User Acceptability and Technical Robustness Evaluation of a Novel Smart Pill Bottle Prototype Designed to Support Medication Adherence

Purpose: Smart medication adherence monitoring devices can provide objective and granular drug utilization data and help patients engaging with their treatment. In this proof-of-concept study, the acceptability and technical robustness of a novel smart pill bottle prototype (SPBP) were assessed in order to allow further optimization. Methods: The SPBP is an app-controlled automatic dispense system, capturing real-time data on a web-based platform, which sends text reminders and measures storage conditions. A heterogeneous group of ten volunteers was asked to dispense placebo capsules with the SPBP and to follow a predefined dosing schedule for a trial period of 2 weeks. Afterwards, a questionnaire was filled out during a short interview. Primary outcome was dispense adherence as measured by the bottle. Other study outcomes included system acceptability (System Usability Scale [SUS]), self-reported adherence (MARS) and technical robustness of the bottle’s mechanics (electronic pill dispenser) and sensors (bottle temperature). Results: The overall dispense adherence rate as measured by the SPBP was 88%. All participants completed the study and four participants had an adherence rate of 100% during the study. The dispense adherence rates corresponded well with participants’ self-reported adherence with an average MARS total score of 23.6 (out of 25). Participants judged the system easy to use, with a mean SUS score of 79.3 (range: 57.5– 97.5). The overall mean temperature difference between the bottle sensor and calibrated external sensor was − 0.82°C (range: − 1.37°C to − 0.21°C). Conclusion: The SPBP was well accepted and this study provides data for further optimization and follow-up studies. Smart adherence technologies such as these may change the way healthcare professionals, trialists and patients manage medication adherence

Ultra-high throughput dual channel liquid chromatography with tandem mass spectrometry for quantification of four immunosuppressants in whole blood for therapeutic drug monitoring

Liquid chromatography with tandem mass spectrometry (LC-MS/MS) is the golden standard for immunosuppressants analyses, where optimising throughput by parallel chromatography can reduce costs and turnaround time. We aimed to double our system throughput using a dual LC-MS/MS setup. Therefore, two independent UPLC systems were hyphenated to one triple quadrupole MS, with staggered injections from one autosampler on alternating columns. The method simultaneously measured the analytes tacrolimus, sirolimus, everolimus, and cyclosporin A in whole blood using isotope dilution, with a run time of 1.5 min. Using the dual LC-MS/MS system, net run-to-run time improved from 2.3 to 0.98 min per injection, where throughput increased from 26 to 61 injections per hour. For Performance Qualification, 1101 clinical samples were measured on the dual LC-MS/MS system in addition to the standard system, during a period of one month, and the results were compared using Passing Bablok regression and Bland Altman analysis. There was excellent agreement for all four analytes, with regression slopes of 0.98-1.02x and intercepts of -0.11-0.88 µg/L. Minor bias was demonstrated between the systems with mean differences from -0.93 to 1.43%. In conclusion, the throughput was doubled and idle MS time was reduced with good agreement to the standard system. Currently, the method is applied for clinical routine with frequent peak intensities of &gt;180 injections per day.</p

Clinical Value of Emerging Bioanalytical Methods for Drug Measurements:A Scoping Review of Their Applicability for Medication Adherence and Therapeutic Drug Monitoring

INTRODUCTION: Direct quantification of drug concentrations allows for medication adherence monitoring (MAM) and therapeutic drug monitoring (TDM). Multiple less invasive methods have been developed in recent years: dried blood spots (DBS), saliva, and hair analyses. AIM: To provide an overview of emerging drug quantification methods for MAM and TDM, focusing on the clinical validation of methods in patients prescribed chronic drug therapies. METHODS: A scoping review was performed using a systematic search in three electronic databases covering the period 2000-2020. Screening and inclusion were performed by two independent reviewers in Rayyan. Data from the articles were aggregated in a REDCap database. The main outcome was clinical validity of methods based on study sample size, means of cross-validation, and method description. Outcomes were reported by matrix, therapeutic area and application (MAM and/or TDM). RESULTS: A total of 4590 studies were identified and 175 articles were finally included; 57 on DBS, 66 on saliva and 55 on hair analyses. Most reports were in the fields of neurological diseases (37%), infectious diseases (31%), and transplantation (14%). An overview of clinical validation was generated of all measured drugs. A total of 62 drugs assays were applied for MAM and 131 for TDM. CONCLUSION: MAM and TDM are increasingly possible without traditional invasive blood sampling: the strengths and limitations of DBS, saliva, and hair differ, but all have potential for valid and more convenient drug monitoring. To strengthen the quality and comparability of future evidence, standardisation of the clinical validation of the methods is recommended

A Joint Pharmacokinetic Model for the Simultaneous Description of Plasma and Whole Blood Tacrolimus Concentrations in Kidney and Lung Transplant Recipients

BACKGROUND AND OBJECTIVE: Historically, dosing of tacrolimus is guided by therapeutic drug monitoring (TDM) of the whole blood concentration, which is strongly influenced by haematocrit. The therapeutic and adverse effects are however expected to be driven by the unbound exposure, which could be better represented by measuring plasma concentrations.OBJECTIVE: We aimed to establish plasma concentration ranges reflecting whole blood concentrations within currently used target ranges.METHODS: Plasma and whole blood tacrolimus concentrations were determined in samples of transplant recipients included in the TransplantLines Biobank and Cohort Study. Targeted whole blood trough concentrations are 4-6 ng/mL and 7-10 ng/mL for kidney and lung transplant recipients, respectively. A population pharmacokinetic model was developed using non-linear mixed-effects modelling. Simulations were performed to infer plasma concentration ranges corresponding to whole blood target ranges.RESULTS: Plasma (n = 1973) and whole blood (n = 1961) tacrolimus concentrations were determined in 1060 transplant recipients. A one-compartment model with fixed first-order absorption and estimated first-order elimination characterised observed plasma concentrations. Plasma was linked to whole blood using a saturable binding equation (maximum binding 35.7 ng/mL, 95% confidence interval (CI) 31.0-40.4 ng/mL; dissociation constant 0.24 ng/mL, 95% CI 0.19-0.29 ng/mL). Model simulations indicate that patients within the whole blood target range are expected to have plasma concentrations (95% prediction interval) of 0.06-0.26 ng/mL and 0.10-0.93 ng/mL for kidney and lung transplant recipients, respectively.CONCLUSION: Whole blood tacrolimus target ranges, currently used to guide TDM, were translated to plasma concentration ranges of 0.06-0.26 ng/mL and 0.10-0.93 ng/mL for kidney and lung transplant recipients, respectively.</p