Proactive drug monitoring in IBD: ‘Not a new concept’
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For some patients with inflammatory bowel disease, treatments can be ineffective, and in patients where they do work, they do not always last.
Therapeutic drug monitoring (TDM) can be used to optimize dosing of medications to achieve better outcomes for patients, Adam Cheifetz, MD, of Beth Israel Deaconess Medical Center, told Healio.
However, primary non-response and secondary loss of response remain a critical problem in the management of patients with IBD. According to the recent personalized anti-TNF therapy in Crohn’s disease study (PANTS), nearly 24% of patients experienced primary non-response at week 14, while non-remission at week 54 occurred in more than 63% of patients. For patients treated with Remicade (infliximab, Janssen) or Humira (adalimumab, AbbVie), the only factor associated with primary non-response was low drug concentration at week 14. Low week 14 concentrations were also associated with non-response at week 54.
Reactive vs. proactive TDM
TDM in IBD comes in two very different packages, reactive and proactive.
In reactive TDM, Cheifetz said you wait until a flare to check drug concentrations and for development of antibodies. Once that information is available, the drug dose is adjusted to ensure the patient has reached a therapeutic concentration. However, if the patient has already developed high level antibodies, the drug will no longer be effective and needs to be switched. The American Gastroenterological Association currently recommends using reactive TDM to guide treatment changes in patients with active IBD on anti-TNF therapy.
While research has shown that it is an improvement on empiric dose escalation, as it better directs care and is more cost-effective, Cheifetz said you are effectively doomed to lose a certain percentage of patients to primary non-response or secondary loss of response.
“When a patient is flaring, they have undetectable drug levels and high antibodies,” he said. “Why wait until someone flares to optimize their drug when you can optimize them ahead of time and dose them appropriately?”
That is where proactive TDM comes in. In that method, physicians monitor drug concentrations and dose patients to a therapeutic threshold at specific time points.
“Most of our data are in post-induction and maintenance, but it’s probably most effective during induction,” Cheifetz said. “There are data from our group and others that show proactive TDM is better than the standard of care of either reactive TDM or empiric dose escalation. We showed with both infliximab and adalimumab that there was less discontinuation and longer time on drug. Specifically with infliximab, there were fewer hospitalizations, IBD surgeries, infusion reactions and antibody development.”
Currently, most data on TDM involved anti-TNF therapy. In a recent study published in the Journal of Crohn’s and Colitis, researchers found that in patients with IBD who received adalimumab, at least one proactive TDM was associated with a reduced risk for treatment failure, compared with patients who receive empiric dose escalation. A study by Amit Assa, MD, and colleagues found that found that proactive monitoring of adalimumab trough concentrations and adjustment of doses and intervals resulted in significantly higher rates corticosteroid-free clinical remission than reactive monitoring.
While most of the trials including the prospective ones are focused on anti-TNF, Cheifetz said there are some exposure-response data for TDM in other biologic therapies used in IBD, including Entyvio (vedolizumab, Takeda) and Stelara (ustekinumab, Janssen).
“[These data] show that higher drug concentrations are associated with better outcomes, and lower concentrations are associated with worse outcomes,” he said.
Point-of-care testing
Although proactive TDM is gaining some traction and becoming less controversial, Cheifetz said some physicians are still fearful of out-of-pocket costs for patients, and some warded off by perceived negative findings, like those found in the TAXIT trial. For its failings, however, Cheifetz said there were clear-cut reasons for them in the study design, and the data still showed a benefit.
“TAXIT showed that a one-time optimization in patients with Crohn’s disease with low drug concentrations resulted in more remission and improved C-reactive protein,” he said. “Even within the first year, despite all patients being initially dose-optimized, fewer patients in the proactive group had flares and undetectable drug concentrations.”
In addition to more prospective studies, Cheifetz said there needs to be better comparisons between assays that help interpret antibody levels, as well as better pharmacokinetic modeling that could help personalize dosing foreach patient.
“The field is heading towards point-of-care testing where you can check a drug concentration and antibodies and have a rapid turn-round time and affect the dose before you give it,” he said. “The turnaround time is upward of 5 days or so. You’ve already given the drug, but you can affect the next dose. With faster testing, someone could be coming in for an infliximab infusion, get their draw their blood drawn and within minutes you’ll have a drug concentration that you can act upon.”
For Cheifetz, the choice between reactive and proactive TDM is clear. He has long been a proponent of proactive monitoring.
“It’s not a new concept,” he said. “We’ve been doing it for years with other medications, including antibiotics, cyclosporine in severe ulcerative colitis and with tacrolimus in organ transplant. You don’t wait until a patient becomes sick. You check levels and optimize, regardless.”
References
- Assa A, et al. Gastroenterology.2019;doi:10.1053/j.gastro.2019.06.003.
- Feuerstein JD, et al. Gastroenterology. 2017;doi: 10.1053/j.gastro.2017.07.032.
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Kennedy NA, et al. Lancet Gastroenterol Hepatol. 2019;doi:10.1016/S2468-1253(19)30012-3.
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Papamichael K, et al. Clin Gastroenterol Hepatol. 2019;doi:10.1016/j.cgh.2019.03.037.>
- Papamichael K, et al. Curr Opin Gastroenterol. 2019;doi:10.1097/MOG.0000000000000536.
- Papamichael K, et al. J Crohns Colitis. 2019;doi:10.1093/ecco-jcc/jjz018.
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Vande Casteele N, et al. Gastroenterology. 2015;doi:10.1053/j.gastro.2015.02.031.
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