Individual levels versus other factors. If 6-TGN
Individualpatients with inflammatory bowel disease (IBD) may require differentmedications based on their current level of disease activity, treatment goals,and tolerance to various medications.
1 The use of therapeutic drugmonitoring (TDM) has shown to benefit the management of these patients, due tothe need to maintain efficacy and minimize the risk of adverse events.1 ThiopurinesHave a Long History of Use for the Treatment of Patients With IBDThiopurines, including azathioprine (AZA) and mercaptopurine(MP), are immunosuppressive drugs that have a long history of use in thetreatment of patients with Crohn’s disease and ulcerative colitis.1Although thiopurine monotherapy has been found to be ineffective at inducingremission in patients with IBD, it is effective for maintaining remission inthese patients. Additionally, thiopurines can be used in combination withcorticosteroids in short-term treatment to allow patients to discontinuecorticosteroid use.2 ThiopurineMonitoring Is Necessary to Ensure the Safety and Efficacy of Therapy3Although many individuals tolerate and respondwell to treatment with thiopurines, roughly one-third of patients discontinueuse due to lack of efficacy or adverse reactions. Variability in thiopurinemetabolism may account for these differences. Both AZA and MP may be convertedinto the active metabolites 6-thioguanine nucleotides (6-TGN), which induce cytotoxicityand immunosuppression by preventing lymphocyte proliferation through theinhibition of RNA, DNA, and protein synthesis.
Alternatively, AZA and MP may beinactivated through methylation by the enzyme thiopurine-S-methyltransferase(TPMT), resulting in elevated levels of a second metabolite,6-methylmercaptopurine (6-MMP), which has been associated with hepatotoxicity.3 “Experience with thiopurines has shown that thepresence of drug over a certain cut point is correlated with efficacy.” – MarlaDubinsky Because TPMT activity is highly variable betweenindividuals and genetic mutations account for some of the interindividualvariability observed, TPMT genotyping prior to initiation of thiopurinetreatment allows clinicians to adjust the dosage according to enzymaticactivity in order to avoid hepatotoxicity and bone marrow suppression (Figure1).
3,4Although TPMT activity can be used to determineinitial dosing, once a patient has initiated thiopurine treatment, it isimportant to continue monitoring 6-TGN levels.3 A critical studydemonstrated that the likelihood of responding to thiopurines was 5 timeshigher in patients with 6-TGN levels above a cutoff of 235 pmol/8 × 108RBCs than in patients with 6-TGN levels below this therapeutic threshold.5Therefore, if a patient does not respond to standard thiopurine dosing, assaying6-TGN and 6-MMP levels can reveal whether nonresponse is due to inadequate druglevels versus other factors. If 6-TGN levels are subtherapeutic (ie, less than235 pmol/8 × 108 RBCs), the patient will likely benefit from doseescalation; however, if 6-TGN levels are within a defined therapeutic window (235to 400 pmol/8 × 108 RBCs) and the patient is still not responding,switching medication classes would be recommended.6 Although 6-TGNis the active metabolite linked to the efficacy of AZA and MP, excessive 6-TGNlevels carry a risk of bone marrow suppression. Therefore, ongoing monitoringof 6-TGN levels can inform dose adjustments, ensuring that metabolite levelsremain within an appropriate therapeutic range in order to maximize efficacyand limit the risk of drug-related toxicity.3 “The concept of TDM for biologics was first introducedwithdata suggesting that having a detectable drug level at all was associated withbetter outcomes, and has since evolved to developing a minimal threshold forefficacy.
” – Marla Dubinsky Drug Levels CorrelateWith the Efficacy of Biologic Agents Used to Manage IBDSimilar to thiopurines, the efficacy of biologictherapies also correlates with drug level.7 All biologic agents,including tumor necrosis factor-? (TNF?) inhibitors, have the potential to elicitthe development of antidrug antibodies; such immunogenic responses have beenobserved in clinical trials with all available agents for the treatment of IBDand may impact the efficacy of these medications, as detection of antibodies insome cases is associated with undetectable drug concentration.7,8 Additional factors such as the rate of drugclearance from circulation also impact drug levels independent of antibodyformation, as some patients experience rapid clearance leading to low or absentdrug levels.7 Thus, while detection of antibody formation may serveas a proxy for active drug levels, serum drug concentration provides a directmeasurement of drug levels.
In 2006, a study by Maser and colleagues showedthat a greater proportion of patients who had detectable trough seruminfliximab (IFX) concentrations achieved complete clinical remission comparedwith patients with undetectable IFX levels. C-reactive protein (CRP) levelswere also lower for patients with detectable trough IFX, and more of thesepatients achieved a normal CRP level. Additionally, significantly more patientswith detectable trough serum IFX showed endoscopic improvements of at least 75%,as well as complete endoscopic remission.7 “This study established the concept that havingany drug, meaning above zero, was helpful.
Subsequent studies have defined anoptimal range in order to improve efficacy.” – Marla Dubinsky Maintenanceof IFX and Adalimumab Levels Within a Therapeutic Window Is Associated WithHigher Rates of Mucosal Healing9Mucosal healing is the ultimate treatment goal forpatients with IBD. In order to guide clinicians in monitoring and adjustingtherapy to improve long-term patient outcomes, a retrospective observationalstudy of patients with IBD aimed to identify optimal anti-TNF? levels forachieving mucosal healing by analyzing patients treated with adalimumab (ADA)or IFX who underwent colonoscopies. Based on endoscopic assessments of mucosalhealing and measurements of ADA and IFX drug levels, the rate of mucosalhealing for each drug serum level was defined (Figure 2). Patients with mucosalhealing had significantly higher ADA and IFX levels; however, the incrementalgain in mucosal healing reached a near plateau of 12 µg/mL for ADA and 8 µg/mLfor IFX. These findings suggest that a “mucosal-healing therapeutic window” canbe defined for each anti-TNF? agent and used as the target drug level range byTDM in order to achieve mucosal healing in 80% to 90% of patients with IBD.Furthermore, these findings suggest that additional dose escalationsabove this range may be futile and should be avoided for cost-effective doseescalation in a treat-to-target strategy.
9 ManagingPatients With Primary and Secondary Nonresponse to BiologicsClinicians can initiate treatment based on an individualpatient’s disease presentation and modify treatment based on response toinitial treatment, which may vary among individuals (Figure 3).8Primary nonresponse may be attributed to various factors, including inadequatedrug levels, rapid drug clearing, and development of antidrug antibodies.10In this case, patients should be switched to a different treatment class.8In the case of patients experiencing secondary loss of response, clinicians maydecide to escalate dosage, cycle to another drug with the same mechanism, orswitch to a different class of medication.8 The use of TDM to measuredrug and antidrug antibody levels may serve as a powerful tool to reveal themechanisms by which loss of response occurs and, ultimately, to guidetherapeutic decision making for many patients with IBD.10 If theconcentration of a TNF? inhibitor is subtherapeutic and antidrug antibodies arelow or absent, the dose should be increased or administered more frequently. Inthe case of patients with low levels of antidrug antibodies, use in combinationwith an immunosuppressive agent, such as a thiopurine or methotrexate, may helpprevent a secondary loss of response resulting from the development of antidrugantibodies against the TNF? inhibitor.
If the drug concentration issubtherapeutic and antidrug antibodies are high, those antibodies will be hardto overcome, and the patient should be switched to a different TNF? inhibitor.2Although this schematic shows how TDM can be usedreactively to reveal the mechanism of loss of response and inform thesubsequent course of therapy, evidence to support the use of proactive drugmonitoring to predict outcomes and modify treatment before a patient relapsescan keep patients in a state of tight control and minimize their risk ofrelapse. “These drugs are easily cleared, and cliniciansneed to be very proactive if they want patients to stay on a drug in the longterm.
” – Marla Dubinsky Antibodiesto ADA Are Predictive of Loss of Response in Patients With Crohn’s Disease11In a retrospective study of patients with IBD who hadbeen treated with ADA, serial serum samples were analyzed for drug levels andantibodies to ADA (ATA) using a homogeneous mobility shift assay. Patients withlower drug levels were more likely to be positive for ATA. Additionally,analysis of drug and antibody levels over time showed that patients with higherdrug levels by 4 weeks postinduction were at a decreased risk of ATA formation.Serum samples were also analyzed for markers of inflammation, including CRP,serum amyloid A proteins, intercellular adhesion molecule-1, and vascular celladhesion molecule-1, using a high-sensitivity enzyme-linked immunosorbent assay.All inflammatory markers were higher in patients who tested positive for ATAthan in those who tested negative for ATA, suggesting that antidrug antibodies areassociated with an overall lack of disease control and poor clinicalconsequences.
11 TDM ExtendsResponses to IFX in Patients With IBD12Anobservational pilot study demonstrated the long-term benefit of continuedconcentration-based IFX dose titration in patients with IBD. Although nodifferences in drug continuation were apparent by one year, patients who weremanaged proactively with treatment decisions informed by TDM were more likelyto stay on IFX long term. Specifically, 86% of patients in the proactive TDM treatmentgroup remained on IFX therapy at 5 years compared with 52% in the group thatdid not receive TDM-based treatment, suggesting that a higher proportion ofpatients in the proactive TDM treatment group continued to respond to treatmentin the long term. None of the 48 patients in the proactive TDM groupdiscontinued IFX due to recurrent symptoms of IBD, whereas 15 of the 78patients without proactive TDM discontinued treatment due to recurrentsymptoms. Because patients in clinical remission frequently experience low orundetectable IFX levels, TDM and subsequent dose escalation are effectivestrategies to keep IFX at therapeutically effective concentrations.12 Early DoseOptimization Is Associated With Improved Long-term Therapeutic Outcomes13A prospective, observational study measured trough IFXlevels in pediatric patients with Crohn’s disease or ulcerative colitis at week14 after the initiation of IFX treatment.
The investigators found that week-14IFX levels positively correlated with IFX levels at week 54, and higher IFXlevels at week 14 were associated with persistent remission at week 54. Themedian IFX level was 4.7 µg/mL at week 14 for patients in persistent remissionat week 54 compared with 2.6 µg/mL at week 14 for those who were not inpersistent remission at week 54. This was the first study to suggest that earlydose optimization is associated with long-term therapeutic outcomes forpatients treated with anti-TNF? agents.13 Another study further supports the benefits of early doseoptimization with evidence that IFX levels measured as early as week 2 are predictiveof short-term mucosal healing in patients with ulcerative colitis.
14Patients included in this retrospective analysis had undergone endoscopicevaluations at baselines and following induction (between week 10 and 14). IFXconcentrations were measured at weeks 0, 2, 6, and 14 following the initiationof treatment with IFX. Higher serum IXF concentrations at each time pointcorrelated with higher rates of short-term mucosal healing, as defined by aMayo endoscopic subscore of 0 or 1. “If you want patients to achieve a target ofmucosal healing, optimize drugs early. Do not wait for patients to fail,because antibody rates can be as high as 40% to 50% by the time a patientfails, at which time it becomes difficult to recapture their response.” – MarlaDubinsky The patient was treated with IFX (5 mg/kg) combined with MP.
IFX infusions were given at weeks 0, 2, and 6, and at week 3 the levels of IFXand antibodies to IFX (ATI) in the blood were assessed. The IFX concentrationone week after the second infusion was only 1.8 µg/mL, and ATI wereundetectable (<3.1 U/mL).
The extremely low drug level was considered to bea possible error, so the third infusion was given as planned at week 6. IFXlevels measured at 2 and 3 weeks after the third infusion were still low (5.3and 2.0 µg/mL, respectively), with undetectable ATI at both points.
The patientremained symptomatic with little clinical improvement.15 Based on these observations, the dose of IFX was increasedto 10 mg/kg for the next infusion. One week following this infusion, the levelof IFX in the blood was 34 µg/mL and remained within the therapeutic range (13.
1to 34.0 µg/mL) over the next 16 weeks with no additional infusions. The patientexperienced clinical remission, endoscopic healing, and improvement ofinflammatory marker levels.
15 Following the 16-week “drug holiday,” the patient resumedtreatment with a reduced dose of IFX, 5 mg/kg every 12 weeks. The patient continued to be inremission on this lowered dose and maintained therapeutic drug levels with noATI.15 In the case of this patient, information providedby TDM indicated that he could remain in remission on a lowered dose of IFX,resulting in more efficient use of the drug.
Because the patient was able toachieve remission soon after receiving an additional 10 mg/kg infusionfollowing his planned loading regimen, not only did he experience prompt relieffrom clinical symptoms, but also considerable cost savings were associated withhis decreased need for the drug. Although there was a cost related to TDM, thiscost is more than offset by the reduction in the cost of IFX, such that theannual cost with TDM is approximately 50% of the cost of standard practice.15SummaryTDMdemonstrates clinical value by allowing clinicians to monitor and adjusttherapy in order to help patients achieve and maintain remission.
TDM may also helpoptimize therapy with newer agents such as vedolizumab (VDZ), a gut-selective?4?7 integrin antagonist that was approved by the US Food and Drug Administration(FDA) in 2014, as VDZ drug levels have been shown to correlate with clinicalefficacy.8,16 Furthermore, with the recent FDA approval of Inflectra(infliximab-dyyb), a biosimilar to IFX, for the treatment of patients withCrohn’s disease and ulcerative colitis, and the anticipated increase in use ofbiosimilars over time, postmarketing surveillance of their safety andimmunogenicity is strongly recommended.17,18 Therefore, the use of TDMto monitor immunogenicity with biosimilar medicines will be integral to their safeand effective introduction to the IBD treatment landscape and to realizing actualcost savings with biosimilars.18 Further, there is cost savingspotential with TDM by identifying patients who should discontinue treatment dueto lack of efficacy, by informing timely dose reductions when high levels ofmedication are no longer needed, and ultimately by helping patients achieve remissionsooner than with standard practice.