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Therapeutic Drug Monitoring

The Goldilocks Story

Over time, the science of medicine has grown into a complex art. Laboratory testing provides useful information for physicians when monitoring the body’s state through body fluid analysis. Now, tests exist to measure the amount of some medications that are circulating in the blood. This measurement is especially important for drugs that have a narrow window of efficacy and the potential for unpleasant side effects when doses escalate.

During the past decade, biologic medications have become increasingly effective for the treatment of inflammatory diseases, such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease (IBD) in patients who are at high risk for disease progression and complications. These diseases involve the overproduction of tumour necrosis factor (TNF-α) by the immune system, which creates a pro-inflammatory response in the body.¹ IBD primarily refers to Crohn’s disease and ulcerative colitis. In Crohn’s disease, the inflammation can be found throughout the gastrointestinal tract and can extend through the entire bowel wall, whereas in ulcerative colitis, the inflammation only occurs within the mucosal lining of the colon.

Treatments using TNF-α inhibitor biologics, such as monoclonal antibodies (mAbs), have revolutionized the treatment of both major forms of IBD. Research has shown that some biologics are effective in reducing disease activity, reducing symptoms, and improving quality of life for many IBD patients. If patients take them appropriately, then biologics can change the progression of the disease.³ However, there have been challenges, as some patients fail to respond while others respond initially, and then lose therapeutic benefits over time, typically requiring arbitrary dose optimization.⁷ When clinicians recognized that biologics have a narrow range of effectiveness, i.e., they can be easily under- or over-dosed and there is variability among patients treated at the same dose level, this helped cultivate the science of therapeutic drug monitoring (TDM).^2,3

Why use Therapeutic Drug Monitoring?

Quite simply, the goal of TDM is to maximize the clinical benefit of a medication while minimizing its side effects. In Robert Southey’s fairy tale of Goldilocks and the Three Bears, Goldilocks found herself trying various dishes of porridge and then beds before she found one that was ‘just right’. In managing patients with IBD, if the biologic dosage is too low, then the patient will receive no clinical benefit and might build a tolerance to the drug. If the dosage is too high, then the patient might be subject to toxicity. At the right dosage for a particular patient, the biologic is free to work as it was designed, yielding many benefits to the patient and overall positive treatment outcome, and the treatment becomes ‘just right’.

Finding a correct dosage to work for everyone is challenging, because how the medication works in the body (pharmacokinetics) can differ significantly between individual IBD patients receiving the same biologic medicine. Pharmacokinetics includes such factors as the rate at which a patient builds immunity against the medication (if at all), the rate of medication clearance from the body, how the medication is absorbed, how the medication is distributed, and more. Through TDM, physicians can learn about an individual’s pharmacokinetic factors in more detail, so that they can better tailor that patient’s specific biologic regimen.

By monitoring the drug levels in the blood (serum) of the patient at varying times during the course of treatment, the physician has valuable information on which to base treatment decisions. These steps can include making appropriate alterations based on TDM, which involves biochemical tests (immunoassays) that track different proteins, hormones, and antibodies, as well as clinical assessments of disease activity.

Researchers have performed many studies with the purpose of finding the most effective measure/marker in a patient’s blood to determine the medication’s effectiveness as well as how the body is responding to the medication after administration. Available data suggests that for IBD patients taking Remicade® (infliximab), the lowest level of medication present in the body (trough serum levels) is closely linked to bowel wall healing and the absence of symptoms.^3,4,5,6 Although some information exists about using TDM with Humira® (adalimumab),^6,7 the majority of research about TDM has been conducted with Remicade®; therefore, most tests available for TDM in Canada are for Remicade®. Canadian researchers have played an important role in these studies, and are at the forefront of this research area.

Due to the complex nature of all biologics and the varied outcomes among patients, therapeutic drug monitoring offers a way to identify the unique therapeutic window of each patient relative to his/her medication regimen. TDM allows for personalized assessment, which increases the likelihood of positive treatment outcomes. We expect that therapeutic drug monitoring will soon become the gold standard for IBD patients taking biologic medications, as physicians strive to ensure patients’ courses of therapy are ‘just right’.

4 Key Points of Therapeutic Drug Monitoring

1. Has the potential to revolutionize patient care by allowing physicians to offer personalized medical management
2. Allows physicians to monitor drug levels and/or antibody levels to the drug, usually just before the next treatment
3. Is typically used when an IBD patient has a secondary loss of response to a biologic
4. Can provide information so a physician can correctly choose to either leave the dosing as is, modify a dose, or change to a different medication.

Want to learn more?

We have several related articles that may be helpful:

• TDM Infographic (for physicians)
• IBD Video
• Ulcerative Colitis Lecture Video
• Ulcerative Colitis Infographic
• Crohn’s Disease Infographic

First published in the Inside Tract® newsletter issue 189 – 2014

1. Ordás I et al. Anti-TNF monoclonal antibodies in inflammatory bowel disease: pharmacokinetics-based dosing paradigms. Clinical Pharmacology & Therapeutics. 2012;91(4):635-646.
2. Therapeutic Drug Monitoring (TDM): An Educational Guide. Siemens. Chapters 1-5.
3. Wang S-L et al. Monitoring of adalimumab and antibodies-to-adalimumab levels in patient serum by the homogenous mobility shift assay. Journal of Pharmaceutical and Biomedical Analysis. 2013;78-89:39-44.
4. Seow CH et al. Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis. Gut. 2009;59:49-54.
5. Maser EA et al. Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn’s Disease. Clinical Gastroenterology and Hepatology.2006;4:1248-1254.
6. Khanna R et al. Review Article: a clinician’s guide for therapeutic drug monitoring of infliximab in inflammatory bowel disease. Ailment Pharmacology and Therapeutics.2013;38:447-459.
7. Llinares-Tello F et al. Analytical and clinical evaluation of a new immunoassay for therapeutic drug monitoring of infliximab and adalimumab. Clinical Chemistry and Laboratory Medicine. 2012;50(10):1845-1847.