In almost all areas of medicine, we accept a role for therapeutic drug monitoring. Whether we consider digoxin levels or vancomycin and cyclosporine troughs, the principles remain the same — there is a range wherein the drug is effective and also one in which there is toxicity. For the purposes of this treatise, we posit that measuring levels of monoclonal antibody-based biologics and thiopurines is beneficial for patient management. At present, we have three classes of antibody-based biologics approved for inflammatory bowel disease (IBD). The one for which we have the most experience is anti-TNF therapy. Recently, we have been gathering data and clinical experience with vedolizumab (anti-homing therapy), and ustekinumab (anti-IL-12/23 therapy). It is our hope that it will take less time than it has for anti-TNF therapy to develop dose optimization strategies.
Therapeutic drug monitoring for monoclonal antibodies involves measuring both the drug and antibodies against the drug (ADAb). Unfortunately for the field, there is variation in the way the measurements are performed with some assays being drug tolerant, i.e. ADAb can be detected even with drug around and others not. For all intents and purposes, significant ADAs will lead to increased drug clearance and are generally associated with very low or undetectable levels of the drug. The big message here is to avoid immunizing your patients to the biologics. Once immunized, patients lose response and are highly likely to lose response to the next anti-TNF.
Our interpretation of the published data and our own clinical experience is that more anti-TNF is generally better! Higher levels of anti-TNFs have been associated with higher rates of mucosal healing,1 higher rates of fistula healing2 and a longer time on drug without loss of response. It is also likely that once patients are in deep remission — feel well and have mucosal healing — the intensity of therapy can be decreased. The patient with severe ulcerative colitis, as an example, needs high doses of drug because of colonic protein losses. But over time, once the inflammation is controlled, the same patient can be de-escalated.
Another reason it makes sense to check for drug levels and ADAb status is to guide choices in therapy.
We are also believers in a proactive strategy of therapeutic drug monitoring, particularly in the setting of induction and optimization to achieve remission. Rather than waiting for patients to lose response or have a middling response to a biologic, it is worth measuring drug levels following induction and dose optimizing early. The study by Papamichael, et al.3 demonstrated that patients whose trough levels of infliximab were kept greater than 5μg/ml maintained response significantly longer than those with lower levels and were less likely to be hospitalized and require surgery. The study by Vande Casteele4 is often quoted as an example that proactive therapeutic drug monitoring is not useful. In it, patients were randomized to therapeutic drug monitoring-based optimization (levels 3-7μg/ml) versus interventions based on clinical parameters. The devil is in the details, however, and patients in this study were cared for in tertiary referral centers in Belgium and Amsterdam, and were closely followed. One can also argue that levels of 3-7μg/ml are not terribly high so not hard to achieve with standard dosing. Sadly, most patients in a typical busy GI practice are not followed so methodically and, therefore, therapeutic drug monitoring is likely to intercept patients with low drug levels at risk for loss of response.
Another reason it makes sense to check for drug levels and ADAb status is to guide choices in therapy. Lost response to an anti-TNF in a patient may be due to the patient creating ADAbs, having low levels of drug or having high levels of drug. Each scenario is handled differently. Patients with ADAbs are likely to respond to a change to a different biologic with the same mechanism — at this point this is only relevant for the anti-TNFs — but should be started on a concurrent immunomodulator to prevent this from happening again. For patients with low drug levels, raising the dose has been shown to be effective. Finally, for patients with arguably high levels of drug and no response, the clinician should ask whether there is active disease or not. Active disease may respond to a change in mechanism of action of the drug. The most common example is patients with high levels of anti-TNFs and inadequate response. These patients may benefit from a change to vedolizumab or ustekinumab.
Thus far, the data we have for ustekinumab and vedolizumab again shows a positive relationship between trough levels and efficacy. Commonly, when patients are losing response to either of these newer biologics, we check drug levels and shorten the intervals between doses — after fights with insurance companies! In general, ADAbs appear to be less common a problem with newer monoclonal antibodies, possibly because of improvements in manufacturing of cell-derived products.
Finally, the case for therapeutic drug monitoring of thiopurine metabolites is a “no-brainer.” Many studies have demonstrated that levels of 6-TGN between 230-420pmol/8×108 RBC are associated with greater efficacy. It also identifies toxicity and flags patients that are doing the 6-MP shuffle — when you raise the thiopurine dose they generate 6-MMP rather than 6-TGN. In those cases, addition of allopurinol (100mg) and a low dose of azathioprine, usually 50mg, is perfect to achieve therapeutic levels of 6-TGN and little to no 6-MMP. Recently, there are a few provocative basic science studies that suggest that allopurinol may also mediate an anti-inflammatory effect by reducing uric acid production by pro-inflammatory intestinal fungi.5
In summary, we favor therapeutic drug monitoring as a way to pro-actively optimize drug levels to maximize efficacy and minimize toxicity in our IBD patients. Our hope is that different laboratories will perform these assays less expensively and that insurance companies will change their arbitrary policies on reimbursement for these tests to make these accessible to all clinicians and their patients.
Dr. Kim has no conflicts to disclose.
Dr. Abreu has done consulting for Abbvie Laboratories, Prometheus Laboratories, Takeda, UCB, Inc., Pfizer, Janssen, Eli Lilly Pharmaceuticals, Celgene Corporation, Theravance Biopharma Us, Inc., Shire Pharmaceuticals, Roche Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, Celltrion Health Care and AMGEN. Dr. Abreu’s laboratory has received an investigator-initiated grant from Takeda and has done several investigator-initiated studies with Prometheus. Dr. Abreu is chair of the AGA Institute Council.
1. Yarur A.J., Jain A., Hauenstein S.I. et al, Higher Adalimumab Levels Are Associated with Histologic and Endoscopic Remission in Patients with Crohn’s Disease and Ulcerative Colitis. Inflamm Bowel Dis. 2016;22(2):409-415.
2. Yarur A.J., Kanagala V., Stein D.J. et al, Higher Infliximab Trough Levels Are Associated with Perianal Fistula Healing in Patients with Crohn’s Disease. Aliment Pharmacol Ther. 2017;45(7):933-940.
3. Papamichael K., Chachu K.A., Vajravelu R.K., et al, Improved Long-Term Outcomes of Patients With Inflammatory Bowel Disease Receiving Proactive Compared With Reactive Monitoring of Serum
Concentrations of Infliximab. Clin Gastroenterol Hepatol. 2017. Epub ahead of print.
4. Vande Casteele N., Ferrante M., Van Assche G. et al, Trough Concentrations of Infliximab Guide Dosing for Patients With Inflammatory Bowel Disease. Gastroenterology. 2015;148(7):1320-1329.
5. Chiaro T.R., Soto R., Stephens W.Z. et al, A Member of the Gut Mycobiota Modulates Host Purine Metabolism Exacerbating Colitis in Mice. Sci Transl Med. 2017;9(380).