Therapeutic drug monitoring of anti-TNF therapy

Thiopurine-S-methyltransferase (TPMT) is a drug-metabolizing enzyme that catalyzes the S-methylation of thiopurine compounds such as 6-mercaptopurine (6-MP), azathioprine (AZA) and thioguanine — drugs with narrow therapeutic windows used to treat inflammatory bowel disease (IBD) and other disorders. Inherited variations in TMPT activity — first described nearly four decades ago — can have profound clinical implications because of their correlation with drug response.

A majority of people, about 89 percent, have wild-type TPMT and respond well to normal doses of thiopurines. Ten percent have one copy of a variant allele, leading to moderately low levels of TPMT and an increased risk of drug toxicity. And 1 in every 300 people is homozygous for alleles that result in low or no TPMT activity and is therefore at risk of profound myelosuppression from thiopurine agents.

For at least 20 years, measurement of TPMT genotypes or enzyme activity before starting thiopurine therapy has been a relatively reliable — and cost-effective — strategy for individualizing dosing.

For example, IBD patients who have no TPMT enzyme activity should not be treated with 6-MP or AZA. Those with moderate TPMT enzyme activity may respond to a more moderate dosing strategy (such as 1.0 mg per kg of 6-MP a day or 1.5 mg per kg AZA a day). And patients with higher-than-normal enzyme activity may need higher doses to achieve a satisfactory clinical response.

"Monitoring enzyme activity is a slow, laborious process, and some doctors don't do it," says Edward V. Loftus Jr., M.D., a gastroenterologist at Mayo Clinic's campus in Rochester, Minnesota. "A lot of people referred to our clinic are on suboptimal doses of these drugs."

Studies have shown that therapeutic efficacy and hepatoxicity correlate with levels of 6-thioguanine and 6-methylmercaptopurine, respectively, so these metabolites should be checked a few months after initiating therapy with AZA or 6-MP, Dr. Loftus says.

Monitoring biologics

Therapeutic drug monitoring is now also extending to newer biologics, including TNF inhibitors such as infliximab, a chimeric monoclonal antibody, and adalimumab, a fully human monoclonal antibody. Although these drugs have improved outcomes for some refractory patients, they have been unsatisfactory for others.

More than one-third of patients fail induction therapy and up to 60 percent of primary responders lose response over time. These failures have been attributed to inadequate serum concentrations of the drug, a high inflammatory burden and the formation of human anti-chimeric antibodies (HACAs). The risk of infusion reactions also is associated with HACAs. Thus, drug monitoring may help determine the most appropriate therapeutic strategy and improve patient outcomes overall.

In a 2010 study published in the American Journal of Gastroenterology, members of the inflammatory bowel disease interest group at Mayo Clinic's campus in Minnesota examined the medical records of 155 IBD patients whose HACA and infliximab concentrations had been measured. The main indications for testing were partial response to the drug, loss of response and possible hypersensitivity reactions. Of the included patients, 35 (23 percent) had HACAs and 51 (33 percent) had therapeutic concentrations of infliximab — results that affected treatment decisions in nearly three-fourths of cases.

In HACA-positive patients, changing to another anti-TNF agent led to a complete or partial response in 92 percent of patients, whereas a dose increase was associated with a 17 percent response. In patients with subtherapeutic infliximab concentrations, increasing the dose resulted in a complete or partial clinical response in 86 percent of patients; changing to another anti-TNF agent resulted in a response in 33 percent of patients.

Dr. Loftus says several strategies can help maintain therapeutic levels of TNF inhibitors: scheduled dosing, loading doses and concurrent use of immunomodulators. "We've also learned that patients with a higher body mass or high inflammatory burden need a larger dose of the drug to counteract that. The idea is to do everything possible to prevent the drug level from going to 0," he explains.

In cases of an incomplete or lost response, drug and antibody levels should be checked just before the next dose. "If the drug level is low and the patient doesn't have antibodies, then we need to increase the dose of the anti-TNF agent. If the patient already has antibodies, then it's fruitless to keep giving higher doses; we need to switch drugs. Right now, most people are measuring anti-TNF drug levels and antibodies in patients who have lost response. But I can see routinely checking these levels and making proactive adjustments in regimens."

He also foresees the possibility of developing assays for vedolizumab and other biologics and for additional drugs with narrow therapeutic windows. "The stakes are high. If we don't reach therapeutic levels, patients not only don't improve, they can also develop complications," he points out.

Mayo Medical Laboratories is in the process of developing assays for both infliximab and adalimumab. The assays should be available by early 2015 and will likely be less expensive than current tests.

For more information

Afif W, et al. Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease. American Journal of Gastroenterology. 2010;105:1133.