Clinical Drug Investigation

Comment on: “Drugs That Can Kill a Toddler with One Tablet or Teaspoonful: A 2018 Updated List”

Response to: “Comment on: Drugs that Can Kill a Toddler with One Tablet or Teaspoonful: A 2018 Updated List”

Glucagon-Like Peptide-1 Receptor Analogues in Type 2 Diabetes: Their Use and Differential Features Abstract Glucagon-like peptide-1 receptor analogues/agonists (GLP-1RAs) are well established as effective adjuncts to lifestyle modification in the treatment of type 2 diabetes (T2D) as monotherapy or in combination with oral glucose-lowering drugs ± insulin. The six subcutaneous GLP-1RA formulations (i.e. twice-daily exenatide, once-daily liraglutide and lixisenatide, and once-weekly dulaglutide, exenatide and semaglutide) currently available in the EU and USA have many similarities, but also some unique features and properties. By stimulating GLP-1 receptors, GLP-1RAs increase insulin secretion and suppress glucagon release in a glucose-dependent manner, thereby improving clinical and patient-reported outcomes related to glycaemic control and weight. They also have been shown to reduce, or at least not increase, the risk of major cardiovascular outcomes. GLP-1RAs are generally well tolerated, with gastrointestinal and injection-site reactions being the most troublesome drug-related adverse events, and are associated with a very low intrinsic risk of hypoglycaemia. Treatment with GLP-1RAs should be customized to meet the clinical needs and personal preferences of the individual.

Lilly Insulin Glargine Versus Lantus ® in Type 2 Diabetes Mellitus Patients: India and East Asia Subpopulation Analyses of the ELEMENT 5 Study Abstract Background and Objectives Lilly insulin glargine (LY IGlar; Basaglar®) and the reference insulin glargine product (IGlar; Lantus®) are basal insulin glargine analogs with identical amino acid sequence and similar pharmacological profiles. ELEMENT 5, a Phase 3, prospective, randomized, multinational, two-arm, active-controlled, open-label, parallel-design study in type 2 diabetes mellitus (T2DM) patients (N = 493) showed similar efficacy and safety profiles with LY IGlar and IGlar. This study reports results from India (N = 100) and East Asia (N = 134) subpopulations. Methods Patients from India and East Asia (Korea and Taiwan) with T2DM who were insulin naïve (glycated hemoglobin (HbA1c) ≥ 7.0% and ≤ 11.0%) or on basal insulin (HbA1c ≤ 11.0%) were randomized to receive LY IGlar or IGlar along with oral antihyperglycemic medications (OAMs) for 24 weeks. Patients were instructed to self-titrate from the starting dose by 1 unit/day until fasting blood glucose (FBG) ≤ 5.6 mmol/L (100 mg/dL) was achieved. The key outcome was HbA1c change from baseline to Week 24. Results Within-group least-squares mean (LSM) decrease (baseline to Week 24) in HbA1c was similar between treatments. The upper limit of confidence interval (CI) for treatment difference was below the defined 0.4% noninferiority margin in India (LY IGlar: − 0.83%; IGlar: − 0.62%; difference [95% CI] − 0.21 [− 0.70, 0.28]) and East Asia (LY IGlar: − 1.28%; IGlar: − 1.26%; difference [95% CI] − 0.02 [− 0.34, 0.30]) subpopulations. Results of other efficacy and safety endpoints at Week 24 were similar between treatments in both subpopulations. LSM self-monitored FBG levels were similar between treatments at all visits in both subpopulations except at Week 24 in the India subpopulation (LY IGlar: 5.65 [0.10] mmol/L or 101.8 [1.86] mg/dL; IGlar: 5.18 [0.10] mmol/L or 93.3 [1.75] mg/dL; p = 0.002). Conclusion Efficacy and safety profiles of LY IGlar and IGlar, in combination with OAMs, were similar in India and East Asia subpopulations. This was consistent with the ELEMENT 5 total population. Clinical Trial Registration NCT02302716.

Development Strategy and Relative Bioavailability of a Pediatric Tablet Formulation of Ticagrelor Abstract Background and Objective Ticagrelor is a P2Y12 receptor inhibitor approved as an antiplatelet drug for patients with acute coronary syndrome or a history of myocardial infarction. Ticagrelor is also being investigated for the reduction of vaso-occlusive crises in pediatric patients with sickle cell disease. A pediatric formulation suitable for this age range was developed; the development strategy is described. Primary objectives were determining the relative bioavailability of ticagrelor pediatric tablets and granules for oral suspension to the adult immediate-release tablet, and the pediatric tablets taken whole and dispersed/suspended in water to the granules for oral suspension. Bioequivalence between the pediatric tablet taken whole or suspended in water was also assessed. Secondary objectives were comparing the formulations’ safety and tolerability. Methods We conducted a randomized, four-period, cross-over, single-dose study. Pharmacokinetic parameters were assessed for ticagrelor and its active metabolite AR-C124910XX. Bioequivalence was concluded if the 90% confidence intervals of the maximum plasma concentration and area under the plasma concentration–time curve ratios were contained completely within the 80.00–125.00% limits for ticagrelor/AR-C124910XX. Results Forty-four healthy adults (95% white; 57% male) were included. Similar bioavailability of ticagrelor (and AR-C124910XX) was demonstrated for all comparisons tested. Ticagrelor pediatric tablets taken whole were bioequivalent to pediatric tablets suspended in water. The plasma concentration–time profiles for ticagrelor and AR-C124910XX were similar, showing rapid ticagrelor absorption and AR-C124910XX formation. All formulations were well tolerated. Conclusion Similar bioavailability of a new pediatric dispersible tablet formulation of ticagrelor for use across a wide age range of pediatric patients was demonstrated compared with other oral ticagrelor formulations. ClinicalTrials.gov Identifier NCT03126695. EudraCT 2017-000371-93.

Assessing the Value of Time Series Real-World and Clinical Trial Data vs. Baseline-Only Data in Predicting Responses to Pregabalin Therapy for Patients with Painful Diabetic Peripheral Neuropathy Abstract Background and Objective Treatment challenges necessitate new approaches to customize care to individual patient needs. Integrating data from randomized controlled trials and observational studies may reduce potential covariate biases, yielding information to improve treatment outcomes. The objective of this study was to predict pregabalin responses, in individuals with painful diabetic peripheral neuropathy, by examining time series data (lagged inputs) collected after treatment initiation vs. baseline using microsimulation. Methods The platform simulated pregabalin-treated patients to estimate hypothetical future pain responses over 6 weeks based on six distinct time series regressions with lagged variables as inputs (hereafter termed “time series regressions”). Data were from three randomized controlled trials (N = 398) and an observational study (N = 3159). Regressions were derived after performing a hierarchical cluster analysis with a matched patient dataset from coarsened exact matching. Regressions were validated using unmatched (observational study vs. randomized controlled trial) patients. Predictive implications (of 6-week outcomes) were compared using only baseline vs. 1- to 2-week prior data. Results Time series regressions for pain performed well (adjusted R2 0.85–0.91; root mean square error 0.53–0.57); those with only baseline data performed less well (adjusted R2 0.13–0.44; root mean square error 1.11–1.40). Simulated patient distributions yielded positive predictive values for > 50% pain score improvements from baseline for the six clusters (287–777 patients each; range 0.87–0.98). Conclusions Effective prediction of pregabalin response for painful diabetic peripheral neuropathy was accomplished through combining cluster analyses, coarsened exact matching, and time series regressions, reflecting distinct patterns of baseline and “on-treatment” variables. These results advance the understanding of microsimulation to predict patient treatment responses through integration and inter-relationships of multiple, complex, and time-dependent characteristics.

Pharmacokinetics of Imipenem in Critically Ill Patients with Life-threatening Severe Infections During Support with Extracorporeal Membrane Oxygenation Abstract Background Extracorporeal membrane oxygenation (ECMO) has become increasingly used for lifesaving respiratory and/or cardiac failure support in critically ill patients, including those with life-threatening severe infections. This cardiopulmonary bypass device has been shown to enhance the profound pathophysiological changes in this patient population, resulting in an alteration of the pharmacokinetics of antimicrobial agents. Objective The aim of this study was to determine the effect of ECMO on the pharmacokinetics of imipenem in critically ill patients supported by this cardiopulmonary bypass device. Methods The study was conducted in critically ill patients with respiratory and/or cardiac failure and severe infections who were supported by ECMO. All patients received a 1-h infusion of 0.5 g of imipenem every 6 h and imipenem pharmacokinetics studies were carried out on the fourth dose of drug administration. Results Ten patients were enrolled in this study. The pharmacokinetics parameters of imipenem were found to be highly variable. The volume of distribution, total clearance, elimination half-life and the area under the concentration–time curve between 0 and 6 h were 33.38 ± 13.89 L, 9.99 ± 10.47 L/h, 12.01 ± 29.63 h and 88.93 ± 54.07 mg∙h/L, respectively. Conclusions Pathophysiological changes in critically ill patients with severe infections during support with ECMO had a greater impact on altered pharmacokinetic patterns of imipenem than those that occur in critically ill patients without ECMO support. Therefore, the largest licensed dose, 1 g every 6 h, of imipenem, may be required to maintain adequate drug concentrations to achieve the pharmacokinetic/pharmacodynamic targets for effective antimicrobial therapy in this patient population.

Emerging Trends in Metformin Prescribing in the United States from 2000 to 2015 Abstract Background Metformin (MET) is used as first-line treatment for type 2 diabetes mellitus but has been shown to have pleiotropic effects that have expanded its use to various conditions. Limited current data exist regarding unconventional use within various patient populations. Objective The aim of this study was to evaluate US FDA-approved and off-label MET utilization in the US from 2000 to 2015. Methods We performed a retrospective analysis of outpatient MET prescribing in the US from 2000 to 2015. Data from the Medical Expenditure Panel Survey (MEPS) administered by the Agency of Healthcare Research and Quality were analyzed. Demographic characteristics, including age, sex, socioeconomic status, comorbidities, and region, were analyzed using the MEPS Household Component (HC). Prescription rates were defined as the annual number of MET prescriptions divided by the corresponding population estimate. Population denominators were derived using the MEPS HC. The MEPS estimates US populations based on sampled persons in the target population (civilian, non-institutionalized) for an entire year. MET prescribing is represented by population per 1000 persons. We determined if changes of MET prescribing were uniform across five age groups: < 18 years, 18–29 years, 30–49 years, 50–64 years, and 64 years and older. Results An estimated 553,291,094 MET prescriptions were dispensed in the US from 2000 to 2015. Prescribing rates steadily increased from 2000 to 2015. FDA-approved MET prescription rates increased from 2.27 per 1000 persons in 2000 to 235 per 1000 persons in 2015, while off-label MET prescription rates increased from 0.74 per 1000 persons in 2000 to 20.3 per 1000 persons in 2015. The top indications for off-label MET use were endocrine disorders (45.8%), cardiovascular disorders (18.2%), female reproductive disorders (12.9%), and metabolic disorders (10.9%). MET prescribing rates for FDA-approved indications increased across all age groups in 2000 and 2015, with the most substantial increase seen in adults aged 50–64 years and > 65 years (1.7 per 1000 persons to 20.6 per 1000 persons, and 2.3 per 1000 persons to 18.7 per 1000 persons, respectively). While off-label MET increased across all age groups from 2000 to 2015, a tenfold increase (< 1.0 to 10.6) was seen in adults aged 30–49 years of age. Conclusion Overall, MET use has substantially increased within the past 15 years, which was mainly driven by older adults. Our study highlights the emerging prevalence of MET use in both FDA-approved and off-label indications.

Inflammatory Bowel Disease Onset During Secukinumab Treatment: Real Concern or Just an Expression of Dysregulated Immune Response? Abstract Background Up to December 2018, eight cases of new-onset inflammatory bowel disease (IBD) were reported in the literature in patients being treated with secukinumab, an interleukin-17A antagonist prescribed for dermatologic or rheumatologic indications. The duration of secukinumab treatment ranged from a single administration to 12 months of treatment. Objective The aim of our investigation was to estimate the cumulative incidence of new-onset IBD in patients treated with secukinumab for either dermatologic or rheumatologic indications. Methods We carried out a survey among the dermatology and rheumatology centres in the Sicilian region (Italy) in order to identify the number of patients treated with secukinumab in the previous 24 months (November 2016–November 2018), and to understand how many of these patients eventually developed IBD after the start of secukinumab therapy. Results Overall, four cases of IBD during secukinumab treatment were identified, with higher variability in time to onset compared with what has been previously reported, i.e. from 1 month to 5 years of secukinumab exposure. Overall, 434 patients were treated with secukinumab in Sicily between November 2016 and November 2018, and approximately 1% of these patients developed new-onset IBD. Conclusions Careful clinical examination of patients with respect to possible susceptibility to IBD prior to secukinumab therapy is advised.

Systematic Review and Meta-analysis of Pharmacist-Led Transitions of Care Services on the 30-Day All-Cause Readmission Rate of Patients with Congestive Heart Failure Abstract Background and Objective A systematic review and meta-analysis were performed to determine the cumulative effect of pharmacist-led transitions of care on the 30-day all-cause readmission rates of patients with congestive heart failure with the objective to isolate and assess the effect of pharmacy intervention to a condition-specific service. Previous studies that review pharmacist-led transitional care services involve multiple condition-specific services or a pharmacy service integrated into the healthcare team that presents complications in interpreting the independent effectiveness of component services by pharmacy professionals. Methods A systematic review was conducted using articles identified from MEDLINE, CINAHL, Web of Science, Embase, the Cochrane Library, and clinicaltrials.gov databases for studies on congestive heart failure readmission rates based on transitions of care pharmacist services using detailed inclusion and exclusion criteria. Abstracts were screened for outcome of interest and appropriate transitions of care program structure. Practice and patient characteristics were described and compared to identify current practice trends. A meta-analysis was then performed utilizing previously identified studies from systematic analysis that reported the required data to calculate the effect size. Evidence was reviewed and appraised according to the Newcastle-Ottawa Scale for cohort studies. Results The database search produced 443 potential articles for inclusion. Six articles were identified for inclusion in the systematic review based on abstract screening. Of the six articles included in the systematic review, three studies met inclusion criteria for a meta-analysis. Two studies in the meta-analysis stated a significant reduction in the 30-day all-cause readmission rate for patients with congestive heart failure, while the third depicted a reduction in readmission that was found to be non-significant. The pooled effect of the included articles found that pharmacist-led transitions of care services for patients with congestive heart failure had an increased odds to have lower all-cause readmission rates of patients with congestive heart failure (odds ratio = 2.19, 95% confidence interval 1.50–3.20). Based on the meta-analysis of three studies, pharmacist-led transitions of care services significantly reduced the odds of 30-day all-cause readmission rates in patients with congestive heart failure compared with standard-of-care discharge protocols. Conclusion Results of the meta-analysis demonstrate the capacity for pharmacist-led transitions of care programs to reduce 30-day all-cause readmission rates in patients with congestive heart failure compared with non-pharmacist discharge care. The financial implications of transitions of care pharmacist involvement have yet to be validated. In general, existing database search results highlight the lack of evidence detailing specific clinical outcomes of pharmacist-led transitions of care services in distinct chronic conditions. Future studies may serve to compare patient-centered outcomes between condition-specific services or across disciplines to provide the most cost-effective delivery of care.