which a given drug is safe and effective. In this blog post, we introduce the practice of TDM and the advantages that dried blood spot testing has to offer as a microsampling method for TDM.

Guiding clinicians to find the ‘right’ dose and optimise treatment

TDM assumes that there is a predictable relationship between drug dose and blood or plasma drug concentration, and between drug concentration and therapeutic outcome.

TDM is not applied to all drugs, but where relevant, it can guide clinicians to find the ‘right’ dose for drugs that might be more difficult to dose, owing for instance to individual differences in drug pharmacokinetic profiles, i.e., the manner in which a drug is absorbed, distributed, metabolised, and excreted.

TDM is also used for monitoring drugs with narrow therapeutic ranges, drugs known to cause therapeutic and adverse effects, and drugs for which target concentrations are difficult to monitor.

Some of the main drug types that are subject to TDM include:

Immunosuppressive drugs: Solid organ transplant recipients depend upon a combination of lifelong immunosuppressive drugs to maintain the function of their transplant by avoiding immune rejection. While prospective and randomised studies to evaluate the clinical benefits of TDM are few, several studies have shown correlations between low immunosuppressant exposure and risk of acute organ rejection, and high immunosuppressant exposure and toxicity (1).

Antibiotics used in intensive care units: TDM helps to guide antimicrobial treatment in intensive care settings, where multi-drug resistant organisms may emerge, and where sepsis is a common and complex complication that may impact the pharmacokinetic profiles of certain drugs.

Antibiotics, anti-fungals, and anti-epileptic drugs used to treat premature babies: Premature babies treated in neonatal units often receive a range of medications to mature their organs, combat infections, and manage seizures. Since organs and metabolic pathways continuously develop in the early stages of life, TDM is important to guide ongoing treatment effectiveness and safety.

Treatments for chronic tuberculosis (TB): Here, TDM may be used in cases of disease relapse, when patients don’t respond as expected to TB treatment, or when aberrant TB drug concentrations are suspected.

Medications given to extremely obese individuals: Impaired organ function, altered gastric emptying and altered absorption due to the presence of excess subcutaneous fat in individuals who are morbidly obese can impact drug pharmacokinetics and render standard dosing ineffective.

Medications used to treat psychiatric disorders, e.g., lithium: Here, TDM may be used to detect issues with treatment compliance, and/or in patients who are taking several other medications, to ensure that blood or plasma drug concentrations are within a safe and effective range.

Anti-seizure drugs: For several drugs in this category, a clear relationship has been established between blood drug concentration and therapeutic effect. TDM can aid in the individualisation of therapy in special groups such as pregnant women, and to adjust for individual variations in pharmacokinetics.

How is therapeutic drug monitoring performed today?

TDM usually begins when a drug is first prescribed, and involves determining an initial dosing regimen appropriate for the medical condition in question, taking into account relevant patient details, including age, weight, overall health and organ function, and any other medications in use.

Sampling for TDM usually entails collecting venous blood samples from patients in special medical facilities including hospitals. These samples are then subjected to a range of pharmacokinetic studies to determine drug exposure in the body over time, and/or measurements of biomarkers related to disease or the drug effect itself (2).

TDM is a complex multidisciplinary discipline and many factors need to be considered when determining blood drug concentrations and suitable dosages, including blood sampling time in relation to drug dose given, dosage history, patient response, and others. The pharmacological considerations for TDM will not be discussed further in this blog post but an overview of the topic is presented elsewhere (3, and references therein).

Since many of the drugs in scope for TDM are administered to patients long-term and in some cases life-long, TDM usually calls for regular and repeated testing in the same individual over long time periods. For individuals living with complex medical conditions who may also be immunosuppressed, regular visits to medical facilities for TDM testing may not always be feasible.

Dried blood spots as an alternative sample format for TDM?

Interest in using dried blood spot (DBS) testing as an alternative to the current TDM sampling methods has risen in recent years (4). Although not yet part of the routine TDM workflow, DBS has been explored in a wide range of TDM applications for several types of drugs, including antimicrobials, anti-seizure drugs, cardiac and blood pressure-lowering medications, antidepressants, immunosuppressive drugs and anti-cancer drugs (reviewed in 5).

DBS is a microsampling method that has been used for qualitative or semi-quantitative analysis of hundreds of molecules, including nucleic acids, elements, small molecule therapeutics, proteins, enzymes and antibodies (6). DBS testing involves removing blood from an individual, either through a venous blood draw or capillary sampling, and immediately applying this blood to a pre-prepared DBS filter paper for drying. The DBS workflow reduces or even eliminates the need for downstream sample preparation, since circular discs punched from the filter paper serve directly as the sample for many downstream testing applications in microtitre plates.

DBS is particularly attractive for TDM because it only requires small volumes of blood, most analytes are more stable in dried blood spots than in frozen blood, and DBS samples are non-contagious and amenable to storage and shipping under ambient conditions.

Capillary sampling with a volumetric self-sampling device makes DBS a very attractive option for home- and remote sampling for TDM because it eliminates the need for a trained phlebotomist, and it allows clinical laboratories to receive samples by mail from larger geographical areas than would otherwise be possible.

Capillary-based DBS sampling is also a much more comfortable sampling option for patients undergoing TDM, because it allows the collection of small volumes of whole blood from the fingertip or heel in a minimally-invasive manner. This is in contrast to currently used venous blood draws that can be uncomfortable or even traumatic, especially when testing children and/or when used regularly.

Stay tuned for our next blog post, where we will dig into some of the studies that have explored DBS in TDM in more deta

By using a safety lancett, microsampling from the fingertip onto a DBS sampling card can easily be performed at home.

References

1. Staatz, C. E., Isbel, N. M., Bergmann, T. K., Jespersen, B., Buus, N. H. (2021). Editorial: Therapeutic Drug Monitoring in Solid Organ Transplantation. Front. Pharmacol. Sec. Drugs Outcomes Research and Policies, https://doi.org/10.3389/fphar.2021.815117.
2. Capiau S., Veenhof H., Koster R.A., Bergqvist Y., Boettcher M., Halmingh O., Keevil B.G., Koch B.C., Linden R., Pistos C., et al. Official International Association for Therapeutic Drug Monitoring and Clinical Toxicology Guideline: Development and Validation of Dried Blood Spot-Based Methods for Therapeutic Drug Monitoring. Ther. Drug Monit. 2019;41:409–430. doi: 10.1097/FTD.0000000000000643.
3. Ceren Ates, H., Roberts, J. A., Lipman, J., Cass, A. E. G., Urban, G. A., Dincer, C. (2020). On-Site Therapeutic Drug Monitoring. Review Trends Biotechnol, 38(11):1262-1277. doi: 10.1016/j.tibtech.2020.03.001.
4. Garza, K. Y., Clarke, W. (2022). Dried Blood Spots and Beyond. A look at established and up-and-coming microsampling techniques. Clinical Laboratory News
5. Wilhelm, A. J., den Burger, J. C., Swart, E. L. (2014). Therapeutic drug monitoring by dried blood spot: progress to date and future directions. Clin Pharmacokinet,53:961–973.
6. Moat, S. J., George, R. S., & Carling, R. S. (2020). Use of Dried Blood Spot Specimens to Monitor Patients with Inherited Metabolic Disorders. International Journal of Neonatal Screening, 6(26), doi: 10.3390/ijns6020026.