Clinical Pharmacology

Balancing medication use in nursing home residents with life-limiting disease Abstract Purpose Balancing medications that are needed and beneficial and avoiding medications that may be harmful is important to prevent drug-related problems, and improve quality of life. The aim of this study is to describe medication use, the prevalence of deprescribing of medications suitable for deprescribing, and the prevalence of new initiation of potentially inappropriate medications (PIMs) in nursing home (NH) residents with life-limiting disease in Flanders. Methods NH residents aged ≥ 65, suffering from end stage organ failure, advanced cancer, and/or dementia (n = 296), were included in this cross-sectional study with retrospective analyses of medication use at the time of data collection (t2) and 3 to 6 months before (t1). The appraisal of appropriateness of medications was done using a list of medications documented as suitable for deprescribing, and STOPPFrail criteria. Results Residents' (mean age 86 years, 74% female) mean number of chronic medications increased from 7.4 (t1) to 7.9 (t2). In 31% of those using medications suitable for deprescribing, at least one medication was actually deprescribed. In 30% at least one PIM from the group of selected PIMs was newly initiated. In the subgroup (n = 76) for whom deprescribing was observed, deprescribing was associated with less new initiations of PIMs (r = − 0.234, p = 0.042). Conclusion Medication use remained high at the end of life for NH residents with life-limiting disease, and deprescribing was limited. However, in the subgroup of 76 residents for whom deprescribing was observed, less new PIMs were initiated.

Prevalence of medication and off-label medication use in acquired brain injury at a neurorehabilitation hospital Abstract Purpose Patients who suffer acquired brain injury (ABI) require a great variety of drugs. Furthermore, the lack of evidence on the medication effects in this type of patient increases off-label prescription. The aim of this study was to describe the pattern of medication use and the practice of prescribing off-label drugs in these patients. Methods A cross-sectional study was conducted in patients with ABI, of either traumatic or non-traumatic cause, admitted to a neurorehabilitation hospital for rehabilitation. Demographic and clinical data and prevalence of medication use and off-label prescription were collected. Results The majority of the studied patients (85.2%) were considered polymedicated since they were prescribed ≥ 6 drugs concomitantly. In traumatic brain injury (TBI) patients, antidepressants (81.5%) were the Anatomical Therapeutic Chemical (ATC) group's most prescribed versus antithrombotic agents (80.5%) in non-traumatic brain injury (N-TBI) patients. Up to 37.3% of all active substances prescribed in TBI patients were off-label compared with 24.9% in N-TBI patients. The most prescribed off-label active substances in both groups were those related to the Nervous System (N) ATC group to treat neurobehavioural problems. Conclusion A multidisciplinary pharmacotherapeutic follow-up of these patients would be essential to address the high prescription rate of medications and the off-label prescription practice. In this way, medication problems related to polypharmacy could be minimised and the benefit-risk ratio of prescribed off-label drugs could be ensured according to the available medical evidence.

Verification of pharmacogenomics-based algorithms to predict warfarin maintenance dose using registered data of Japanese patients Abstract Purpose Large inter-individual differences in warfarin maintenance dose are mostly due to the effect of genetic polymorphisms in multiple genes, including vitamin K epoxide reductase complex 1 (VKORC1), cytochromes P450 2C9(CYP2C9), and cytochrome P450 4F2 (CYP4F2). Thus, several algorithms for predicting the warfarin dose based on pharmacogenomics data with clinical characteristics have been proposed. Although these algorithms consider these genetic polymorphisms, the formulas have different coefficient values that are critical in this context. In this study, we assessed the mutual validity among these algorithms by specifically considering racial differences. Methods Clinical data including actual warfarin dose (AWD) of 125 Japanese patients from our previous study (Eur J Clin Pharmacol 65(11):1097–1103, 2009) were used as registered data that provided patient characteristics, including age, sex, height, weight, and concomitant medications, as well as the genotypes of CYP2C9 and VKORC1. Genotyping for CYP4F2*3 was performed by the PCR method. Five algorithms that included these factors were selected from peer-reviewed articles. The selection covered four populations, Japanese, Chinese, Caucasian, and African-American, and the International Warfarin Pharmacogenetics Consortium (IWPC). Results For each algorithm, we calculated individual warfarin doses for 125 subjects and statistically evaluated its performance. The algorithm from the IWPC had the statistically highest correlation with the AWD. Importantly, the calculated warfarin dose (CWD) using the algorithm from African-Americans was less correlated with the AWD as compared to those using the other algorithms. The integration of CYP4F2 data into the algorithm did not improve the prediction accuracy. Conclusion The racial difference is a critical factor for warfarin dose predictions based on pharmacogenomics.

Relationship between hemoglobin levels and vancomycin clearance in patients with sepsis Abstract Purpose It is important to accurately estimate accurate vancomycin (VCM) clearance (CLvcm) for appropriate VCM dosing in the treatment of patients with sepsis. However, the pathophysiology of sepsis can make CLvcm prediction less accurate. Clearance of hydrophilic antibiotics is disturbed by organ dysfunction, and hemoglobin levels are negatively correlated with sequential organ function assessment scores. We investigated whether hemoglobin levels are associated with CLvcm in sepsis patients. Methods We performed a retrospective cohort study of patients treated with VCM in the Emergency and Critical Care Center of Nihon University Itabashi Hospital between 2005 and 2015. We enrolled 72 patients after exclusion of patients who received renal replacement therapy or surgery, had a change in hemoglobin levels more than 2 g/dL or received an erythrocyte infusion during the interval between initial VCM administration and measurement of initial trough levels, had a serum baseline creatinine level of ≥ 2 mg/dL, or were under 18 years old. Results Enrolled patients consisted of 13 non-sepsis patients and 59 sepsis patients. In sepsis patients, although CLvcm was correlated with CrCl in HGB ≥ 9 group as well as in non-sepsis patients, its correlation was not observed in HGB < 9 group. Hemoglobin levels were correlated with CLvcm in sepsis patients but not in non-sepsis patient. Multiple linear regression analysis also indicated that lower CLvcm was associated with lower hemoglobin and CrCl. Conclusion Lower hemoglobin levels influence a relationship between CLvcm and CrCl in sepsis patients. We propose that VCM dosing should be adjusted for hemoglobin levels in sepsis patients.

Antipsychotic utilization patterns among patients with schizophrenic disorder: a cross-national analysis in four countries Abstract Purpose The aim of the present study was to describe antipsychotic utilization patterns among patients with schizophrenic disorder in Italy, Spain, the UK, and the USA. Methods A retrospective cohort study was conducted. Patients aged 15 and over with schizophrenic disorder were identified in the Caserta claims database (Italy), the Valencia electronic medical record (EMR) database (Spain), in The Health Improvement Network EMR database (UK), and in databases of publicly and privately insured populations in the United States (US). Results The frequency of first-generation or second-generation antipsychotic use and of long-acting or other formulations was described. Persistence to antipsychotics was estimated. Overall, 1,403,240 patients with schizophrenic disorder having a total of 765,573 new antipsychotic treatment episodes were identified. The median follow-up time ranged from 0.8 (IQR 0.2–1.9) years in the US commercially-insured population to 1.2 (IQR 0.1–1.7) years in the Spanish population. Second-generation antipsychotics were more frequently used than first-generation antipsychotics in all countries (on average, from 64.4% in the UK to 87% in US): the use of this class increased over time in Italy, Spain, and US (Medicaid). The use of long-acting formulations was heterogeneous across countries, but generally much lower than other formulations. Persistence to antipsychotic treatment at 1 year was low in all countries, ranging from 40 in Spain to 30% in Italy. Conclusions Antipsychotic utilization was heterogeneous among persons with schizophrenic disorder. Nevertheless, low persistence was an issue in all the countries, as less than half of the patients continued their treatment beyond 1 year.

Use of statins in the elderly according to age and indication—a cross-sectional population-based register study Abstract Purpose To investigate statin use in the elderly by age (≥ 80 vs. 65–79 years) in relation to established indications. Methods A population-based cohort, including data from four registers, encompassing inhabitants in Region Västra Götaland, Sweden, was used. Statin users were defined as those filling statin prescriptions ≥ 75% of the year 2010. Primary care and hospital diagnoses in 2005–2010 regarding ischemic heart disease, stroke, transient ischemic attacks, and diabetes were considered established indications. Results A total of 278,205 individuals were analyzed. In individuals aged ≥ 80 and 65–79 years (n = 81,885 and n = 196,320, respectively), 17% (95% confidence interval 17%; 18%) and 23% (23%; 23%) respectively, were statin users. Among the statin users, 74% (73%; 74%) of those aged ≥ 80 and 60% (59%; 60%) of those aged 65–79 years had ≥ 1 established indication. Conversely, of those with ≥ 1 established indication, 30% (30%; 31%) and 53% (52%; 53%) were on statins in the respective age groups. Logistic regression revealed that age, nursing home residence, and multi-dose drug dispensing were the most prominent negative predictors for statin use; adjusted odds ratios (95% confidence interval): 0.45 (0.44; 0.46), 0.39 (0.36; 0.42), and 0.47 (0.44; 0.49), respectively. Conclusions In the oldest old (≥ 80 years), statin users were fewer and had more often an established indication, suggesting that physicians extrapolate scientific evidence for beneficial effects in younger age groups to the oldest, but require a more solid ground for treatment. As the oldest old, nursing home residents, and those with multi-dose drug-dispensing were statin users to a lesser extent, physicians may often refrain from treatment in those with lower life expectancy, either due to age or to severely reduced health status. In both age groups, our results however also indicate some over- as well as undertreatment.

Evaluation of the effects of ontogenetic or maturation functions and chronic heart failure on the model analysis for the dose-response relationship of warfarin in Japanese children Abstract Purpose We previously demonstrated that the rational pediatric dosage of warfarin can be well-described by a SIZE parameter that includes an allometry exponent of weight. On the other hand, allometry alone is considered to be insufficient to predict drug clearance in neonates and infants. The primary purpose of the present study was to evaluate the effects of incorporation of the maturation process into the analysis model for the dose-response relationship of warfarin in Japanese children. In addition, we evaluated the effect of chronic heart failure (CHF) on the response to warfarin as an independent risk factor for increased anticoagulant effects. Methods Thirty-eight patients with stable anticoagulation by warfarin were enrolled. During a mean follow-up period of 4.74 ± 3.51 years, 1092 data points including prothrombin time-international normalized ratio (PT-INR) were obtained. The data were subjected to multiple regression analysis to identify covariates related to the anticoagulant effects. Results Two different models describing the maturation process did not improve the predictive performance for the dose-response relationship in pediatric patients. In addition to the SIZE-normalized daily dose, the vitamin K epoxide reductase complex 1 (VKORC1) genotype, and concomitant use of bosentan, CHF was identified as a covariate increasing the anticoagulant effects of warfarin to 118%. Conclusion The SIZE parameter was useful even without incorporation of maturation models to describe the response to warfarin in pediatric patients, and our longitudinal follow-up study design with multiple observations was beneficial to detect changes within individual subjects.

The effect of neutropenia on the clinical pharmacokinetics of vancomycin in adults Abstract Aim There is accumulating evidence that neutropenic patients require higher dosages of vancomycin. To prevent sub-therapeutic drug exposure, it is of utmost importance to obtain adequate exposure from the first dose onwards. We aimed to quantify the effect of neutropenia on the pharmacokinetics of vancomycin. Methods Data were extracted from a matched patient cohort of patients known with (1) hematological disease, (2) solid malignancy, and (3) patients not known with cancer. Pharmacokinetic analysis was performed using non-linear mixed effects modeling with neutropenia investigated as a binary covariate on clearance and volume of distribution of vancomycin. Results A total of 116 patients were included (39 hematologic patients, 39 solid tumor patients, and 38 patients not known with cancer). In total, 742 paired time-concentration observations were available for the pharmacokinetic analysis. Presence of neutropenia showed to significantly (p = 0.00157) increase the clearance of vancomycin by 27.7% (95% CI 10.2–46.2%), whereas it did not impact the volume of distribution (p = 0.704). Conclusions This study shows that vancomycin clearance is increased in patients with neutropenia by 27.7%. Therefore, the vancomycin maintenance dose should be pragmatically increased by 25% in neutropenic patients at the start of treatment. Since the volume of distribution appeared unaffected, no adjustment in loading dose is required. These dose adjustments do not rule out the necessity of further dose individualization by means of therapeutic drug monitoring.

Reduction of exposure to tacrolimus trough level variability is associated with better graft survival after kidney transplantation Abstract Purpose High tacrolimus trough drug level variability was found to be associated with reduced graft survival. The primary goal of this study was to find whether reduction of exposure to high tacrolimus trough level variability in patients in which previously had high variability was associated with better graft survival. Methods All tacrolimus drug level values in patients that underwent kidney transplantation at our center between 2006 and 2015 were collected. Exposure to variability was calculated using a time-weighted coefficient of variability (TWCV). Time-dependent univariate and multivariate Cox proportional hazard models were used to analyze the primary outcome of graft survival and to determine a cutoff value for TWCV as a predictor of this outcome. Results A total of 878 patients were included in the study with a median follow-up of 1263 days. TWCV above 25% was significantly associated with reduced graft survival (HR3.66, 95% CI 2.3–5.8, p < 0.001). Of the 480 patients (54.7%) who had a cumulative TWCV of > 25% at a certain time during the follow-up, 110 (22.9%) later returned to a cumulative TWCV of less than 25%. Reduction of TWCV to values below 25% was associated with a hazard of graft loss that was not different from patients who had cumulative TWCV of less than 25% during the entire follow-up period (HR 1.81, 95% CI 0.71–4.62, p = 0.218 and HR 1.08, 95% CI 0.39–2.99, p = 0.780) in univariate and multivariate analyses, respectively. Conclusions Monitoring TWCV can help detect the high-risk patients. Interventions intended to reduce variability on long-term graft survival may have a positive effect on graft survival.

Discontinuation of therapy among COPD patients who experience an improvement in exacerbation status Abstract Purpose A subset of patients with chronic obstructive pulmonary disease (COPD) experience a decrease in exacerbation frequency, leading to a diminished need for treatment with inhaled corticosteroids (ICS). We investigated prescribing and discontinuation patterns of long-acting bronchodilators and ICS in COPD patients according to exacerbation frequency. Methods Using the nationwide Danish health registries, we conducted a drug utilization study among patients who had at least two exacerbations or one hospitalization due to an exacerbation during 2011–2012. This study population was stratified according to consistency of exacerbation occurrence after 12, 24, 36, and 48 months of follow-up and the groups were described according to use of ICS, long-acting β2-agonists (LABA), and long-acting anticholinergics (LAMA), and combinations thereof. Results We identified 29,010 COPD exacerbators during 2011–2012. Upon inclusion, 70% received ICS-containing regimens, in combination with LABA (23%) or both LABA and LAMA (41%). The proportion of prevalent users of ICS-containing regimens decreased to 56% during follow-up among exacerbation-free individuals, while it increased to 86% in individuals who experienced at least one exacerbation annually. Persistence to ICS-containing regimens was 58% after 4 years in individuals without exacerbations compared to 74% among those with annual exacerbations. Similar patterns were observed for triple therapy which was the most extensively used drug combination regardless of consistency of exacerbation occurrence. Conclusions The extensive use of ICS and the relatively high persistence to ICS-containing regimens in individuals who had a decrease in exacerbation occurrence highlight a need for the development and implementation of de-escalation strategies in clinical practice.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com