Claims-based pharmacy markers for comprehensive medication management program case identification: Validation against concurrent and prospective healthcare costs and utilization

BackgroundThree claims-based pharmacy markers (complex, costly and risky medications) were developed to help automatically identify patients for comprehensive medication management.ObjectiveTo evaluate the association between newly-developed markers and healthcare outcomes.MethodsThis was a two-year retrospective cohort study using PharMetrics Plus patient-level administrative claims in 2014 and 2015. We included all claims from 1,541,873 individuals with: (1) 24-month medical and pharmacy enrollment in 2014 and 2015, (2) aged between 18 and 63 in 2014, and (3) known gender. Independent/control variables came from 2014 while outcomes came from 2014 (concurrent analysis) and 2015 (prospective analysis). Three pharmacy markers, separately or together, were added to four base models to predict concurrent and prospective healthcare costs (total, medical, and pharmacy) and utilization (having any hospitalization, having any emergency department visit, and having any readmission). We applied linear regression for costs while logistic regression for utilization. Measures of model performances and coefficients were derived from a 5-fold cross-validation repeated 20 times.ResultsIndividuals with 1+ complex, risky or costly medication markers had higher comorbidity, healthcare costs and utilization than their counterparts. Nine binary risky category markers performed the best among the three types of risky medication markers; the Medication Complexity Score and three-level complex category both outperformed a simpler complex medication indicator. Adding three novel pharmacy markers separately or together into the base models provided the greatest improvement in explaining pharmacy costs, compared with medical (non-medication) costs. These pharmacy markers also added value in explaining healthcare utilization among the simple base models.ConclusionsThree claims-based pharmacy indicators had positive associations with healthcare outcomes and added value in predicting them. This initial study suggested that these novel markers can be used by pharmacy case management programs to help identify potential high-risk patients most likely to benefit from clinical pharmacist review and other interventions.     

Evaluation of a medication error monitoring system to reduce the incidence of medication errors in a clinical setting

BackgroundMedication errors have significant health and economic consequences. Monitoring medication errors by implementing monitoring systems proved in the USA and European countries since 1990s to be an effective method for error detection, leading to improved safety at all levels of health care. Currently, China does not have a universal medication error monitoring system.ObjectiveTo evaluate the effectiveness of the Medication Error Monitoring System for the reduction of medication errors in Xiamen Maternity and Child Care Hospital.MethodsBetween January–June 2014, the Medication Error Monitoring System developed by Xiamen Maternity and Child Care Hospital was employed to monitor medication errors through error reporting by physicians and pharmacists. The errors collected by this system were then thoroughly assessed and addressed by specific improvements including more frequent training, introducing computerised prescribing systems and a bar-coding medicine dispensing system. Data collected from January–June 2015, was then compared with the data collected in 2014 to determine whether medication errors had been reduced.ResultsBetween 2014 and 2015, the total medication errors in prescribing and dispensing were reduced by approximately 27%. Compared with 2014, there was a marked reduction in the number of errors due to misdiagnoses and inappropriate usage/dosage in 2015, while the number of data entry errors increased and became the most common cause of medication error. The success rate of pharmacy interventions increased from 95.25% to 96.88%, albeit modest. However, across all medication errors in the stage of prescribing and dispensing, non-human-related errors significantly decreased from 44.25% in 2014 to 37.94% in 2015 with a p value of 0.021.ConclusionThe Medication Error Monitoring System is effective at monitoring medication error data, leading to a reduction in reported medication errors. Better training for hospital staff including doctors and pharmacists will be critical to reduce human-related medication errors in the hospital.     

Spanish translation of the ABC taxonomy for medication adherence

BackgroundThe Ascertaining Barriers to Compliance (ABC) taxonomy was developed aiming at systematizing definitions and operationalizations of medication adherence. Its translation is crucial to improve the generalizability, application and comparison of study findings.ObjectiveTo provide a consensus translation of the ABC taxonomy from English to Spanish.MethodsA two-phased approach was used, according to the Preferred Methods for the Translation of the ABC Taxonomy for Medication Adherence. Two literature reviews were conducted: to identify Spanish synonyms and definitions of the ABC taxonomy, and to identify a panel of Spanish-speaking experts in medication adherence. A Delphi survey was designed based on the synonyms and definitions found. The experts previously identified were invited to participate in the Delphi. A consensus of ≥85% was established for the first round. A moderate consensus (50–75%), a consensus (75–95%) or a strong consensus (>95%) were considered to be necessary in the second round.ResultsForty potential synonyms of the ABC taxonomy terms were identified from a total of 270 papers. The response rate during the first Delphi round was 32% (63/197) and in the second round 86% (54/63). A strong consensus was reached for the term “inicio del tratamiento” (96%) and consensus for the term “implementación” (83%). A moderate consensus was obtained for “adherencia a la medicación” (70%), “interrupción del tratamiento” (52%), “manejo de la adherencia” (54%) and “disciplinas relacionadas con la adherencia” (74%). No consensus was reached for the term persistence. Five out of the seven definitions reached a consensus in the first round, and two definitions a moderate consensus after the second round.ConclusionThe adoption of the Spanish taxonomy will increase transparency, comparability and transferability of results in the field of medication adherence. This may facilitate benchmarking of adherence strategies between Spanish-speaking researchers and practitioners, and other language speakers.     

Assessing adherence to infusion-based biologic therapies in patients with inflammatory bowel disease

BackgroundThe intravenous biologics infliximab and vedolizumab are effective long-term therapies for inflammatory bowel disease (IBD). Though highly effective, suboptimal adherence may result in loss of response and adverse sequelae. The extent and outcomes of suboptimal adherence with intravenous biologics, including in IBD, requires further evaluation.ObjectivesTo ascertain adherence to infliximab and vedolizumab infusions, and determine factors associated with poorer adherence within an IBD cohort.MethodsA retrospective single-centre cohort study of IBD patients, assessing adherence to infliximab and vedolizumab over 2 years (July 1, 2017 to June 30, 2019) was conducted. Medical and pharmacy dispensing records were used to determine date of infusion. Adherence was assessed using the continuous, multiple interval measure of medication gaps (CMG). Objectively measured disease remission was achieved if one or more of endoscopic remission, faecal calprotectin <100 μg/mL and/or CRP <5 mg/mL occurred within 3 months of end of follow-up. Bivariate analysis and multiple linear regression elucidated factors associated with poorer adherence.ResultsOf 193 IBD patients, 132 (68.4%) had Crohn's disease. One hundred and thirty six (70.5%) patients received infliximab and 57 (29.5%) received vedolizumab with a median 13 [IQR 11–14] doses administered per patient over 2 years. Adherence according to CMG was similar between infliximab and vedolizumab groups (median 1.5% vs 1.2%, p = 0.31). In multiple linear regression analysis male sex, shorter IBD duration and clinic non-attendances were each associated with poorer adherence (Beta 4.69, 3.90, 3.56 respectively, p < 0.05) and objective disease remission was inversely associated with poorer adherence (Beta ?3.27, p < 0.05).ConclusionThere was a wide range of adherence to biologic infusions in this IBD cohort with poorer adherence associated with patient related factors. Conversely, objectively measured remission was strongly associated with adherence. This emphasises the need for targeted interventions to improve adherence and monitoring, and mitigate treatment delays.     

Pharmacist-led medication reconciliation at patient discharge: A scoping review

BackgroundOne of the strategies to promote patient safety in care transitions is medication reconciliation (MR), which is conducted by the pharmacist at the patient's discharge from hospital. However, there are divergences about this process and about the pharmacist's role in conducting such intervention.ObjectiveTo systematically review the literature that reports the MR process led by pharmacists at patient discharge and map the different methods, strategies and tools used in the process.MethodsRelevant studies were searched in the following databases: EMBASE, MEDLINE (PubMed), The Cochrane Library, and LILACS. No language restriction or publication date was applied. The studies considered eligible were those involving and describing pharmacist-led MR processes at acute patient discharge from hospital, with an experimental, quasi-experimental, or observational design. The characteristics of the studies and the MR processes were identified and then a qualitative synthesis was performed.ResultsFifty studies were included. The majority of them were observational ones (82%), and the main outcome was medication discrepancies (42%). The studies were mostly conducted in university hospitals (70%) and in internal medicine wards (54%). Pharmacists were responsible mainly for gathering medication histories (72%), and identifying (96%) and solving (98%) pharmacotherapeutic problems. The main sources of information on pre-admission medications were patient/caregiver interviews (66%) and records from other care providers (40%). Only 30% of the studies described a patient discharge plan, and 14% shared information of the patient's pharmacotherapy with community pharmacists.ConclusionThe concept of MR and the pharmacist-led activities in the process varied in the literature, as well as the pharmacotherapy assessment focus and the communication strategies towards patients and other care providers, showing that standardization of the process and concepts is necessary.     

Discovery of the anti-angiogenesis effect of eltrombopag in breast cancer through targeting of HuR protein

HuR (human antigen R), an mRNA-binding protein responsible for poor prognosis in nearly all kinds of malignancies, is a potential anti-tumor target for drug development. While screening HuR inhibitors with a fluorescence polarization (FP) based high-throughput screening (HTS) system, the clinically used drug eltrombopag was identified. Activity of eltrombopag on molecular level was verified with FP, electrophoretic mobility shift assay (EMSA), simulation docking and surface plasmon resonance (SPR). Further, we showed that eltrombopag inhibited in vitro cell proliferation of multiple cancer cell lines and macrophages, and the in vivo anti-tumor activity was also demonstrated in a 4T1 tumor-bearing mouse model. The in vivo data showed that eltrombopag was efficient in reducing microvessels in tumor tissues. We then confirmed the HuR-dependent anti-angiogenesis effect of eltrombopag in 4T1 cells and RAW264.7 macrophages with qRT-PCR, HuR-overexpression and HuR-silencing assays, RNA stability assays, RNA immunoprecipitation and luciferase assays. Finally, we analyzed the in vitro anti-angiogenesis effect of eltrombopag on human umbilical vein endothelial cells (HUVECs) mediated by macrophages with cell scratch assay and in vitro Matrigel angiogenesis assay. With these data, we revealed the HuR-dependent anti-angiogenesis effect of eltrombopag in breast tumor, suggesting that the existing drug eltrombopag may be used as an anti-cancer drug.     

Biomimetic carbon nanotubes for neurological disease therapeutics as inherent medication

Nowadays, nanotechnology is revolutionizing the approaches to different fields from manufacture to health. Carbon nanotubes (CNTs) as promising candidates in nanomedicine have great potentials in developing novel entities for central nervous system pathologies, due to their excellent physicochemical properties and ability to interface with neurons and neuronal circuits. However, most of the studies mainly focused on the drug delivery and bioimaging applications of CNTs, while neglect their application prospects as therapeutic drugs themselves. At present, the relevant reviews are not available yet. Herein we summarized the latest advances on the biomedical and therapeutic applications of CNTs in vitro and in vivo for neurological diseases treatments as inherent therapeutic drugs. The biological mechanisms of CNTs-mediated bio-medical effects and potential toxicity of CNTs were also intensely discussed. It is expected that CNTs will exploit further neurological applications on disease therapy in the near future.     

The Impact of Product and Process Related Critical Quality Attributes on Immunogenicity and Adverse Immunological Effects of Biotherapeutics

The pharmaceutical industry has experienced great successes with protein therapeutics in the last two decades and with novel modalities, including cell therapies and gene therapies, more recently. Biotherapeutics are complex in structure and present challenges for discovery, development, regulatory, and life cycle management. Biotherapeutics can interact with the immune system that may lead to undesired immunological responses, including immunogenicity, hypersensitivity reactions (HSR), injection site reactions (ISR), and others. Many product and process related critical quality attributes (CQAs) have the potential to trigger or augment such immunological responses to the product. Tremendous efforts, both clinically and preclinically, have been invested to understand the impact of product and process related CQAs on adverse immunological effects. The information and knowledge are critical for the implementation of Quality by Design (QbD), which requires risk assessment and establishment of specifications and control strategies for CQAs. A quality target product profile (QTPP) that identifies the key CQAs through process development can help assign severity scores based on safety, immunogenicity, pharmacokinetics (PK) and pharmacodynamics (PD) of the molecule. Gaps and future directions related to biotherapeutics and emerging novel modalities are presented.     

Extended Characterization and Impact of Visible Fatty Acid Particles - A Case Study With a mAb Product

In recent years, there has been increased scrutiny on the presence and formation of product-related particles in biopharmaceutical formulations. These types of particles, originating from the degradation of the active pharmaceutical ingredient or the excipients, can be challenging to identify and characterize due to their fragility. Additionally, the mechanisms of their formation as well as the impact of their presence on drug product safety can be complicated to elucidate. In this work, a case study is presented in which multiple batches of one formulated monoclonal antibody (mAb-A) were analyzed at different batch ages to better understand the formation of visible particles resulting from degradation of the surfactant polysorbate 20. The particle identity was determined by Raman spectroscopy as free fatty acid (FFA) and the particle composition over time was monitored by mass spectrometry. Further experimental work includes the counts and morphologies of subvisible particles by flow imaging microscopy. Finally, we evaluated the consequences of saline and human plasma exposure to the visible particles to better understand their fate upon dilution and/or administration which is routinely performed in the clinical setting. The experiments performed in this work can be used to support risk assessments of visible product-related particles.     

Pharmacists’ experience of a diabetes risk-assessment service and analytical quality control in community pharmacies – A focus-group study

BackgroundHealthcare services such as diabetes risk-assessment are increasingly common in community pharmacies. Knowledge of community pharmacists’ experiences of such services could ease the implementation of a larger-scale service.ObjectivesTo explore Norwegian pharmacists’ experience of a diabetes risk-assessment service, including analytical quality control, in a community-pharmacy setting.MethodsThree focus-group interviews were conducted in Norway between August and September 2017. Systematic text condensation was used, an analytic approach well suited for thematic content analysis across interview data. Fourteen pharmacists took part, recruited from a project offering a diabetes risk-assessment service, including measurements of Glycated hemoglobin A1c (HbA1c), in Norwegian community pharmacies.ResultsThe pharmacists emphasized the importance of using their knowledge and skills to promote good health. They considered offering this service as being compatible with their role as pharmacists. As communication is an essential part of their work, the pharmacists evaluated their communication skills as being good. Nevertheless, how to communicate the offering of this service was seen as a challenge, for instance recruiting participants and communicating in an understandable and professional way. Inclusion of the whole pharmacy staff as a team was experienced as an important success factor for implementation of a risk-assessment service. Analytical quality control was perceived as being a natural part of their job and a manageable task.ConclusionsOffering a diabetes risk-assessment service is in line with the way a selected group of Norwegian community pharmacists perceived their professional role. However, they were uncomfortable recruiting participants, and expressed the wish for more support from the pharmacy chain. Our results add performance of analytical quality control as part of the ongoing development involving expansion of pharmacists' professional role. Future implementation studies may also benefit from giving both the pharmacy staff and customers sufficient time to familiarize themselves with the new service before measuring effects.     

Safety and tolerability of Empagliflozin use during the holy month of Ramadan by fasting patients with type 2 diabetes: A prospective cohort study

BackgroundType 2 Diabetes Mellitus (T2DM) patients are exposed to a 7.5 times higher risk of hypoglycemia while fasting during Ramadan. Relevant diabetes guidelines prioritize the use of SGLT2 inhibitors over other classes. There is a great need to enrich data on their safe and effective use by fasting patients at greater risk of hypoglycemia. Therefore, this study aims to assess the safety and tolerability of Empagliflozin in T2DM Muslim patients during Ramadan.MethodologyA prospective cohort study was conducted for adult Muslim T2DM patients. Patients who met the inclusion criteria were categorized into two sub-cohorts based on Empagliflozin use during Ramadan (Control versus Empagliflozin). The primary outcomes were the incidence of hypoglycemia symptoms and confirmed hypoglycemia. Other outcomes were secondary. All patients were followed up to eight weeks post-Ramadan. A propensity score (PS) matching and Risk Ratio (RR) were used to report the outcomes.ResultsAmong 1104 patients with T2DM who were screened, 220 patients were included, and Empagliflozin was given to 89 patients as an add-on to OHDs. After matching with PS (1:1 ratio), the two groups were comparable. The use of other OHDs, such as sulfonylurea, DPP4 inhibitors, and Biguanides, was not statistically different between the two groups. The risk of hypoglycemia symptoms during Ramadan was lower in patients who received Empagliflozin than in the control group (RR 0.48 CI 0.26, 0.89; p-value = 0.02). Additionally, the risk of confirmed hypoglycemia was not statistically significant between the two groups (RR 1.09 CI 0.37, 3.22; p-value = 0.89).ConclusionEmpagliflozin use during Ramadan fasting was associated with a lower risk of hypoglycemia symptoms and higher tolerability. Further randomized control trials are required to confirm these findings.     

Characterization of a novel bispecific antibody targeting tissue factor-positive tumors with T cell engagement

T cell engaging bispecific antibody (TCB) is an effective immunotherapy for cancer treatment. Through co-targeting CD3 and tumor-associated antigen (TAA), TCB can redirect CD3⁺ T cells to eliminate tumor cells regardless of the specificity of T cell receptor. Tissue factor (TF) is a TAA that involved in tumor progression. Here, we designed and characterized a novel TCB targeting TF (TF-TCB) for the treatment of TF-positive tumors. In vitro, robust T cell activation, tumor cell lysis and T cell proliferation were induced by TF-TCB. The tumor cell lysis activity was dependent upon both CD3 and TF binding moieties of the TF-TCB, and was related to TF expression level of tumor cells. In vivo, in both tumor cell/human peripheral blood mononuclear cells (PBMC) co-grafting model and established tumor models with poor T cell infiltration, tumor growth was strongly inhibited by TF-TCB. T cell infiltration into tumors was induced during the treatment. Furthermore, efficacy of TF-TCB was further improved by combination with immune checkpoint inhibitors. For the first time, our results validated the feasibility of using TF as a target for TCB and highlighted the potential for TF-TCB to demonstrate efficacy in solid tumor treatment.     

Impact of Precipitation of Antibody Therapeutics After Subcutaneous Injection on Pharmacokinetics and Immunogenicity

Antibody therapeutics with poor solubility in the subcutaneous matrix may carry unintended risks when administered to patients. The objective of this work was to estimate the risk of antibodies that precipitate in vitro at neutral pH by determining the impact of poor solubility on distribution of the drug from the injection site as well as immunogenicity in vivo. Using fluorescence imaging in a mouse model, we show that one such precipitation-prone antibody is retained at the injection site in the subcutaneous space longer than a control antibody. In addition, we demonstrate that retention at the injection site through aggregation is concentration-dependent and leads to macrophage association and germinal center localization. Although there was delayed disposition of the aggregated antibody to draining lymph nodes, no overall impact on the immune response in lymph nodes, systemic exposure of the antibody, or enhancement of the anti-drug antibody response was evident. Unexpectedly, retention of the precipitated antibody in the subcutaneous space delayed the onset of the immune response and led to an immune suppressive response. Thus, we conclude that precipitation due to poor solubility of high doses of antibody formulations delivered subcutaneously may not be of special concern in terms of exposure or immunogenicity.