Therapeutic drug monitoring, half-dosing may not be ready for prime-time

Therapeutic drug monitoring (TDM) for patients with immune-mediated inflammatory diseases did not lead to better clinical remission rates, while routine dose reduction of anti-rheumatic drugs for patients with rheumatoid arthritis (RA) in remission offered modest benefits, according to two Norwegian trials.

In the NOR-DRUM Part A trial, clinical remission at week 30 was achieved in 50.5% of 198 patients with TDM versus 53% of 200 patients in the standard therapy group, for an adjusted difference of 1.5% (95% CI −8.2% to 11.1%, P=0.78), reported Silje Watterdal Syversen, MD, PhD, of Diakonhjemmet Hospital in Oslo, and co-authors.

In the ARCTIC REWIND trial, disease flare occurred in 25% of 77 patients in the half-dose conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) group versus 6% in the stable-dose csDMARD group for a risk difference of 18% (95% CI 7%-29%), reported Siri Lillegraven, MD, MPH, PhD, also of Diakonhjemmet Hospital, and co-authors.

While there were “significantly fewer flares in the stable-dose group,” the “findings do not support treatment with half-dose therapy,” Lillegraven’s group concluded in JAMA. Also in JAMA, Syversen’s group determined that their results “do not support routine use of therapeutic drug monitoring during infliximab induction for improving disease remission rates.”

In an editorial accompanying the studies, Jeffrey R. Curtis, MD, MS, MPH, of the University of Alabama at Birmingham, and co-authors discussed why the trials were unable to offer clarity on the “best medical strategies by which these medications might attain the most optimal outcomes.”

First, they posed the question, “Why was TDM not different from standard care?,” and offered several possible reasons, such as the fact that “drug metabolism, optimal drug levels, and ADA [antidrug antibodies] formation may vary across diseases and between individuals.” As a result, TDM only offer benefits in select patients, such as those with RA who are more likely to form ADA and those not on concomitant immunomodulation.

In NOR-DRUM, “patients with RA comprised only 20% of participants in the trial, and more than two-thirds of patients received concomitant immunomodulation, which may have reduced immunogenicity and attenuated benefits from TDM,” according to Curtis and co-authors.

Also, the study was “not powered to detect heterogeneity of treatment effect by disease,” and there was a fairly high rate of infliximab discontinuation, they noted. However, the authors wrote that, “as in the NOR-SWITCH study, the primary end point was designed to evaluate the occurrence of clinical remission across the disease groups. Results were consistent across diagnoses of included patients.”

Finally, the “study focused on induction therapy and assessed clinical remission at 30 weeks, but it is also important to determine whether TDM might improve durability of treatment effects by maintaining adequate drug levels and preventing ADA formation… Results might differ in a randomized trial examining the maintenance phase of infliximab treatment rather than induction,” according to Curtis’ group.

As for ARTIC REWIND results, they concluded that the “study does not support mandatory reduction in csDMARDs for all patients in remission,” but it does offer “some evidence to guide discussions of dose reductions for patients who have adverse drug effects or who have other reasons to reduce immunomodulatory treatment.”

Moving forward, adaptive trial designs, such as SMART, “may identify characteristics of patients most likely to benefit from individualized strategies,” Curtis and co-authors suggested.

TDM is defined as an “individualized treatment strategy in which drug doses and timing of administered doses are adjusted based on scheduled measurements of serum drug levels,” Syversen’s group explained, but there’s insufficient data to justify use of proactive TDM of tumor necrosis factor (TNF) inhibitor therapy for improving clinical outcomes versus standard therapy.

NOR-DRUM was a 38-week randomized, open-label, parallel-group, phase IV multicenter superiority study with patients from 21 hospitals in Norway. Median patient age was 44, and there were more women in the TDM group versus the standard therapy group (56% versus 47%). The most common diagnosis in both groups was spondyloarthritis (about 30% of patients). Median disease duration was >3 years. Over half of the patients in both groups were on concomitant immunosuppressive, such as methotrexate, leflunomide, sulfasalazine, and azathioprine,

Infliximab (Remicade) was administered by IV doses of 5 mg/kg (3 mg/kg for RA) at 0, 2, and 6 weeks and every 8th week after that. “In the TDM group, infliximab administration was adjusted according to an algorithm designed to maintain infliximab levels within the therapeutic range,” the authors explained. “During the induction phase, the dose was adjusted by decreasing the time between infusions if serum infliximab was low (<20 mg/L at the second infusion, <15 mg/L at the third infusion, and <3 mg/L at subsequent infusion[s] up to week 14).” Ultimately, mean on-trial infliximab doses were 4.9 mg/kg in the TDM group and 4.8 mg/kg in the standard therapy groups.

After week 14, the infliximab dose or interval could be either adjusted to reach the therapeutic range of 3 to 8 mg/L and if a patient developed antidrug antibodies of >50 µg/L), a recommendation was made to switch the patient to another therapy. Finally, pre-study concomitant immunosuppressive treatment was maintained in both groups.

The authors reported that the median time to remission was 56 days in the TDM group and 46 days in the standard therapy group, but that there were no significant differences between groups in time to remission (hazard ratio 1.21, 95% CI 0.97-1.52) or time to sustained remission (HR 1.25, 95% CI 0.89-1.75).

Also, ADA ≥5 μg/L development happened in 18% of the TDM group and 17% in the standard therapy group for a between-group difference of −1.2% (95% CI −8.7% to 1.8%). Infliximab was discontinued in 30% of the TDM group and 22% in the standard therapy group for a between-group difference of −9.5% (95% CI −18% to 1%). Nineteen patients in the TDM group discontinued because of formation of ADA.

As for adverse events (AEs), 68% in the TDM group experienced AEs as did 70% in the standard therapy groups, most often upper respiratory tract infections (RTI, 20% in both groups). Study limitations included it’s open-label design, and the fact that the TDM strategy was “based on available literature and clinical experience within the investigative team…it is possible that some patients might benefit from higher drug levels than prescribed in this study.”

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ARTIC REWIND was done to clarify “the optimal method of dose reduction and withdrawal of csDMARD in RA,” explained Lillegraven, and was a multicenter, randomized, parallel, open-label non-inferiority study done at 10 Norwegian hospital-based rheumatology practices with 160 patients with RA in remission for 12 months, all of whom were on stable csDMARD therapy.

Mean patient age was 55 and 66% were female. Oral methotrexate monotherapy was the primary treatment in ≥65% of the patients at a mean dose ≥4.3 mg/wk. In the half-dose group, csDMARD treatment was reduced by half at the baseline visit and if a patient in this group used a combination of csDMARDs, each csDMARD was cut by half, the authors explained.

Of the total study population, 156 received the allocated therapy, and one patient was excluded from the study because of prolonged withdrawal of methotrexate due to surgery.

The authors reported that there were 54 AEs in the half-dose group and 75 in the stable-dose group, most often mild RTIs. Serious AEs, such as supraventricular tachycardia and tubulointerstitial nephritis, occurred in 5% and 3%, respectively. But “[n]o deaths occurred, and none of the adverse events led to study discontinuation,” according to Lillegraven’s group.

Finally, in the post-hoc analysis, 95% of 19 patients in the half-dose had their DMARD medication adjusted following the flare versus 40% of five patients in the stable-dose group. Time to first flare was a mean 212 days in the half-dose group and 123 days in the stable-dose group.

Study limitations included the open-label design and that “the results cannot be extrapolated beyond the 12-month follow-up period, ” the authors cautioned. Also, the dominance of methotrexate monotherapy limited the generalizability to other csDMARD regimens.

And the results need to be taken in the context of findings from other trials—TARA and RETRO — that showed varying results with dose tapering and half dosing, Lillegraven and co-authors pointed out, noting that ARTIC REWIND, “included patients who were in sustained remission for at least 12 months, had no swollen joints, and fulfilled a set of remission inclusion criteria that included an extensive joint examination. Therefore, the trial participants correspond to patients for whom previous data indicated that csDMARD tapering could be successful.”

  1. Results from the NOR DRUM trial do not support routine use of proactive therapeutic drug monitoring during infliximab induction for improving disease remission rates in patients with chronic immune-mediated inflammatory diseases.

  2. Results from the ARCTIC REWIND trial do not support the use of half-dose treatment in patients with rheumatoid arthritis in remission taking conventional synthetic disease-modifying antirheumatic drugs.

Shalmali Pal, Contributing Writer, BreakingMED™

NOR-DRUM was supported by the Norwegian Regional Health Authorities/KLINBEFORSK, the South-Eastern Norway Regional Health Authorities, and Diakonhjemmet Hospital.

Syversen reported relationships with Thermo Fisher. Co-authors reported relationships with Pfizer, AbbVie, Boehringer Ingelheim, Roche, Orion Pharma, Sandoz, Novartis, Celltrion, AOP Orphan Pharmaceuticals, Norgine, LEO Pharma. Novartis Norge, ACO Hud Norge, Celgene, Galderma Nordic, UCB, Bristol-Myers Squibb (BMS), Merck Sharp& Dohme (MSD), Hospira/Pfizer, Lilly, Hikma, Orion, Sanofi, Celltrion, Biogen, Amgen, Egis, Ewopharma, Mylan, EVA Pharma, Gilead, and Janssen.

ARCTIC-REWIND was supported by the Research Council of Norway and South-Eastern Norway Regional Health Authority.

Lillegraven reported support from the Research Council of Norway and South-Eastern Norway Regional Health Authority. Co-authors reported support from, and/or relationships with, the Research Council of Norway and South-Eastern Norway Regional Health Authority, AbbVie, Eli Lilly, Novartis, Pfizer, Diakonhjemmet Hospital, UCB, Amgen, Corrona, Janssen, Genentech, Astellas, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi Sankyo, Eisai Galapagos, Gilead, GlaxoSmithKline (GSK), Merck, Regeneron, Roche, Sanofi, Takeda, and UCB Pharma, Rheumatology BV, MSD, Biogen, Celltrion, Egis, Mylan, Hikma, Oktal, Orion Pharma, and Sandoz.

Curtis reported relationships with, and/or support from, Amgen, BMS, Janssen, Eli Lilly, Pfizer, Sanofi, AbbVie, Genentech, Gilead, GSK, Eli Lilly, and Novartis. Co-authors reported relationships with, and/or support from, AbbVie, Amgen, BMS, Corrona, Celgene, Gilead, Janssen, Eli Lilly, Novartis, Pfizer and UCB.

Cat ID: 158

Topic ID: 90,158,730,187,192,158,925