Best Practice for Therapeutic Drug Monitoring of Infliximab: Position Statement from the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.

BACKGROUND: Infliximab, an anti-tumor necrosis factor monoclonal antibody, has revolutionized the pharmacological management of immune-mediated inflammatory diseases (IMIDs). This position statement critically reviews and examines existing data on therapeutic drug monitoring (TDM) of infliximab in patients with IMIDs. It provides a practical guide on implementing TDM in current clinical practices and outlines priority areas for future research. METHODS: The endorsing TDM of Biologics and Pharmacometrics Committees of the International Association of TDM and Clinical Toxicology collaborated to create this position statement. RESULTS: Accumulating data support the evidence for TDM of infliximab in the treatment of inflammatory bowel diseases, with limited investigation in other IMIDs. A universal approach to TDM may not fully realize the benefits of improving therapeutic outcomes. Patients at risk for increased infliximab clearance, particularly with a proactive strategy, stand to gain the most from TDM. Personalized exposure targets based on therapeutic goals, patient phenotype, and infliximab administration route are recommended. Rapid assays and home sampling strategies offer flexibility for point-of-care TDM. Ongoing studies on model-informed precision dosing in inflammatory bowel disease will help assess the additional value of precision dosing software tools. Patient education and empowerment, and electronic health record-integrated TDM solutions will facilitate routine TDM implementation. Although optimization of therapeutic effectiveness is a primary focus, the cost-reducing potential of TDM also merits consideration. CONCLUSIONS: Successful implementation of TDM for infliximab necessitates interdisciplinary collaboration among clinicians, hospital pharmacists, and (quantitative) clinical pharmacologists to ensure an efficient research trajectory.

Blocking interleukin-17 in psoriasis: Real-world experience from the PsoPlus cohort.

BACKGROUND: Real-world studies on the use of biologics in psoriasis (Pso) are increasing, but still scarce. Trough concentrations (Ct s) of interleukin-17 inhibitors (IL-17i) seem promising for clinical decision-making, but their value in daily practice has yet to be proven. OBJECTIVES: To report on IL-17i effectiveness, treatment modifications and Ct use in our clinic. METHODS: Data were collected from IL-17i-treated Pso patients followed up in the PsoPlus clinic at the Dermatology department, Ghent University Hospital, Belgium. Descriptive statistics and Kaplan-Meier analysis were performed. RESULTS: A total of 111 patients were included, counting for 134 IL-17i courses (secukinumab, ixekizumab, and brodalumab). Fifty-five per cent of the patients were bio-naive prior to IL-17i initiation. During maintenance, merely 97.0% and 77% achieved near-complete and complete skin clearance, respectively. Major reasons for treatment modification were suboptimal response (63.0%) and safety issues (9.3%). Reported modifications were switch (25.4%), dose escalation (11.9%), dose de-escalation (6.7%), treatment association (6.0%) and IL-17i stop (3.0%). Overall drug survival was 69.0 months, without difference between the different IL-17i (p = 0.078). Ixekizumab tended to have the highest survival. Drug survival was higher in bio-naive subjects compared to bio-experienced subjects (p = 0.011). Ct was measured in 20 patients and interpreted post hoc. In 85%, the clinical decision was in accordance with the Ct (e.g. substantiated need for dose escalation). For the other cases, the Ct would have led to another clinical decision if known at that time. CONCLUSIONS: This real-world study showed that IL-17i are very effective drugs for Pso, with ixekizumab as leading biologic. Prior bio-experience seemed to impact IL-17i drug survival. Treatment modifications were mainly performed in case of insufficient response, primarily via switch and dose escalation, and least frequently in ixekizumab patients. Ct might rationalize clinical decision-making; however, there is need for standardized algorithms to corroborate its use.

Promising Tools to Facilitate the Implementation of TDM of Biologics in Clinical Practice.

Therapeutic drug monitoring (TDM) of biologics-encompassing the measurement of (trough) concentrations and anti-drug antibodies-is emerging as a valuable tool for clinical decision making. While this strategy needs further validation, attention on its implementation into the clinic is warranted. Rapid testing and easy sampling are key to its implementation. Here, we aimed to evaluate the feasibility and volunteers' perception of home microsampling for quantification of adalimumab (ADM) concentrations in psoriasis patients. In addition, we compared lateral flow testing (LFT) with enzyme-linked immunosorbent assay (ELISA). Patients participating in the SUPRA-A study (clinicaltrials.gov NCT04028713) were asked to participate in a substudy where volumetric absorptive microsampling (VAMS) was performed at home. At three time points, whole blood and corresponding serum samples were collected for ADM measurement using an in-house ELISA. In addition, the patients' perspective on microsampling was evaluated via a questionnaire. LFT-obtained ADM concentrations agreed very well with ELISA results (Pearson's correlation = 0.95 and R2 = 0.89). ADM concentrations determined in both capillary (via finger prick) and corresponding venous blood VAMS samples correlated strongly with serum concentrations (Pearson's correlation = 0.87). Our preliminary data (n = 7) on rapid testing and home-based microsampling are considered promising with regard to TDM implementation for adalimumab, warranting further research.

Therapeutic drug monitoring in dermatology: the way towards dose optimization of secukinumab in chronic plaque psoriasis.

BACKGROUND: Despite the favourable efficacy profile of secukinumab, clinicians encounter varying clinical responses among patients potentially associated with under- and overdosing. As biologics are expensive, their rational use is crucial and evident. Therapeutic drug monitoring could guide clinicians in making decisions about treatment modifications. AIM: In this multicentre, prospective study, we aimed to develop and validate a secukinumab immunoassay and searched for the therapeutic window in patients with psoriasis. METHODS: We determined secukinumab concentrations at trough in sera from 78 patients with psoriasis at multiple timepoints (Weeks 12, 24, 36, 48 and 52; after Week 52, measurements could be taken at an additional three timepoints) during maintenance phase, using an in-house secukinumab immunoassay consisting of a combination of MA-SEC66A2 as capture antibody and MA-SEC67A9, conjugated to horseradish peroxidase, as detecting antibody. At each hospital visit, disease severity was assessed using the Psoriasis Area and Severity Index (PASI). RESULTS: After quantification, 121 serum samples were included for dose-response analysis. Based on a linear mixed-effects model, secukinumab trough concentrations were found to decrease with increasing body mass index (BMI). Based on receiver operating characteristic (ROC) analysis, we concluded that the minimal effective secukinumab threshold was 39.1 mg/L in steady state, and that this was associated with a 92.7% probability of having an optimal clinical response (PASI ≤ 2 or reduction in PASI of ≥ 90%). CONCLUSIONS: Monitoring and targeting a secukinumab trough concentration of 39.1 mg/L may be a viable treatment option in suboptimal responders. In patients with higher BMI, weight-based dosing may be needed in order to prevent underdosing.

Dermatologists on the medical need for therapeutic drug monitoring of biologics in psoriasis: results of a structured survey.

BACKGROUND: Therapeutic drug monitoring (TDM) may lead to more rational use of biologics. Still, TDM is largely underexplored in psoriasis. Little is known about the dosing behavior of biologics by dermatologists, and their attitude toward TDM. OBJECTIVE: Exploration of the awareness and need for the concept of TDM in psoriasis amongst (inter)national dermatologists. METHOD: A survey was distributed at the Belgian Dermatology Days 2019 and Skin Inflammation & Psoriasis International Network (SPIN) Congress 2019. Next, an online survey version was launched amongst the SPIN Scientific Committee members. We collected physician's characteristics, prescription behavior of biologics, data regarding clinical response to biologics and attitude toward TDM. RESULTS: A total of 107 surveys were included for analysis. Most dermatologists were Belgium-based (54.2%), others from European (23.4%) or non-European countries (19.6%). Seventy percent performed either dose increase (64.8%), time interval shortening (74.6%), dose lowering (16.9%) or time interval extension (33.8%). The majority who performed dose adaptations acknowledged the need for TDM. CONCLUSION: This study showed most dermatologists perform dose adaptations empirically. The need for TDM was indicated by the majority, implying the need for effective communication regarding availability, utility and implementation of TDM assays in daily dermatology practice.

Development and validation of immunoassays for monitoring of guselkumab and anti-guselkumab antibodies in patients with moderate-to-severe psoriasis.

Therapeutic drug monitoring, which is the measurement of drug concentrations in the blood, is a useful tool to guide clinical decision-making and treatment adjustments, on the condition that drug concentrations are correlated with treatment response. For guselkumab, an anti-IL-23 monoclonal antibody for the treatment of moderate-to-severe psoriasis, such a concentration-response relationship could not yet be determined as no commercial assays for the quantification of this drug or antibodies against this drug are available. Therefore, the aim of this study was to develop and validate immunoassays for the quantification of guselkumab and anti-guselkumab antibodies according to the guidelines of the European Medicines Agency (EMA). A diverse panel of 20 highly specific anti-guselkumab monoclonal antibodies (MA-GUS) was generated of which eight revealed a neutralizing capacity of ≥65 %. At least seven different antibody clusters were identified based on their epitope binning profile. Using MA-GUS9F6 as the capture antibody and MA-GUS12G12 as the detection antibody, an ELISA was developed with a dose-response curve ranging from 0.08 to 5 ng/mL. The assay was specific, selective and could accurately and precisely quantify guselkumab concentrations in spiked healthy control serum and serum from guselkumab-treated psoriasis patients with a cut-off for quantification of 0.014 µg/mL. The presence of IL-23 in physiological concentrations or of non-neutralizing antibodies did not impact the quantification of guselkumab, while the presence of neutralizing antibodies did. Using MA-GUS12A9 as a calibrator, two anti-guselkumab antibody assays were developed to detect anti-guselkumab antibodies, which differ in the threshold for detection and quantification and the tolerance to the presence of guselkumab. Together, these validated immunoassays are essential to establish a concentration-response relationship and will allow the future implementation of therapeutic drug monitoring in moderate-to-severe psoriasis patients receiving guselkumab treatment.

Creasensor: SIMPLE technology for creatinine detection in plasma.

The lab-on-a-chip (LOC) field has witnessed an excess of new technology concepts, especially for the point-of-care (POC) applications. However, only few concepts reached the POC market often because of challenging integration with pumping and detection systems as well as with complex biological assays. Recently, a new technology termed SIMPLE was introduced as a promising POC platform due to its features of being self-powered, autonomous in liquid manipulations, cost-effective and amenable to mass production. In this paper, we improved the SIMPLE design and fabrication and demonstrated for the first time that the SIMPLE platform can be successfully integrated with biological assays by quantifying creatinine, biomarker for chronic kidney disease, in plasma samples. To validate the robustness of the SIMPLE technology, we integrated a SIMPLE-based microfluidic cartridge with colorimetric read-out system into the benchtop Creasensor. This allowed us to perform on-field validation of the Creasensor in a single-blind study with 16 plasma samples, showing excellent agreement between measured and spiked creatinine concentrations (ICC: 0.97). Moreover, the range of clinically relevant concentrations (0.76-20 mg/dL), the sample volume (5 µL) and time-to-result of only 5 min matched the Creasensor performance with both lab based and POC benchmark technologies. This study demonstrated for the first time outstanding robustness of the SIMPLE in supporting the implementation of biological assays. The SIMPLE flexibility in liquid manipulation and compatibility with different sample matrices opens up numerous opportunities for implementing more complex assays and expanding its POC applications portfolio.