Early At-Home Measurement of Adalimumab Concentrations to Guide Anti-TNF Precision Dosing: A Pilot Study.

BACKGROUND AND OBJECTIVE: Underdosing of adalimumab can result in non-response and poor disease control in patients with rheumatic disease or inflammatory bowel disease. In this pilot study we aimed to predict adalimumab concentrations with population pharmacokinetic model-based Bayesian forecasting early in therapy. METHODS: Adalimumab pharmacokinetic models were identified with a literature search. A fit-for-purpose evaluation of the model was performed for rheumatologic and inflammatory bowel disease (IBD) patients with adalimumab peak (first dose) and trough samples (first and seventh dose) obtained by a volumetric absorptive microsampling technique. Steady state adalimumab concentrations were predicted after the first adalimumab administration. Predictive performance was calculated with mean prediction error (MPE) and normalised root mean square error (RMSE). RESULTS: Thirty-six patients (22 rheumatologic and 14 IBD) were analysed in our study. After stratification for absence of anti-adalimumab antibodies, the calculated MPE was -2.6% and normalised RMSE 24.0%. Concordance between predicted and measured adalimumab serum concentrations falling within or outside the therapeutic window was 75%. Three patients (8.3%) developed detectable concentrations of anti-adalimumab antibodies. CONCLUSION: This prospective study demonstrates that adalimumab concentrations at steady state can be predicted from early samples during the induction phase. CLINICAL TRIAL REGISTRATION: The trial was registered in the Netherlands Trial Register with trial registry number NTR 7692 ( www.trialregister.nl ).

Infliximab Level Between Venous and Capillary Blood Using Novel Device Strongly Correlate in Paediatric Inflammatory Bowel Disease Patients.

OBJECTIVES: Blood to measure infliximab (IFX) levels is typically obtained with venipuncture. Dried blood sampling (DBS), using capillary blood obtained from a finger prick, would be an alternative to measure IFX blood levels while being more patient friendly. The aim of this study is to compare IFX blood level measured by venipuncture versus DBS in patients with paediatric inflammatory bowel disease (PIBD) to assure accuracy. METHODS: A prospective clinical pilot study was performed in patients with PIBD. Before IFX infusion, blood was collected simultaneously through venipuncture and DBS from a finger prick, using Mitratips (Neoteryx). All IFX concentrations were measured by an enzyme-linked immunosorbent assay. The Bland-Altman analysis was used to measure limits of agreement. The interrater reliability was measured with the interclass correlation coefficient and Cohen kappa. To calculate Cohen kappa, IFX levels were categorized into 3 groups; low <5 µg/mL, adequate 5 to 10 µg/mL, and high >10 µg/mL. RESULTS: Twenty patients were included. Median age was 12.1 year (interquartile range 8-16 year). The mean difference between the 2 methods was -0.14 as calculated with Bland-Altman plot. The limits of agreement were between -1.39 and 1.12. The interclass correlation coefficient was with 0.998 excellent. The Cohen kappa between 3 IFX level categories was strong K = 0.911 (P = 0.0001). There was a strong correlation between venous IFX serum levels and DBS (r = 0.991, P = 0.0001) in the included patients. CONCLUSIONS: This is the first study in patients with PIBD to show that bloodspot technology is a patient friendly alternative method to measure IFX blood levels in PIBD.

Monoclonal antibody treatment during pregnancy and/or lactation in women with MS or neuromyelitis optica spectrum disorder.

OBJECTIVE: To assess possible adverse effects on breastfed infants of mothers receiving monoclonal antibodies (MAbs) during pregnancy and/or lactation. METHODS: We identified 23 patients from the German Multiple Sclerosis and Pregnancy Registry (DMSKW) who received MAbs (17 natalizumab and 6 anti-CD20) during lactation. Thirteen were already exposed to natalizumab during the third trimester of pregnancy, and 1 received ocrelizumab during pregnancy. Data were obtained from standardized, telephone-administered questionnaires completed by the mother during pregnancy and at 1, 3, 6, and 12 months postpartum. Natalizumab concentration in mother's milk was analyzed in 3 patients and natalizumab serum concentration in 2 of these patients and their breastfed infants. RESULTS: We did not observe a negative impact on infant health and development attributable to breast milk exposure after a median follow-up of 1 year. Infants exposed to natalizumab during the third trimester had a lower birth weight and more hospitalizations in the first year of life. The concentration of natalizumab in breast milk and serum of infants was low; B cells normal in infants breastfed under anti-CD20. CONCLUSION: More data on the effect of Mab exposure during pregnancy are needed. Otherwise, our data suggest that treatment with natalizumab, ocrelizumab, or rituximab during lactation might be safe for breastfed infants.

Monitoring of Adalimumab Concentrations at Home in Patients with Inflammatory Bowel Disease Using Dried Blood Samples.

BACKGROUND: Adalimumab (ADL) is a subcutaneously administered anti-tumor necrosis factor (TNF) agent used in the treatment of patients with inflammatory bowel disease. Higher ADL trough concentrations are associated with improved clinical and endoscopic outcomes. Therapeutic drug monitoring (TDM) of ADL might be facilitated by using dried blood samples (DBSs) from capillary blood obtained at home. The study aimed to compare serum ADL concentrations obtained through venipuncture to ADL concentrations in DBSs. METHODS: Patients with Crohn's disease and ulcerative colitis receiving induction or maintenance ADL therapy were enrolled in this prospective cohort study. Blood was obtained through venipuncture and through DBSs during a regular outpatient visit (time point 1). Just before the next ADL administration, patients performed DBSs at home (time point 2). For this time point, serum ADL concentrations were estimated by Bayesian analysis. RESULTS: Thirty-three patients with inflammatory bowel disease were enrolled. During the outpatient visit, samples were obtained after a median (interquartile range) of 6 (4-10) days after the last ADL dose. A high correlation was found between DBSs and venipuncture results (Pearson correlation: ≥0.96), without any clinically relevant bias. For DBSs performed by patients at home, initial comparison showed a moderate correlation between DBS results and predicted ADL serum concentrations (Pearson correlation: 0.51), although no bias was present. In addition, DBS eluate results compared with predicted ADL serum concentrations showed a mean absolute percentage error (ie, accuracy) of 45%. CONCLUSIONS: High correlations were found between ADL serum concentrations obtained through conventional venipuncture and DBSs, which indicates that this home-based test can facilitate therapeutic drug monitoring-based ADL dose adjustments in daily practice.

Dried blood samples can support monitoring of infliximab concentrations in patients with inflammatory bowel disease: A clinical validation.

AIMS: Therapeutic drug monitoring (TDM) can optimize the efficacy of infliximab (IFX) in patients with inflammatory bowel disease (IBD). Because of the delay between blood samples taken at trough and availability of results, dose adjustments can only be carried out at the next infusion, typically 8 weeks later. Dried blood samples (DBS) performed at home to measure IFX concentrations can reduce the time to adapt dose/dosing interval. Here, we aimed to validate the clinical application of DBS for IFX in IBD patients and to evaluate the feasibility of home sampling. METHODS: DBS results from 40 IBD patients on IFX treatment were compared to serum sample results at trough, peak, and 3-5 weeks after IFX infusion. Subsequently, patients performed DBS home sampling one week before the next IFX infusion. These were compared to serum concentrations as predicted by Bayesian analysis. RESULTS: IFX concentrations from finger prick and venous puncture correlate well. DBS IFX concentrations showed high correlation with serum IFX concentrations (Spearman correlation: ≥0.965), without bias. Passing-Bablok regression for IFX concentrations in DBS from home sampling also showed no bias (intercept: 1.02 mg L-1 (95% CI -1.77-2.04 mg L-1 ), slope: 0.82 (95% CI 0.63-1.40)), with reasonable correlation (Spearman correlation: 0.671). CONCLUSIONS: Timely adjustment of IFX dose/dosing interval can be facilitated by IFX concentration measurement in home-sampled DBS. DBS is a reliable method to measure IFX and can be used to predict IFX trough concentrations.

Capillary blood microsampling to determine serum biopharmaceutical concentration: Mitra® microsampler vs dried blood spot.

AIM: For assessment of concentrations of biopharmaceuticals, for example, therapeutic drug monitoring, dried blood sampling of capillary blood is a convenient alternative to traditional venepuncture sampling. We investigated an alternative to dried blood spot collection on filter paper: sampling capillary blood using the Mitra® microsampler. MATERIALS AND METHODS:  Therapeutic monoclonal antibodies were spiked in whole blood, sampled using filter paper and Mitra microsampler and concentrations measured using specific ELISAs. RESULTS: Good recoveries of adalimumab, infliximab, ustekinumab, vedolizumab, tocilizumab, natalizumab and rituximab were found up to 1 month of storage at room temperature, averaging 95.2% for the Mitra microsampler and 92.9% for Whatman® paper. Both hemoglobin and potassium yield satisfactory estimates for the volume of the cellular fraction of blood samples in combination with the Mitra microsampler. CONCLUSION: We established practical protocols for the estimation of serum/plasma concentrations of therapeutic antibodies via capillary blood microsampling.

Dried blood spots from finger prick facilitate therapeutic drug monitoring of adalimumab and anti-adalimumab in patients with inflammatory diseases.

AIMS: Development of a self-sampling method for therapeutic drug monitoring (TDM) of biologicals will enhance TDM implementation in routine care and pharmacokinetic knowledge. The aim of this study was to compare adalimumab and anti-adalimumab antibody (ADA) concentration measurements in dried blood spots (DBS) obtained from finger prick with measurements in serum obtained via venepuncture, from patients with rheumatic inflammatory diseases. METHODS: In this cross-sectional study, 161 consecutive patients were included. For clinical validation, DBS from finger prick and serum from venepuncture were collected simultaneously and adalimumab and ADA concentration were assessed by ELISA and antigen binding test (ABT), respectively. To convert DBS eluate results to values which can be compared to serum concentrations, five different methods were investigated, using a marker protein or a volumetric approach. RESULTS: Adalimumab and ADA concentrations obtained from the finger prick/DBS method correlated well with serum results from the same patient (correlation coefficient > 0.87). Interestingly, antibody concentrations (either adalimumab, ADA or total immunoglobulin G) in DBS from finger prick, but not albumin, were systematically lower compared to serum. Spike experiments demonstrated a quantitative recovery for all tested proteins in DBS, suggesting a slightly different protein composition of blood collected via finger prick vs. venepuncture. We established a correction factor to relate finger prick/DBS values with serum values (approximately 1.2). CONCLUSIONS: We show here for the first time that adalimumab and ADA serum concentrations can be satisfactorily estimated by measuring concentrations in DBS eluates, collected by finger prick. This method offers great opportunity to simplify TDM of adalimumab.