Therapeutic Drug Monitoring Testing Research Articles

COMPARING REAL-WORLD OUTCOMES, MEASURED AS 12 AND 24-MONTH IBD-RELATED SURGERIES, BETWEEN INFLIXIMAB DOSE OPTIMIZED PATIENTS USING THERAPEUTIC DRUG MONITORING (TDM) VS AN UNOPTIMIZED CONTROL GROUP, IN A LARGE US COMMUNITY-BASED GASTROENTEROLOGY PRACTICES

Abstract BACKGROUND Anti-TNFs such as infliximab (IFX) continue to be the standard of care to treat moderate-to-severe IBD. Remission and reducing detrimental outcomes are achievable goals when therapeutic drug monitoring (TDM) is implemented to assist with IFX therapy optimization. TDM aids in achieving & maintaining adequate drug exposure to avoid loss of response by offering actionable information to guide treatment adjustments. The value of TDM has been described in numerous studies which show that optimization of anti-TNFs correlates with improved clinical outcomes & the use of TDM is recommended by IBD guidelines and expert consensus. A potential evidence gap is the lack of real-world outcomes data when Anser®, a TDM test, is implemented in a community setting. OBJECTIVE Describe & compare the real-world outcomes, measured as IBD-related surgeries, in IFX dose optimized patients using Anser® TDM as part of ongoing IBD care as compared to a no TDM control group in a community-based practice setting. METHODS De-identified patient charts from a US-based community gastroenterology practice were analyzed for all patients (ages 8 to 89) treated with IFX from 2016 to 2022. Matching records to Prometheus Laboratories test results were then tokenized. Two cohorts were structured, Anser TDM as part of ongoing IBD care & no TDM. Groups were matched by propensity score, baseline disease, demographics, and comorbidities for comparison. Real-world outcomes were accessible via Lynx.MD online database. Analysis was conducted, stratifying patients as all IFX patients or anti-TNF naïve patients (TNF-N), to compare the percentage of IBD-related surgeries for 12 or 24-month outcomes. IBD surgeries were recorded in patient charts as colectomies, surgeries for fistula, bowel perforations, drainage of abscesses, adhesiolysis and other surgical bowel procedures. Statistical analysis was completed by Lynx.MD. RESULTS The size of Anser TDM (n= 235 to 337) and no TDM (n= 223 to 321) cohorts varied depending on the analysis criteria. Crohn’s disease was majority (2/3) and median age ranged from 36 to 39. For all IFX patients the 12-month outcomes of any IBD surgery was 1.2% for Anser TDM vs 6.5% for no TDM (5.4%, P=0.001). For TNF-N patients, the rate was 1% and 6.8%, respectively (5.7%, P=0.001). The results for 24-month outcomes for all IFX patients were 4.1% for Anser TDM vs 9.8% for no TDM (4.1%, p=0.016), and 4.3% vs 9% respectively for TNF-N (4.8%, P=0.06). CONCLUSIONS Real-world outcomes data for 12 and 24-months demonstrate that the Anser IFX TDM group had significantly lower rates of IBD surgeries for all patients, including for 12-month outcomes in TNF-N. This finding provides the first analysis, on Anser® TDM used to optimize patient’s IFX dosing, in comparison to a matched cohort of no TDM patients within the same community gastroenterology clinic setting.

Clinical impact of therapeutic drug monitoring for newer anti-seizure medications in patients with epilepsy: A real-world observation study

BackgroundThe clinical value of therapeutic drug monitoring (TDM) for newer anti-seizure medications (ASMs) remains uncertain. This study aimed to assess the impact of newer ASM TDM on clinical decision making in patients with epilepsy. MethodsWe retrospectively identified all plasma requests for newer ASM level measurement as part of routine clinical management in the outpatient departments of seven medical institutes across Taiwan between September 2016 and May 2019. Data collected from reviewed medical records included clinical and medication details, indications for TDM request, test results, interpretation, and impact on patient management. ResultsA total of 682 visits with 1051 plasma samples were included. The most frequently analyzed ASMs were levetiracetam (36.1%), oxcarbazepine (18.4%), and lamotrigine (12.0%). Reasons for TDM included poorly controlled seizures (55.3%), concerns about drug-drug interactions (12.3%), and suspicion of drug overdose (10.6%). 68.8% of samples were within the orienting therapeutic range, even for patients with poorly controlled seizures. TDM for non-adherence concerns showed 54.3% below the orienting therapeutic range, while ASM-related adverse events assessment only 8.9% showed levels exceeding the orienting therapeutic range. Following TDM results, 64.2% of cases had medication adjustments, mainly dosage increases. Overall, 55.9% of newer ASM TDM visit showed improved outcomes, including reduced seizures (47.5%) and fewer ASM-related side effects (8.4%). ConclusionsThese findings suggest that appropriate utilization of TDM for newer ASMs provides clinical benefits in adjunct to complement clinical decision making in the management of epilepsy patients in a real-world clinical setting.

Antifungal Therapeutic Drug Monitoring Practices: Results of an Emerging Infections Network Survey.

In a survey of 523 infectious disease specialists, a moderate to high percentage reported using any antifungal therapeutic drug monitoring (TDM) during itraconazole (72%), posaconazole (72%), and voriconazole (90%) treatment, and a low to moderate percentage reported using any antifungal TDM during prophylaxis (32%, 55%, and 65%, respectively). Long turnaround times for send-out TDM testing and logistical difficulties were frequent barriers.

A national survey of individualized pharmaceutical care practice in Chinese hospitals in 2019.

Background: Individualized pharmaceutical care, which consists of therapeutic drug monitoring (TDM), pharmacogenetic (PGx) testing and pharmacist-managed clinic (PMC), is one of the most important trends in clinical pharmacy development in the future. While relevant studies in China were primarily single-center or regional. This study aims to explore the current status of individualized pharmaceutical care in China, find out the existing problems and provide references for its further development. Methods: An electronic questionnaire was used and national hospitals' pharmaceutical administration data from January to December 2019 were collected. The data were sorted into Excel for further statistical analysis. All analyses were descriptive. Results: The proportions of hospitals that performed TDM and PGx testing were 12.83% and 9.48%, respectively. The major responsible departments were the clinical laboratory and pharmacy department. External quality control was carried out in around 70% of hospitals for both TDM and PGx testing. More than half of hospitals provided TDM services for valproate sodium, digoxin, carbamazepine, vancomycin and cyclosporine. And an average of 6.84 drugs were performed TDM in 540 hospitals. Clopidogrel and warfarin were the top two drugs that performed PGx testing. As for the PMC, 10.03% of hospitals opened PMC, of which 60.00% had independent PMC. Approximately 80% of PMC services were free of charge. Conclusion: The development of individualized pharmaceutical care in China is still in the early stage. Different sectors have to coalesce to promote its implementation, including the appropriate education, coverage, reimbursement policies, high-quality evidence, data systems, health system processes and health policies, etc.

A Survey of Therapeutic Drug Monitoring Status in China.

To understand the status of therapeutic drug monitoring (TDM) in China Mainland, and thus lay down the foundation for further improvement in TDM. In the present study, a nationwide questionnaire survey was conducted, which was distributed and collected using a mobile-based application. Clinicians, pharmacists, and clinical laboratory physicians belonging to different levels of public hospitals were involved as subjects/objects. The contents of the survey included TDM implementation in their hospital and information regarding their opinions and suggestions on TDM work. Mann-Whitney test was used to compare the difference between top tertiary hospitals and non-top tertiary hospitals. A total of 475 questionnaires were collected, 383 from top tertiary hospitals (3A hospitals) and 92 from non-top tertiary hospitals (other than 3A hospitals). A total of 240 clinicians, TDM pharmacists, and clinical laboratory physicians were involved, with an effective rate of 50.5%. Top tertiary hospitals were associated with certain advantages, such as the number of TDM testing facilities, annual sample size, number of monitoring varieties, and interpretation rate of monitoring reports, compared with non-top tertiary hospitals. In particular, β-lactamase inhibitor, olanzapine, carbamazepine, and glucocorticoids seemed to be the main projects that clinicians wanted to assess. The drugs for which TDM was commonly performed included vancomycin, valproic acid, carbamazepine, phenytoin sodium, and methotrexate. The most commonly used detection methods include high-performance liquid chromatography, immunization, 2D-LC, and LC-MS. The monitoring concentration range was found to be inconsistent for most of the drugs. Currently, no unified regulation exists for TDM charges in China, which is no more than ¥200 in general. Clinicians rely on pharmacists for professional guidance. Importantly, improvement in the interpretation of monitoring reports, proficiency testing, and cooperation with clinical departments may aid in improving the level of TDM service. This survey objectively reflected the current status of TDM work in hospitals in China, and provided a strong reference base for devising strategies for improvement and effective execution of TDM work.

Assessment of recombinant beta-Glucuronidase vs native beta-Glucuronidase and alkaline conditions for the hydrolysis of THC-glucuronide

The use of enzymes plays an important role in the hydrolysis of conjugated molecules during the preparation of biological samples, especially urine. Several clinical and forensic applications, including Therapeutic Drug Monitoring (TDM) and toxicological analyses, can take advantage of an effective, easy, time-saving procedure. In this perspective, we aimed to assess the yield of two different beta-glucuronidase enzymes, one recombinant and one native, in comparison with the alkaline hydrolysis routinely used in our laboratory for the analysis of cannabinoids in urine samples. A total of 82 anonymous urine samples were tested with an ISO 17025 accredited UHPLC-MS/MS method for the detection of THC-carboxylated metabolite. During the sample preparation, three different pre-analytical hydrolysis steps were performed: (A) 100 μL of urine were added with 4 μL of NaOH 10 N, then incubated at 55° for 15 minutes; (B) 100 μL of urine were added with 200 μL of recombinant beta-glucuronidase (rec-β-gluc), then incubated at room temperature for 5 minutes; (C) 100 μL of urine were added with 10 μL of native beta-glucuronidase from Helix Pomatia (nat-β-gluc), then incubated at 55° for 15 minutes. In a second experiment, further 37 anonymous urine samples were tested with different volumes (respectively, 20, 50 and 100 μL) of rec-β-gluc, to optimize the working conditions. According to the concentrations obtained with the routine procedure, the 82 samples were divided into “high concentration” (HC, above 55 ng/mL) and “low concentration” (LC, below 55 ng/mL) samples. For the HC samples, the yield obtained using rec-β-gluc was on average 13.7% higher than alkaline hydrolysis and 23.4% higher than nat-β-gluc procedure. For the LC samples, the yield with rec-β-gluc was on average 12.4% higher than alkaline hydrolysis and 15.5% higher than the nat-β-gluc procedure. A Wilcoxon test was run, and all procedures proved significantly different. The second experiment showed that the THC-carboxylated metabolite concentrations were not significantly different using the three different volumes of rec-β-gluc, proving that a minimum amount of 20 μL is enough to obtain the highest hydrolysis efficiency. The recombinant beta-glucuronidase provided the most efficient hydrolytic activity to cleave the glucuronide of THC-carboxylated metabolite. Further experiments are needed to verify that similar results are obtained for other glucuronate metabolites, including pharmaceuticals and other cannabinoids, primarily cannabidiol. By achieving a high yield in only 5 minutes without a heating step, the laboratories, especially in clinical, forensic, TDM, and workplace drug testing, will be enabled to increase the number of processed urine samples, with no detriment of the analytical performances.

Therapeutic Drug Monitoring for Evaluation of the Efficacy and Safety of Vancomycin in Patients with Orthopaedic Infections

Vancomycin is a drug of choice for the infections caused by methicillin-resistant strains of staphylococci. Its use requires individualised dosing and renal function monitoring.The aim of the study was to evaluate, using therapeutic drug monitoring (TDM), the frequency of reaching target trough serum concentrations (TSCs) and the frequency of renal function impairment in orthopaedic infection patients receiving vancomycin therapy.Materials and methods: the authors carried out a retrospective analysis of vancomycin TSC test results of 457 patients admitted to a purulent osteology department in 2019–2021. The results were grouped according to the number of TSC determination performed as part of TDM (tests 1, 2, and 3). Each of the 3 groups was further divided into 4 subgroups according to the TSCs of vancomycin: ≤9.9 µg/ml (extremely low), 10–14.9 µg/ml (recommended for mild infections), 15–19.9 µg/ml (recommended for bone and joint infections), ≥20 µg/ml (potentially toxic). The results obtained in each group were analysed separately.Results: according to the 1st TDM test, only 9.6% of patients achieved the TSCs of vancomycin recommended for bone and joint infections. Extremely low TSCs, insufficient for treatment of the infections, were found in 64.8% of patients. According to the 2nd and 3rd TSC determinations, dose corrections decreased the percentage of patients with extremely low TSCs to 49.9% and 41.2%, respectively. Potentially toxic TSCs of vancomycin were detected in 48 (10.5%) patients, but renal dysfunction was observed only in 8 (1.75%) of them. The authors exemplify the use of TDM to control the efficacy and safety of vancomycin in patients with pronounced signs of renal function impairment by two clinical cases.Conclusion: with a standard dose of vancomycin, the concentrations recommended for bone and joint infections were reached only in every tenth patient. There was a large percentage of patients with extremely low serum concentrations of the medicinal product (64.8%), but it decreased after dose adjustments. Monitoring of vancomycin concentrations allows for individualised dosing, efficacy control and significant reduction of the risk of adverse kidney reactions.

P327 Comparison of adalimumab drug levels and drug survival in proactive vs reactive therapeutic drug monitoring

Abstract Background The therapeutic landscape for inflammatory bowel disease (IBD) has expanded in recent years. The anti-TNF drug adalimumab remains one of the most commonly prescribed treatments. However, rates of loss of response to adalimumab are significant. Therapeutic Drug Monitoring (TDM) has emerged as a tool to prevent loss of response to treatment but there is no consensus on the optimum TDM testing strategy., 2 testing strategies are commonly used - proactive TDM (pTDM), performed during sustained clinical response and reactive TDM (rTDM), performed following loss of response. The aim of this work was to compare adalimumab drug levels (DL) and drug survival (DS) for patients exposed to pTDM compared to rTDM testing strategies. Methods Data for patients with IBD, treated with adalimumab, and exposed to TDM, was extracted from the Scottish Biologic TDM database. Patients were assigned to pTDM or rTDM groups based on the indication of their first TDM test. Prescribing information was extracted from the NHS Scotland Safe Haven homecare prescribing database. Homecare delivery dates were used to infer start and end dates of adalimumab treatment. Where adalimumab start date was before, 2017, a start date of, 1/1/2017 was used to coincide with the introduction of the Scottish TDM service. The study period was, 1/1/2017 to, 1/3/2020 giving a maximum duration of drug exposure of, 38 months. The most recent drug level was used for each patient to reflect the impact of the TDM strategy employed. SPSS was used to perform statistical analysis. Results 367 patients were included for analysis, 190 males and, 177 females, 262 with Crohn’s disease and, 105 with Ulcerative Colitis., 314 patients were assigned to the pTDM group, and, 53 to the rTDM group. The mean DL across both groups was, 9.5 mcg/ml, with no significant difference seen between pTDM and rTDM groups (p=0.642). Median DS in the pTDM group was, 21 months versus, 15.6 months in the rTDM group. 277 patients (75.5%) remained on treatment at the end of the study, 244 (77.7%) in the pTDM group, versus, 33 (62.3%) in the rTDM group. DS was significantly higher in the pTDM group compared to the rTDM (p=0.004) group (Fig., 1), with divergence of the survival curve seen after, 6 months. Conclusion pTDM has been clearly favoured by clinicians from the outset of the TDM service. Whilst our data shows that DLs do not vary significantly between TDM groups, importantly, the DS with adalimumab is longer with pTDM as part of routine clinical care, when compared to rTDM. Further evaluation of clinical outcomes including steroid prescription, hospital admissions and surgery rates in the context of pTDM and rTDM strategies is therefore warranted, and in progress.

P022 Biologic Therapy and Therapeutic Drug Monitoring in Patients With Inflammatory Bowel Disease and Primary Sclerosing Cholangitis.

Primary sclerosing cholangitis (PSC) is associated with inflammatory bowel disease (IBD). Patients with concomitant PSC-IBD are at higher risk for IBD-related complications including dysplasia and malignancy, however the typical clinical IBD course is less severe. The aim of this study was to identify the prevalence of biologic use and therapeutic drug monitoring (TDM) in a cohort of PSC-IBD patients. Retrospective analysis of patients with PSC-IBD on biologic therapy who underwent TDM from Jan. 2018 to Aug. 2020 at the University of Virginia. Demographic data including age, disease duration, and comorbidities were recorded. IBD categorizations were recorded according to the Montreal Classification. Treatment outcomes including therapy changes after TDM were obtained. A total of 157 patients with PSC-IBD were identified. Of these, 29 patients (19%) were treated with biologic therapy during the study period. 13 patients underwent reactive TDM due to primary or secondary loss of response and one patient underwent proactive TDM during the study period. Median duration of IBD in this group was 9 years, and the median duration of concomitant PSC-IBD was 5.8 years. 20 TDM tests were obtained in these 14 total patients. Sub-therapeutic drug levels were found in 12 tests among 8 patients, and 3 showed detectable anti-drug antibodies. 8 showed appropriate trough levels. TDM resulted in a change to IBD therapy (i.e., dose escalation, change in biologic therapy used, or addition of IBD medication) in 17 out of 20 tests. Herein we describe epidemiologic data of biologic use in PSC-IBD patients at an academic center. PSC-IBD classically follows a less severe clinical presentation and course. However, our study demonstrates that a subset of PSC-IBD patients exist which require biologic therapy and follow a more refractory clinical trajectory. In this subset, TDM showed a high incidence of sub-therapeutic trough levels and anti-drug antibodies, leading to a change in therapy in 85% of TDM instances. Larger studies are recommended to better understand this unique subset of PSC-IBD patients.

Therapeutic Drug Monitoring and Pharmacogenetic Testing in Northern China.

Background: Therapeutic drug monitoring (TDM) and pharmacogenetic (PGx) testing are widely used as approaches to improve individualized (personalized) pharmacotherapy. Little is known about TDM and PGx testing services in China. This study is aimed to describe the TDM and PGx testing services in northern China, and to lay the foundation for improving these services. Methods: We developed an electronic survey using online software and disseminated it to 32 public hospitals in northern China from May to July 2019. The data were analyzed using the Statistical Package for Social Sciences (SPSS) program (Ver.27.0). Results: We collected 29 of the 32 questionnaires (90.6% response rate) from public hospitals in seven provinces of northern China. Twenty-two public hospitals (76%) utilized TDM; immune suppressants, antiepileptic drugs and anti-infective drugs were the main drugs monitored. The hospitals that did not provide TDM service were traditional Chinese medicine hospitals and hospitals with a smaller number of hospital beds. Seventeen public hospitals (58.6%) had PGx testing programs. The hospitals that did not offer PGx testing service had a smaller number of hospital beds and had fewer daily outpatients. Conclusion: TDM is available in the vast majority of public hospitals in northern China, although mainly in tertiary hospitals. PGx testing, a newer approach, is less widely available. We recommend that more hospitals be encouraged to provide TDM and PGx testing services and more efforts be directed toward quality control, delivery of results and counseling of patients based on those results.

Emerging therapeutic drug monitoring of anti-infective agents in Australian hospitals: Availability, performance and barriers to implementation.

The purpose of the study was to assess the status of emerging therapeutic drug monitoring (TDM) of anti-infective agents in Australian hospitals. A nationwide cross-sectional survey of all Australian hospitals operating in the public and private health sector was conducted between August and September 2019. The survey consisted of questions regarding institutional TDM practice for anti-infective agents and clinical vignettes specific to β-lactam antibiotics. Responses were received from 82 unique institutions, representing all Australian states and territories. All 29 (100%) of principal referral (major) hospitals in Australia participated. Five surveys were partially complete. Only 25% (20/80) of hospitals had TDM testing available on-site for any of the eight emerging TDM candidates considered: β-lactam antibiotics, anti-tuberculous agents, flucytosine, fluoroquinolones, ganciclovir, human immunodeficiency virus (HIV) drugs, linezolid and teicoplanin. A considerable time lag was noted between TDM sampling and reporting of results. With respect to β-lactam antibiotic TDM, variable indications, pharmacodynamic targets and sampling times were identified. The three greatest barriers to local TDM performance were found to be (1) lack of timely assays/results, (2) lack of institutional-wide expertise and/or training and (3) lack of guidelines to inform ordering of TDM and interpretation of results. The majority of respondents favoured establishing national TDM guidelines and increasing access to dose prediction software, at rates of 89% and 96%, respectively. Translating emerging TDM evidence into daily clinical practice is slow. Concerted efforts are required to address the barriers identified and facilitate the implementation of standardised practice.

Therapeutic drug monitoring in inflammatory bowel disease reduces unnecessary use of infliximab with substantial associated cost-savings.

Therapeutic drug monitoring (TDM) of infliximab (IFX) levels in inflammatory bowel disease (IBD) patients can help to guide dose adjustments or changes to therapy for selected patients in remission or with secondary loss of response (LOR). To determine how IFX TDM is utilised in a real-life clinical setting and to quantify the potential for TDM to reduce the unnecessary use of IFX. Data from all public IBD IFX level testing performed across Australia were prospectively collected from June 2016 to July 2017 to assess physician-reported for testing indications (induction, in remission or LOR) and associated results. The hypothetical influence of IFX TDM was based on an optimal therapeutic range of 6-10 mg/L for mucosal healing. Secondary LOR (reactive TDM) was the most common indication for TDM. These patients have consistently lower median IFX levels: 3.02 mg/L (IQR 1.14-6.67 mg/L) versus 5.22 mg/L (IQR 2.70-8.12 mg/L), P = 0.0001 compared with patients in remission (proactive TDM). TDM helped to identify unnecessary use of IFX in 30.6% of the TDM tests performed in luminal Crohn disease and ulcerative colitis patients, with an associated drug cost saving of $531.38 per IFX TDM test episode. Unnecessary IFX use was identified in 38.9% (96/247) of reactive IFX TDM tests performed and in 19.3% (35/181) of proactive testing. Use of both reactive and proactive IFX TDM is cost-effective for IBD management as it informs the clinician where unnecessary use of IFX can be stopped.

POS-737 IMMUNOSUPPRESSANT THERAPEUTIC DRUG MONITORING OF TACROLIMUS AND CYCLOSPORINE LEVELS AT AN INDEPENDENT CENTRAL LABORATORY IN KENYA

Tacrolimus (or FK506) and cyclosporine are key standard immunosuppressive drugs that are widely used for prevention of rejection in kidney transplant patients. In Kenya, the number of kidney transplants continue to steadily rise and so is the use of these immunosuppressive drugs. However, little published data exists on therapeutic drug monitoring (TDM) for the two drugs among the kidney transplant patients in Kenya and Africa. We therefore set out to review information in our database pertaining to TDM tests done for tacrolimus and cyclosporine over a 10-year period with the aim of assessing the distribution of the drug levels in relation to the therapeutic ranges.

PMS68 PROMONITOR FOR THERAPEUTIC DRUG MONITORING IN PATIENTS WITH SEVERE RHEUMATOID ARTHRITIS TREATED WITH ADALIMUMAB IN ENGLAND AND WALES

Adalimumab is used for severe rheumatoid arthritis (RA), but its efficacy is hampered by the presence of low drug levels and anti-drug antibodies (ADAs). Although not currently part of standard National Health Service (NHS) practice, patients who achieve remission may be eligible for supervised dose tapering. This could be done through the use of enzyme-linked immunosorbent assay (ELISA) tests, capable of measuring both drug and ADAs concentrations, alongside conventional clinical assessment. In this study, the economic outcomes of adding therapeutic drug monitoring (TDM) using Promonitor (Grifols–Progenika) assays to standard care in people with severe RA (Disease Activity Score 28>5.1) treated with adalimumab who had either achieved remission or low disease activity were evaluated. A cost-utility analysis based on a decision tree model was informed by a non-randomised trial INGEBIO identified following a systematic review. Since there is a substantial variation in clinical practice for TDM testing, dose-tapering and flare-management strategies in people with RA, and the actual cost of adalimumab to the NHS, incremental cost-effectiveness ratios (ICERs) were estimated for various clinically plausible scenarios and discounts for the list price of adalimumab (Humira®, AbbVie). Costs and resource use were considered from the NHS and Personal Social Services perspective. No discounting was applied to costs and effects due to the short-term time horizon of 18 months. ICERs in all except two scenarios were located in the north-east quadrant of the cost-effectiveness plane and ranged from £4,230 to £164,009 per quality-adjusted life-year gained. When the frequency of testing was one test per year or the cost of phlebotomy appointments to collect trough samples was excluded, the intervention dominated standard care. The cost-effectiveness of TDM with Promonitor for optimizing adalimumab treatment in people with RA is highly uncertain due to data limitations. Thus, future clinical studies are warranted.

What Is the Clinical Relevance of TNF Inhibitor Immunogenicity in the Management of Patients With Rheumatoid Arthritis?

Tumor necrosis factor-α inhibitors (TNFis) have revolutionized the management of rheumatoid arthritis (RA), however despite considerable progress, only a small proportion of patients maintain long-term clinical response. Selection of, and switching between, biologics is mainly empirical, experiential, and not evidence-based. Most biopharmaceutical proteins (BP) can induce an immune response against the foreign protein component. Immunogenicity and the development of anti-drug antibodies (ADAs) is considered one of the main reasons for loss of therapeutic efficacy (secondary failure). ADAs may neutralize and/or promote clearance of circulating BP with resultant low serum drug levels, loss of clinical response, poor drug survival and adverse events, such as infusion reactions. ADA identification is technically difficult and not standardized, making interpretation of immunogenicity data from published clinical studies challenging. Trough TNFi drug levels correlate with clinical outcomes, exhibiting a “concentration-response” relationship. Measurement of ADA and drug levels may improve patient care and improve cost-effectiveness of BP use. However, in the absence of clinically-validated, reliable assays and consensus guidelines, therapeutic drug monitoring (TDM) and immunogenicity testing have not been widely adopted in routine clinical practice in Rheumatology. Here we discuss the utility and relevance of TDM and immunogenicity testing of TNFis in RA (focusing on the most widely used TNFis globally, with the most available data, i.e., infliximab, adalimumab, and etanercept), the limitations of currently available assays and potential future immunopharmacological strategies to personalize disease management.

P582 Adalimumab therapeutic drug monitoring: Does time of testing matter?

Abstract Background Whilst anti-TNF drugs such as adalimumab (ADL) have revolutionised the management of inflammatory bowel disease treatment outcomes are not universally favourable with 30% primary non-response (PNR) and 46% secondary loss of response (SLOR) rates reported.1,2 Therapeutic drug monitoring (TDM)—the measurement of serum drug levels and anti-drug antibodies—has become popular with clinicians who use it to optimise biologic therapy through serum drug-level guided dose adjustment. Conventionally TDM is based on the interpretation of trough drug levels (DL) which are obtained by drawing a blood sample immediately prior to the next drug dose. Obtaining an ADL trough DL can be challenging as the drug is administered as a subcutaneous injection usually in the patient’s own home. The aim of this project was to determine the current use of non-trough ADL TDM in clinical practice and determine whether timing of ADL TDM in relation to the next planned dose is clinically important. Methods All ADL DLs performed in 2018 in the Scottish Biologic TDM service3 were identified. DLs were included for patients in sustained clinical remission (SCR), on 40mg every other week dosing, and if the time from the last dose was ≤14 days. TDM performed during induction and for PNR or SLOR were excluded, as were patients on nonstandard dosing or with missing data on dose and interval. Results were analysed by quartile according to time from the last drug dose. Results 338 DLs were included. Median DL is 8µg/ml (range <0.4–36). Median time from last dose is 12 (range 0–14) days. The first quartile (n = 83, median 5 (range 0–7) days) had a median DL of 8.2µg/ml (<0.4–28.1). The second quartile (n = 90, median 11 (8–12) days) had a median DL of 7.9µg/ml (<0.4–36). The third quartile (n = 80, 13 days from last dose) had a median DL of 8µg/ml (<0.4 – 28.1). fourth quartile samples (n = 85, 14 days from last dose – true trough DLs) had a median DL of 8 µg/ml (<0.4–34.8). No relationship was identified between observed DL and the time of DL testing (ρ= -0.3162, p = 0.23). Conclusion It is not necessary to use trough DLs when performing ADL TDM for individuals in SCR. These data should give clinicians the confidence to use opportunistic ADL TDM testing in a clinical setting. Further work should be undertaken on non-trough testing of ADL DLs in other clinical scenarios. Disclosure Biogen GmbH contributed funding for this research. Authors had full editorial control and approval of all content. References

National mycology laboratory diagnostic capacity for invasive fungal diseases in 2017: Evidence of sub-optimal practice

A survey of laboratory testing capabilities for systemic fungal pathogens was undertaken in the UK, to identify where improved compliance with published standards and guidelines is required and to inform antifungal stewardship (AFS). The survey captured information from laboratories in the UK on diagnostic capacity for invasive fungal diseases (IFD), including identification, serology, molecular diagnostics and susceptibility testing. The survey was circulated in March 2017 through key networks. Of 154 laboratories providing diagnostic mycology services in the UK, 80 (52%) responded to the survey. Results indicated that 85% of respondents identified fungal isolates from high risk patients to species level, and that many laboratories (78%) could access local susceptibility testing for yeasts, whereas 17% could for Aspergillus species. However, direct microscopy was only used in 49% as a first line investigation on samples where it would be appropriate. A low number of respondents identified yeasts cultured from intravascular line tips to species level (63%) and even fewer fully identified urine isolates from critically ill patients (42%) or the immunocompromised (39%). Less than half of respondents advised therapeutic drug monitoring (TDM) for flucytosine. Few laboratories had access to local β-glucan (4%) or galactomannan (20%) testing. The survey highlights that the current level of fungal diagnostics in the UK is below accepted best practice with an urgent need to improve across many diagnostic areas including the timely accessibility of fungal biomarkers, susceptibility testing and provision of TDM testing. Improvements are important to facilitate the delivery of diagnostic driven AFS strategies as well as appropriate management of IFD.

P431 Validation of a therapeutic drug monitoring test to measure the adalimumab biosimilar SB5 in comparison with the reference adalimumab

Validation of therapeutic drug monitoring (TDM) tests is an essential requirement for using these tools to help assess reasons for non-response. The arrival of biosimilars has prompted a need to validate that existing TDM tests are suitable to determine drug levels for all versions of a given molecule. The adalimumab (ADL) biosimilar SB5 (IMRALDI®, Biogen) was authorised by the European Commission in August 2017, and has recently become available for prescription in several European countries. Promonitor®-ADL test is routinely used to monitor IBD patients treated with ADL. In this study, we validated the suitability and performance of Promonitor-ADL CE-marked TDM test for quantifying SB5 serum concentrations in comparison to reference adalimumab (HUMIRA®, Abbvie). The study evaluated imprecision and bias applied to the reference ADL and SB5 biosimilar. The validation study was in line with the design requirements established in the Clinical and Laboratory Standards Institute (CLSI) guideline EP10-A3 for the determination of imprecision and bias. Imprecision was evaluated using three replicates of five human serum sample matrices representative of clinically relevant ADL concentrations and spanning the measurement range of Promonitor-ADL.1 Validations were ran on one instrument with one kit lot by one operator over six non-consecutive operating days and one run per testing day, with an acceptance criterium of CV% ≤20%. The Lower Limit of Quantification (LLOQ) of Promonitor-ADL was determined according to CLSI guideline EP17-A2. The imprecision of Promonitor-ADL was calculated by estimating the components of variance due to within-run and between-day factors meet the accuracy goals proposed at all concentration levels of SB5 vs. HUMIRA (CV% between 5% and 12%). The assessment of accuracy showed that Promonitor-ADL equally measures the active moiety of HUMIRA or SB5. The test is able to quantify SB5 in the measurement range of 0.9 to 10.9 μg/ml with a bias estimate of −0.124 (1%) to 0.897 (10%) μg/ml and an overall imprecision of 5% to 11%. The measurement range includes the recommended clinical decision points. LLOQ of the test to determine ADL was determined to be 0.36 μg/ml. This study demonstrates that Promonitor-ADL test can measure either the reference ADL drug or the biosimilar SB5 (IMRALDI) with equivalent sensitivity, precision and accuracy. Reference 1. Feuerstein JD, Nguyen GC, Kupfer SS, et al. American Gastroenterological Association Institute guideline on therapeutic drug monitoring in inflammatory bowel disease. Gastroenterology 2017;153:827–34.

P329 Adalimumab therapeutic drug monitoring test validated for measuring ABP 501 biosimilar

P329 Adalimumab therapeutic drug monitoring test validated for measuring ABP 501 biosimilar

Therapeutic Drug Monitoring of the Biosimilar SB2 (RENFLEXIS™, Infliximab-abda) Using LabCorp Infliximab Assays for Drug Level and Anti-drug Antibodies

BACKGROUND: Therapeutic drug monitoring (TDM) of infliximab (IFX) concentration and anti-infliximab antibody (ADA) titer has helped physicians make informed clinical decisions in the management of inflammatory bowel disease (IBD). A TDM-based approach to treating IBD patients has been used to improve clinical efficacy of anti-TNF agents. The LabCorp IFX TDM test (drug and ADA levels) has been validated in peer-reviewed literature and is widely used by clinicians to help maximize treatment response. Recently approved by the FDA for treatment of IBD, RENFLEXIS (SB2, infliximab-abda) is a biosimilar of the originator infliximab (TNF alpha inhibitor). The aim of this study was to validate the LabCorp IFX TDM test for the quantification of serum SB2 concentrations and ADA. METHODS: To demonstrate ability to measure RENFLEXIS using the LabCorp IFX TDM test, SB2-specific immunoassays were developed. SB2 calibrators and SB2-conjugated key reagents were used to compare with IFX TDM kits. Analytical performance including accuracy, precision, spike and recovery, specificity and selectivity was assessed. Exogenous SB2 was spiked into donor serum to assess recovery using the IFX drug assay. 124 IFX-treated IBD patients were split-tested using SB2 and IFX drug and ADA assays to assess equivalency and interchangeability between the two methods. RESULTS: Both SB2 drug level and ADA showed excellent agreement to IFX drug level and ADA respectively. SB2 assay accuracy (<11% bias) and precision (<7% CV) were equivalent to IFX accuracy (<5% bias) and precision (<10% CV) across the measuring range of the assay. More importantly, spike and recovery of RENFLEXIS using the IFX drug assay was equivalent to the recovery of reference product IFX using the IFX drug assay. SB2 was spiked into the donor serum pool to generate 0.25, 0.5, 1.0, 2.0, 4.0, 5.0, 6.0, & 8.0 ug/mL targets. The same target concentrations were generated for IFX. Both sets of targets were read using the IFX drug assay. Percent recovery of SB2 ranged from 87% to 114%; IFX recovery was 83% to 113%. Average spike and recovery was 99% for both SB2 and IFX using the IFX drug assay. Both the SB2 drug assay and IFX drug assay were used to analyze 59 serum samples of IBD patients treated with reference product IFX. The calculated linear regression between the two methods was Y=1.11x-0.13 and r2=1.0. The SB2-specific anti-drug antibody assay performed essentially identically to the reference product IFX ADA assay in terms of precision (<10% CV), accuracy (<10% bias), linearity, drug tolerance and sensitivity. 65 ADA positive serum samples from IBD patients were tested using the SB2 ADA assay. Antibody titer values were compared. Linear regressions of Y=1.09x-8.7, r2=0.99 were obtained. CONCLUSION(S): This study demonstrates complete cross-reactivity of RENFLEXIS (infliximab-abda) in LabCorp IFX TDM assay. Healthcare providers can confidently use LabCorp IFX TDM test to monitor RENFLEXIS (infliximab-abda) serum drug levels and ADA titers in their patients.