European Journal of Clinical Pharmacology

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Online ISSN: 1432-1041
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Conceivable trajectories of auxiliary pain medication use (concomitant or rescue) during a hypothetical chronic pain trial where study medication (active drug or placebo) is given from baseline (randomization) until the end of the study. The time prior to baseline could be the screening or run-in phase. Use of auxiliary pain medication could be attributable to the randomized treatment such as pain reduction due to active drug, or non-attributable, such as spontaneous improvement or deterioration over time. Patient I: No change. Patient II: Reduced early during the treatment phase. Patient III: Reduced early, but later increased during the treatment phase. Patient IV: Reduced late during the treatment phase. Patient V: Continued but variable use prior to randomization and throughout the study. Patient VI: Gradual decreased over the course of the study. Patient VII: Intermittent prior to and throughout the study. Patient VIII: Gradual increase over the course of the study. Patient IX: Increased early during the treatment phase. Patient X: Increased late during the treatment phase. Patient XI: Brief intermittent use
Directed acyclic graph (DAG) visualizing the causal effects of a randomized treatment (A0) on pain intensity at end-of-study (Y), partly going through the combination of post-randomization auxiliary medication use (M1) and intermediate treatment (A1). In this setting, auxiliary pain medication use is an intercurrent event (APMICE). The randomized treatment (A0) influences post-randomization pain (L1), which again influences later auxiliary pain medication use (M1), and possibly treatment adherence (A1). Note that post-randomization pain (L1) and auxiliary medication use (M1) here are time-dependent confounders for the effect of intermediate treatment (A1) on the outcome (Y). Note also that in reality, L could also include other factors than pain, such as drug-related adverse events. To estimate the de jure effect, the influence of any APMICE must be accounted for in the analysis, but simply adjusting for (conditioning on) APMICE is inappropriate. Over time, auxiliary pain medication plays both the role of a confounder, collider and a mediator. For such a time-dependent confounder, standard methods for confounding adjustment are inappropriate [15]. For example, since M1 is an intermediate in the chain between exposure and outcome, conditioning on it would block the effect of any past exposure on Y that goes through M1, resulting in over-adjustment bias [16]. Also, as M1 is a collider on the path A0 → L1 → M1 ← U → Y, adjustment for this variable would open the previously blocked path via unobserved (U) common causes of M1 and Y, introducing selection bias because of collider stratification [17]. The unobserved confounders (U) could, for example, be prior experience with pain medication or pain-related beliefs. To make the illustration clearer, the DAG is simplified to a setting with two time points, and certain variables, such as baseline auxiliary pain medication, are omitted
Article
Chronic pain trials commonly allow auxiliary pain medications such as rescue and concomitant analgesics in addition to the randomized treatment. Changes in auxiliary pain medications after randomization represent intercurrent events that may affect either the interpretation or the existence of the measurements associated with the clinical question of interest, complicating the assessment of treatment efficacy. In chronic pain trials, pain intensity typically varies and patients may take the auxiliary medications 1 day but not the next or increase and decrease the dosages temporarily while continuing their randomized study medication. This distinctive feature of auxiliary pain medications as an intercurrent event has received little attention in the literature. Further clarifications on how to manage these issues are therefore pressing. Here we provide perspectives on issues related to auxiliary pain medication-related intercurrent events in randomized controlled chronic pain trials considering the strategies suggested in the E9(R1) addendum to the ICH guideline on statistical principles for clinical trials.
 
Flowchart of the study population 2009–2015
Proportion of high-intensity treatment, i.e., either atorvastatin ≥ 40 mg or rosuvastatin ≥ 20 mg, initiated over the study years (2009–2915), by the setting of the initiating prescriber
Article
Purpose To investigate the prevalence and initiation of statins as well as treatment intensity in the oldest old, with younger olds as a reference. Methods A population-based cohort was used, including record-linked data from the Total Population Register, the Swedish Prescribed Drug Register, and the Swedish Patient Register. In each year over the study period (2009–2015), statin use was described in individuals 85 years or older and 65–84 years of age, and initiation rates were calculated among individuals with no statin treatment during a preceding 3-year period. Results A total of 1,764,836 individuals ≥ 65 years in 2009, increasing to 2,022,764 in 2015, were included in the analyses. In individuals 85 years or older, the prevalence of statin therapy increased from 11% in 2009 to 16% in 2015, the corresponding initiation rates being 1.3% and 1.7%, respectively. Corresponding prevalence and incidence figures in 65–84-year-olds were 23 to 25% and 3.0 to 3.3%, respectively. Overall, the proportion of individuals initiating statin with high-intensity treatment (atorvastatin ≥ 40 mg or rosuvastatin ≥ 20 mg) in the oldest old increased from 1 to 36% during the study period, and a similar increase was seen in the younger age group. Over the study years, the presence of an established indication for statin treatment varied between 70 and 76% in the oldest old and between 30 and 39% in the younger olds. Conclusion Prevalence and initiation of statin therapy are increasing among the oldest old, despite the fact that randomized controlled trials focusing on this age group are lacking and safety signals are difficult to detect.
 
Article
Objective Adverse Drug Reactions (ADR) add a significant clinical and economic burden to the healthcare system of a country. We present an overview of the different approaches of ADR reporting systems worldwide and their evolution over time. Methods A systematic review of the literature was made based on PubMed and the Cochrane database of systematic reviews. The articles searched for included original articles, WHO and FDA reports and institute of medicine reports. Summary Reporting ADRs is the cornerstone of detecting uncommon ADRs once the drugs are on the market. In many countries, ADR reporting is regulated by national regulatory bodies and various methods are employed to report ADRs. Direct reporting by healthcare professionals has been adopted by many developed and developing countries. With emerging new technologies in the field of medicine, there is a great potential to develop better ADR reporting systems in the countries where they have poor reporting. Conclusion Development and acquisition of newer technologies to promote ADR monitoring and reporting is a necessity for an effective pharmacovigilance system in a country.
 
Article
Purpose The aim of this study was to analyze the clinical characteristics of fatal adverse events (AEs) of rivaroxaban combined with aspirin and to underline the importance of the rational use of drugs. Methods The WHO global database of reported potential side effects of medicinal products (VigiBase) was searched for fatal AEs in the combined use of rivaroxaban and aspirin, and the clinical characteristics of those cases with sufficient information (vigiGrade completeness score ≥ 0.80) were analyzed. Results By January 19, 2020, 2309 fatal adverse event reports of rivaroxaban combined with aspirin from 21 countries were entered in VigiBase. One hundred and twenty cases contained further information, of which 42 were female (35%) and 78 were male (65%). The median age was 75 (range 34 to 93) years, and 109 cases (91%) were elderly patients (≥ 65 years). The AEs listed in the fatal case reports included bleeding in 114 cases (mainly intracranial hemorrhage and gastrointestinal hemorrhage, 59 and 46 respectively, accounting for 88%) and ischemic events in six cases (ischemic stroke in three, acute myocardial infarction in two, myocardial infarction combined with acute liver failure in one). Among the patients with bleeding events, 108 (95%) had existing risk factors for bleeding or for interacting with aspirin or rivaroxaban. These may be divided into the following: diseases (hypertension, renal impairment, history of stroke, peptic ulcer, or previous bleeding), drugs (high dose aspirin, antiplatelet drugs, anticoagulants, P-gp inhibitors/CYP3A4 inhibitors, non-steroidal anti-inflammatory drugs, steroids, and selective serotonin reuptake inhibitors), or other factors (e.g., elderly, low body weight, or excessive intake of ginger, fish oil, or alcohol). There were 45 cases with two or more of these risk factors in addition to rivaroxaban and aspirin. Patients with ischemic events are often in very high-risk groups of atherosclerotic cardiovascular disease (ASCVD) or self-discontinuation of treated drugs. Medication errors occurred in 24 patients (20%): excessive treatment in 17 cases, contraindication in three, frequency error in two, excessive treatment combined with contraindication in one, and self-discontinuation in one. Conclusions Fatal AEs related to rivaroxaban combined with aspirin, including bleeding and ischemic events, have been reported mostly in the elderly, and sometimes involved medication errors. The fatal AEs mainly manifested as serious bleeding, and most of them occurred in patients with concurrent multiple risk factors. Monitoring coagulation during rivaroxaban treatment is recommended in very high-risk ASCVD populations, and attention should be paid to prevention of medication errors.
 
Flowchart of the study participants
Frequency of anticholinergic burden evaluated by the Anticholinergic Cognitive Burden (ACB) Scale (n = 13,065)
Article
Objectives Using multiple drugs with anticholinergic properties is common and might lead to cumulative anticholinergic toxicity and increased risk of cognitive impairment. Therefore, we sought to investigate the association between the Anticholinergic Cognitive Burden (ACB) Scale and cognitive performance among middle-aged and older adults. Methods In this cross-sectional study with 13,065 participants from the baseline visit of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil), mean age was 51.7 ± 9.0 years old, 55% women, and 53% white. The ACB was calculated based on the medications in use. We investigated the association of ACB with global cognition and memory, verbal fluency (VF), and trail-making test version B (TMT-B) z-scores, using multiple linear regression models adjusted for sociodemographic and clinical variables. Results Overall, 16% of participants had an ACB score greater than 0. ACB was associated with poor cognitive performance in all tests in crude analysis. After adjustment for sociodemographic characteristics, the association remained significant for the global cognitive score, as well as the memory and the TMT-B z-scores. However, after further adjustments for clinical variables, only trend associations of ACB with poor memory (β = − 0.02, 95% Cl = − 0.05, 0.00, p = 0.056) and the TMT-B z-scores (β = − 0.02, 95% Cl = − 0.04, 0.00, p = 0.054) were found. In stratified analyses by age groups, ACB was associated with poor cognitive performance on the TMT-B (β = − 0.03, 95% Cl = − 0.05, − 0.01, p = 0.005) in individuals aged less than 65 years old. Conclusion Although the ACB was associated with poor executive function only among middle-aged adults in adjusted analysis, residual confounding may partly explain our results.
 
Visual predictive check (VPC) of the external data set for candidate models (A-F). Black dots represent observed concentrations, red solid line is the median of observed concentrations, blue solid lines are the 5th and 95th percentiles of observed concentrations, and shaded areas represent confidence intervals around simulation percentile
Distribution of NPDE for model F. A Quantile–quantile graph of standard normal distribution. B Histogram and density of the NPDE distribution (red lines: distribution trend of NPDE; black dashed lines: density of the normal distribution). C Scatter plot of NPDE to population prediction value
Predictive performance of different number of samples. A: Plot of the prediction was based on one observation (dashed lines: PE % = ±30). B: Plot of the prediction was based on two observations (dashed lines: PE % = ±30)
Article
Objectives Patients with hematological malignancies are prone to invasive fungal disease due to long-term chemotherapy or radiotherapy. Voriconazole is a second-generation triazole broad-spectrum antibiotic used to prevent or treat invasive fungal infections. Many population pharmacokinetic (pop PK) models have been published for voriconazole, and various diagnostic methods are available to validate the performance of these pop PK models. However, most of the published models have not been strictly evaluated externally. The purpose of this study is to evaluate these models externally and assess their predictive capabilities. Methods The external dataset consists of adults receiving voriconazole treatment at Fujian Medical University Union Hospital. We re-established the published models based on their final estimated values in the literature and used our external dataset for initial screening. Each model was evaluated based on the following outcomes: prediction-based diagnostics, prediction- and variability-corrected visual predictive check (pvcVPC), normalized prediction distribution errors (NPDE), and Bayesian simulation results with one to two prior observations. Results A total of 237 samples from 166 patients were collected as an external dataset. After screening, six candidate models suitable for the external dataset were finally obtained for comparison. Among the models, none demonstrated excellent predictive performance. Bayesian simulation shows that all models’ prediction precision and accuracy were significantly improved when one or two prior concentrations were given. Conclusions The published pop PK models of voriconazole have significant differences in prediction performance, and none of the models could perfectly predict the concentrations of voriconazole for our data. Therefore, extensive evaluation should precede the adoption of any model in clinical practice.
 
Article
Purpose Benzodiazepines (BZD), Z-drugs (ZD), and opioids share a high risk of abuse. This study assessed and characterised adverse events (AEs) related to BDZ, ZD, and opioids leading to emergency department (ED) visits in the Italian setting. Methods ED accesses related to BDZ, ZD, and/or opioids were analysed from the MEREAFaPS database. Information on AEs, suspected and concomitant medications was retrieved. Multivariate logistic regression was used to estimate the reporting odds ratios (RORs) of hospitalisation according to the different treatments. Results A total of 5,970 pharmacovigilance reports involving BZD/ZD (n = 3,106), opioids (n = 2,767), or their combination (n = 97) were analysed. Compared to opioids, patients with BZD/ZD-related AEs were often younger (51 vs 64 years), more frequently presented 2+ suspected medications (13 vs 3%), and often had a history of abuse (4%). Twenty-three percent of BZD/ZD-related AEs were related to drug abuse (vs 2% of opioid-related ones) and frequently required patient hospitalisation (52% vs 24%), despite the significantly lower clinical complexity of these patients as compared to those on opioids. An increased risk of hospitalisation was found for flurazepam (ROR 1.62; 95% CI, 1.18–2.22), prazepam (2.66; 1.05–6.70), lorazepam (1.26; 1.07–1.49), and morphine (1.76; 1.11–2.79). Conclusions These results indicate that, in Italy, the inappropriate use of BZD/ZD is a relevant heath issue, often leading to serious AEs requiring patients’ ED visits and hospitalisation, especially in young women and patients with a history of substance abuse.
 
Article
This editorial describes the clinical trials related to antidiabetic drugs, most of them following an “add-on” design of where the new drug is added to metformin and the comparative arm is metformin plus placebo. Many drugs are already approved for therapy following this design; the authors believe that it is unethical to continue this trend because it makes it impossible to stratify the many antidiabetic drugs according to their efficacy and toxicity.
 
Results of a meta-analysis of aspirin use on COVID-19 mortality
Article
Purpose The coronavirus disease 2019 (COVID-19) pandemic has shown unprecedented impact world-wide since the eruption in late 2019. Importantly, emerging reports suggest an increased risk of thromboembolism development in patients with COVID-19. Meanwhile, it is found that aspirin reduced mortality in critically ill patients with non-COVID-19 acute respiratory distress syndrome. Therefore, a meta-analysis was performed to investigate the effects of aspirin on COVID-19 mortality. Methods A systematic literature search was conducted in 10 electronic databases and 4 registries. Random effects models were used to calculate pooled relative risks (RRs) with 95% confidence intervals (Cis) to estimate the effect of aspirin on COVID-19 mortality. Relevant subgroup analyses and sensitivity analyses were also performed. Results The results showed that aspirin use was associated with a reduction in COVID-19 mortality (adjusted RR 0.69; 95% CI 0.50–0.95; P < 0.001). Subgroup analysis found that the low-dose group was associated with a reduced COVID-19 mortality (adjusted RR 0.64; 95% CI 0.48–0.85; P < 0.01). Aspirin use was associated with reduced COVID-19 mortality in Europe and America (crude RR 0.71; 95% CI 0.52–0.98; P = 0.04), and results from cohort studies suggested that aspirin use was a protective factor for COVID-19 mortality (adjusted RR 0.73; 95% CI 0.52–0.99; P = 0.04). Meanwhile, aspirin use was not associated with bleeding risk (crude RR 1.22; 95% CI 0.80–1.87; P = 0.96). Conclusions This meta-analysis found that aspirin use was associated with a reduction in mortality in patients with COVID-19 and not with an increased risk of bleeding.
 
Flow diagram of search strategy and study selection based on PRISMA
Forest plots for primary safety outcomes comparing oral CGRP receptor antagonist group and placebo group
Forest plots for primary safety outcomes comparing oral CGRP receptor antagonist group and triptan group
Forest plots for any adverse event to compare ubrogepant across different dosages (range from 1 to 100 mg) and placebo
Article
Objective Calcitonin gene-related peptide (CGRP) receptor antagonists have been suggested as novel treatments for acute migraine. This study aimed to use meta-analysis to compare the safety and tolerability of five existing oral CGRP receptor antagonists (BI44370TA, MK-3207, rimegepant, telcagepant, and ubrogepant) with that of a placebo or triptans against acute migraine. Methods Five prominent databases were searched to identify randomized controlled trials on this topic. The primary safety outcomes of interest were any adverse events (AEs) and treatment-related adverse events (TRAEs), and secondary outcomes were individual events, namely diarrhea, dizziness, dry mouth, fatigue, nausea, paresthesia, somnolence, upper abdominal pain, and vomiting. Results Fifteen studies met the eligibility criteria and were examined in detail. Although, compared to placebo, oral CGRP receptor antagonists significantly increased the incidence of any AEs (risk ratio [RR] = 1.15; 95% confidence interval [CI] = 1.07–1.23), there was no difference in the incidence of TRAEs (RR = 1.18; 95% CI = 1.00–1.38). Moreover, CGRP receptor antagonists were safer than triptans with respect to primary safety outcomes, such as any AEs (RR = 0.78; 95% CI = 0.63–0.98) and TRAEs (RR = 0.68; 95% CI = 0.58–0.79). Conclusion Despite oral CGRP receptor antagonists posing a significantly higher risk of AEs when compared to placebo, CGRP receptor antagonists have a favorable safety profile compared to triptans. Our findings inform strategies to enhance safety and tolerability in the treatment of acute migraine.
 
Article
Background To date, no study has identified a clear relationship between drug and a specific clinical presentation of DRESS. Objectives To investigate the particularities of DRESS and analyze the variation of DRESS pattern according to culprit drugs. Methods We analyzed cases of DRESS notified to the Department of Clinical Pharmacology at the University Hospital of Monastir over a 15-year period. The statistical study was performed using the comparative and multivariate analysis. Results DRESS was mostly induced by anticonvulsive agents (27%) followed by allopurinol (26.3%) and antibiotics (24%): For anticonvulsive agents, the occurrence of lymphadenopathy was higher, renal involvement was rare and mild, and positive skin tests were more frequent. The allopurinol group was associated with the patient’s older age and a lower incidence of lymphadenopathy and kidney injury. For antibiotics, eosinophilia rate was lower, time to recovery was shorter, and RegiSCAR score was low. The multivariate analysis showed a link of allopurinol with severe renal impairment, antibiotics with short latency period and low RegiSCAR score, and anticonvulsants with high propensity of positive skin test. Conclusion We report the largest African and south Mediterranean cohort of DRESS and evaluated the usefulness of skin tests in identifying the culprit drug. The prominent finding was that latency period and renal involvement may independently differ according to culprit drugs.
 
Dose reductions in renal impairment. The number of hospitals that did resp. did not apply LMHW dose reduction, categorised by LMWH type and by eGFR cutoff value. LMWH doses were reduced at certain eGFR cutoff values and below. DR, dose reduction. The number of hospital regimens exceeds the aforementioned 56 hospitals, as there are a number of hospitals that uses multiple LMWHs
Anti-Xa monitoring in renal impairment. The number of hospital regimens that did or did not apply anti-Xa monitoring, categorised by LMWH type and by renal function. No anti-Xa, no anti-Xa monitoring. Unknown: Three hospitals reported that they monitor anti-Xa, but an eGFR cutoff value was not noted. The number of hospital regimens exceeds the aforementioned 56 hospitals, as there are a number of hospitals that use multiple LMWHs
Overview treatment regimens per LMWH. An overview of the treatment regimens per LMWH is shown. DR, dose reduction; eGFR, estimated glomerular filtration rate; ISTH, International Society of Thrombosis and haemostasis; ASH, American Society of Haematology; ESC, European Society of Cardiology; ACCP, American College of Chest Physicians; BCSH, British Society for Haematology; SIGN, Scottish Intercollegiate Guidelines Network; NfN, Dutch Federation of Nephrology; NIV, Dutch Internists Association; KNMP, Royal Dutch Pharmacists Association * Three hospitals reported to monitor anti-Xa, but an eGFR cutoff value was not noted. The number of hospitals exceeds the aforementioned 56, as a number of hospitals use multiple LMWHs
Article
Purpose International guidelines vary in their recommendations whether or not to reduce the therapeutic dose of low molecular weight heparins (LMWHs) in renal impairment. The use of anti-Xa monitoring as a basis of dose adjustments is also a matter of debate. As this may lead to variations in treatment policies, we aimed to study the treatment policies of therapeutically dosed LMWHs in renal impairment in Dutch hospitals. Methods An 11-item survey was distributed between June 2020 and March 2021 to hospital pharmacists, representing Dutch hospital organisations. Primary outcomes were the dosing regimens of therapeutically dosed LMWHs in renally impaired patients. Secondary outcomes were the proportion of hospitals that used anti-Xa monitoring and the anti-Xa target range used. Results There was a response from 56 of 69 (81%) Dutch hospital organisations where in each case a hospital pharmacist completed the survey. In these hospitals, 77 LMWH regimens were in use. In 76 of 77 (99%) regimens, a regular dose reduction was used at the start of treatment. Fifty-five of these hospitals used a dose reduction if estimated glomerular filtration rate (eGFR) < 50 ml/min and 17 used a dose reduction if eGFR < 30 ml/min. Anti-Xa levels were not routinely monitored in 40% of regimens, while 22% monitored anti-Xa if eGFR < 50 ml/min, 27% if eGFR < 30 ml/min and 10% in other eGFR cutoff values. Target ranges of 1.0–2.0 IU/ml (once daily) and 0.5/0.6–1.0 IU/ml (twice daily) were used in 69% of regimens that included monitoring of anti-Xa. Conclusion Treatment policies show substantial diversity in therapeutically dosed LMWHs in renally impaired patients. The most commonly used treatment regimen was a regular dose reduction if eGFR is < 50 ml/min, without anti-Xa monitoring.
 
Simulated drug concentration–time curve M1 after the administration of IV FPC 6.5 mg for 4 h in healthy subjects, M2 after the administration of FPC 6.5 mg for 4 h via dialysate in patients with CKD-5HD, and M3 after the pre-dialyzer administration of FPC 6.5 mg for 3 h in patients with CKD-5HD. CKD-5HD, hemodialysis-dependent stage 5 chronic kidney disease; IV, intravenous; LBM, lean body mass
Goodness of fit of FPC in (M1) IV model of healthy subjects, (M2) dialysate model of patients with CKD-5HD, and (M3) pre-dialyzer model of patients with CKD-5HD. Blue circles represent observed or model-predicted data points; black lines represent the line of unity or horizontal line with y = 0; and red lines represent the regression lines. CWRES, conditional weighted residuals; CKD-5HD, hemodialysis-dependent stage 5 chronic kidney disease; IV, intravenous
Visual predictive check of FPC in A IV model of healthy subjects, B dialysate model of patients with CKD-5HD, and C pre-dialyzer model of patients with CKD-5HD. Blue circles represent observed values; blue solid lines and red solid line represent 5th, 95th, and 50th percentiles of the observed data; blue and red shaded areas represent the model-predicted 95% confidence interval for the 5th, 95th, and 50th percentiles. CKD-5HD, hemodialysis-dependent stage 5 chronic kidney disease; IV, intravenous
Article
Purpose To evaluate the potential ethnic differences of ferric pyrophosphate citrate (FPC, Triferic) in healthy subjects and patients with hemodialysis-dependent stage 5 chronic kidney disease (CKD-5HD) and identify covariates that may influence pharmacokinetics (PK) of FPC. Methods Data were collected from 2 Asian and 4 non-Asian clinical studies involving healthy subjects and CKD-5HD patients. Three population PK models were developed: M1 for intravenous (IV) administration of FPC in healthy subjects; M2 for dialysate administration of FPC in CKD-5HD patients; M3 for pre-dialyzer administration of FPC in CKD-5HD patients. All the models were fitted to concentration versus time data of FPC using the nonlinear mixed effect approach with the NONMEM® program. All statistical analyses were performed using SAS version 9.4. Results In total, 26 Asians and 65 non-Asians were included in the final model analysis database. Forty healthy subjects were administered FPC via intravenous (IV) route and 51 patients with CKD-5HD via dialysate (N = 50) and pre-dialyzer blood circuit administration (N = 51). The PK parameters of FPC IV were similar. The population PK model showed good parameter precision and reliability as shown by model evaluation, and no relevant influence of ethnicity on PK parameters was observed. In healthy subjects, the maximum observed plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) decreased with increase in lean body mass (LBM) and the average serum total iron at 6 h before the baseline period (Feav), whereas, in both patient populations, Cmax and AUC decreased with increase in LBM and decrease in Febaseline. Other factors such as gender, age, Feav, and ethnicity had no influence on PK exposures in patients. The influence of LBM on PK exposures in patients was smaller than that in healthy subjects (ratio of AUC0-24 for the 5th [68 kg] and 95th [45 kg] patient’s LBM was almost 1). The influence of Feav and LBM on PK exposures was < 50%. Conclusion The population pharmacokinetics model successfully described the PK parameters of FPC in healthy subjects and CKD-5HD patients and were comparable between Asian and non-Asian populations.
 
Description of treatment intensification done during a 5-year course of hypertension therapy at selected public hospitals in Southern Ethiopia
Affordability of antihypertensive drugs used at the outpatient department at selected public hospitals in Southern Ethiopia
Article
Purpose: To determine the impact of drug prescribing pattern, outpatient drug price of medicines, and level of adherence to evidence-based international guidelines on blood pressure (BP) control at selected hospitals in Southern Ethiopia. Methods: Hospital-based cross-sectional study was conducted. The data entry and analysis were done by using SPSS version 21.0. Results: A mean age of participants was 55.87 ± 11.02 years. The rate of BP control was 17.5% based on International Society of Hypertension (ISH) guidelines 2020. In about two-thirds of patients, 270 (66.5%) were taking combination therapy. Mean annual cost of drugs for hypertension was 11.39 ± 3.98 US dollar (USD). Treatment was affordable for only 91 (22.4%) of patients. There was considerable variation on prescriber's adherence to evidence-based guidelines. Body mass index (BMI) of 18-24.9 kg/m 2 , adjusted odds ratio (AOR) = 3.63 (95% confidence interval (C.I), 1.169-11.251, p = 0.026), physically activity, AOR = 12.69 (95% C.I, 1.424-113.17, p = 0.023), presence of no comorbidity, AOR = 12.82 (95% C.I, 4.128-39.816, p = 0.000), and taking affordable antihypertensive regimen, AOR = 3.493 (95% C.I, 1.4242-9.826, p = 0.018), were positively associated BP control. Conclusion: The level of BP control, affordability of drugs for the management of hypertension and related comorbidities, and the prescriber's adherence to evidence-based guidelines were inadequate. Therefore, addressing factors associated with good BP control including affordability and clinician adherence to evidence-based guidelines by responsible stakeholders could improve BP control and reduce associated complications.
 
Number of opioid users/year (grey dashed line) and total use of opioids measured in milligram OMEQ per 1000 individuals per day (black line) in the 5 years before KR among 77,168 patients with severe knee OA
Total use of opioids measured in milligram OMEQ per 1000 individuals per day in the 5 years before KR stratified by type of opioid among 77,168 patients with severe knee OA
Lorenz curve illustrating the distribution of opioid use among 77,168 patients with severe knee OA. The curve denotes the cumulative proportion of the study population against the cumulative opioid used in OMEQ of the patients at or below that percentile
Article
Purpose Knee osteoarthritis (OA) is one of the most common musculoskeletal diseases. Opioids have been increasingly used in the treatment of severe knee OA-related pain, particularly in the USA. Less is known about the patterns of use of opioids among Danish patients with severe knee OA. We investigated opioid use among Danish patients with severe knee OA in the 5 years preceding knee replacement surgery (KR). Methods We identified adults who had undergone KR from January 1st, 2005, to December 31st, 2018, using the Danish National Patient Register. These patients were considered to have severe knee OA in the 5-year period leading up to KR. Individual-level data on prescribed opioids were retrieved from the Danish National Prescription Registry. Results We identified 77,168 severe knee OA patients (mean age 66 years). The prevalence of opioid users increased from 21% 5 years before KR to 40% 1 year before. Total use of opioids increased each year and doubled from 3254 mg oral morphine equivalents (OMEQ)/1000 individuals/day 5 years before to 6396 mg OMEQ/1000 individuals/day the year before KR corresponding to an increase of 3141 mg OMEQ (95% confidence interval 3010 to 3273). Tramadol was the most frequently used opioid. About 10% of the population accounted for 90% of the total opioid use. Conclusion Among patients with severe knee OA, the prevalence and total use of opioids doubled during the 5 years before KR. In addition, 10% of the study population was responsible for 90% of the opioids used.
 
Article
Purpose To develop a mathematical model combined between physiologically based pharmacokinetic and BTK occupancy (PBPK-BO) to simultaneously predict pharmacokinetic (PK) and pharmacodynamic (PD) changes of acalabrutinib (ACA) and active metabolite ACP-5862 in healthy humans as well as PD in patients. Next, to use the PBPK-BO to determine the optimal dosing regimens in patients alone, with different CYP3A4 variants, when co-administration with four CYP3A4 modulators and in patients with hepatic impairment, respectively. Methods The PBPK-BO model was built using physicochemical and biochemical properties of ACA and ACP-5862 and then verified by observed PK and PD data from healthy humans and patients. Finally, the model was applied to determine optimal dosing regimens in various clinical situations. Results The simulations demonstrated that 100 mg ACA twice daily (BID) was the optimal dosing regimen in patients alone. Additionally, dosage regimens might be reduced to 50 mg BID in patients with five CYP3A4 variants. Moreover, the dosing regimen should be modified to 100 mg (even to 50 mg) once daily (QD) when co-administration with erythromycin or clarithromycin, and be increased to 200 mg BID with rifampicin, and but be avoided co-administration with itraconazole. Furthermore, dosage regimen simulations showed that optimal dosing might be decreased to 50 mg BID in patients with mild and moderate hepatic impairment, and be avoided taking ACA in severely hepatically impaired patients. Conclusion This PBPK-BO model can predict PK and PD in healthy humans and patients and also predict the optimal dosing regimens in various clinical situations.
 
Trial flow diagram
Histological analysis of inflammatory cells within thrombi. A Representative histologic transverse sections stained with hematoxylin and eosin illustrate the presence of inflammatory cells within thrombi. Scar bar: 0.1 mm. B The numbers of inflammatory cells per mm² thrombus area were calculated (clopidogrel group: n = 24; ticagrelor group: n = 23). Data are presented as mean ± standard deviation and analyzed by t tests
Immunohistochemical analysis of neutrophils, MPO-positive cells, and monocytes within thrombi. A Representative immunohistochemical transverse sections stained with CD11b illustrate the presence of neutrophils within thrombi. Scar bar: 0.1 mm. B The numbers of neutrophils per mm² thrombus area were calculated (clopidogrel group: n = 24; ticagrelor group: n = 23). Data are presented as mean ± standard deviation and analyzed by t tests. C Representative immunohistochemical transverse sections stained with MPO illustrate the presence of MPO-positive cells within thrombi. Scar bar: 0.1 mm. D The numbers of MPO-positive cells per mm² thrombus area were calculated (clopidogrel group: n = 24; ticagrelor group: n = 23). Data are presented as mean ± standard deviation and analyzed by t tests. E Representative immunohistochemical transverse sections stained with CD14 illustrate the presence of monocytes within thrombi. Scar bar: 0.1 mm. F The numbers of CD14-positive cells per mm² thrombus area were calculated (clopidogrel group: n = 24; ticagrelor group: n = 23). Data are presented as mean ± standard deviation and analyzed by t tests. G The ratio of CD14-positive cells number higher than 250 per mm² thrombus area were calculated (clopidogrel group: n = 24; ticagrelor group: n = 23). Data were analyzed by χ² tests
The concentration of hs-CRP. The serum concentration of hs-CRP was detected before and 24 h after PCI (clopidogrel group: n = 24; ticagrelor group: n = 23). Data are presented as mean ± standard deviation and analyzed by t tests
Article
Background Ticagrelor provides more rapid, potent, and consistent anti-platelet efficacy than clopidogrel. This randomized trial aimed to evaluate the anti-inflammation effects of ticagrelor versus clopidogrel on thrombus aspirated from the ST-elevation myocardial infarction (STEMI) patients. Method A total of 98 patients with STEMI and intended percutaneous coronary intervention (PCI) were randomly assigned to receive clopidogrel (600-mg loading dose) or ticagrelor (180-mg loading dose), of whom 55 with large thrombus burden underwent thrombus aspiration during PCI. Thrombus specimens were successfully aspirated from 49 patients. Finally, 24 patients in the clopidogrel group and 23 in the ticagrelor group completed the study. Inflammatory cells within thrombi were assessed by hematoxylin–eosin and immunohistochemistry stainings. Results Compared with the clopidogrel group, the number of total inflammatory cells per mm² thrombus area in the ticagrelor group was decreased by 28% (P = 0.009). The numbers of neutrophils and myeloperoxidase-positive cells per mm² thrombus area in the ticagrelor group were respectively decreased by 35% (P = 0.016) and 28% (P = 0.047), as compared with those in the clopidogrel group. Moreover, ticagrelor treatment reduced the ratio of monocytes number higher than 250 per mm² thrombus area compared with clopidogrel treatment (4% versus 29%, P = 0.048). Conclusion In patients with undergoing PCI for STEMI, the loading dose ticagrelor regimen was associated with a reduction in inflammatory cell infiltration within thrombus compared with the loading dose clopidogrel regimen.
 
PRISMA flow diagram
Article
Purpose The absence of specific treatments for COVID-19 leads to an intense global effort in the search for new therapeutic interventions and better clinical outcomes for patients. This review aimed to present a selection of accepted studies that reported the activity of antidepressant drugs belonging to the selective serotonin receptor inhibitor (SSRI) class for treating the novel coronavirus. Methods A search was performed in PubMed and SciELO databases using the following search strategies: [(coronavirus) OR (COVID) OR (SARS-CoV-2) AND (antidepressant) OR (serotonin) OR (selective serotonin receptor inhibitors)]. In the end, eleven articles were included. We also covered information obtained from ClinicalTrials.gov in our research. Results Although several clinical trials are ongoing, only a few drugs have been officially approved to treat the infection. Remdesivir, an antiviral drug, despite favorable preliminary results, has restricted the use due to the risk of toxicity and methodological flaws. Antidepressant drugs were able to reduce the risk of intubation or death related to COVID-19, decrease the need for intensive medical care, and severely inhibit viral titers by up to 99%. Among the SSRIs studied so far, fluoxetine and fluvoxamine have shown to be the most promising against SARS-CoV-2. Conclusion If successful, these drugs can substantially reduce hospitalization and mortality rates, as well as allow for fully outpatient treatment for mild-to-moderate infections. Thus, repositioning SSRIs can provide benefits when faced with a rapidly evolving pandemic such as COVID-19.
 
Article
Purpose Transcatheter aortic valve replacement (TAVR) is increasingly carried out in patients with aortic valvular conditions. Atrial fibrillation (AF) is a common comorbidity among patients undergoing TAVR. Despite this, there remains a paucity of data and established guidelines regarding anticoagulation use post-TAVR in patients with AF. Methods Four databases were searched from inception until 12 October 2021. A title and abstract sieve, full-text review and data extraction were conducted by independent authors, and articles including patients without AF were excluded. The Review Manager (Version 5.4) was utilised in data analysis. Results A total of 25,199 post-TAVR patients with AF were included from seven articles, with 9764 patients on non-vitamin K antagonist oral anticoagulants (NOAC) and 15,435 patients on vitamin K antagonists (VKA). In this analysis, there was a significantly lower risk of all-cause mortality at 1 year (RR: 0.75, CI: 0.58–0.97, p = 0.04, I² = 56%), and bleeding at 1 year (RR: 0.73, CI: 0.68–0.79, p = < 0.00001, I² = 0%), between patients on NOAC and VKA. There were no detectable differences between patients on NOAC and VKA for all-cause mortality at 2 years, stroke within 30 days, stroke within 1 year, ischaemic stroke at 1 year and life-threatening bleeding at 30 days. Conclusion While the results of this analysis reveal NOAC as a potential alternate treatment modality to VKA in post-TAVR patients with AF, further research is needed to determine the full safety and efficacy profile of NOAC (PROSPERO: CRD42021283548).
 
Article
Management and dose adjustment are a major concern for clinicians in the absence of specific clinical outcome data for patients on antiepileptic drugs (AEDs), in the event of short-term (5 days) nirmatrelvir/ritonavir co-exposure. Therefore, in this report, we identified drugs that require dose adjustment because of drug-drug interactions (DDIs) between nirmatrelvir/ritonavir and AEDs. We hereby used four databases (Micromedex Drug Interaction, Liverpool Drug Interaction Group for COVID-19 Therapies, Medscape Drug Interaction Checker, and Lexicomp Drug Interactions) and DDI-Predictor. In the light of applying the DDI-Predictor; for carbamazepine, clobazam, oxcarbazepine, eslicarbazepine, phenytoin, phenobarbital, pentobarbital, rufinamide, and valproate as CYP3A4 inducers, we recommend that a dose adjustment of short-term nirmatrelvir/ritonavir as a substrate (victim) drug would be more appropriate instead of these AEDs to avoid impending DDI-related threats in patients with epilepsy.
 
Responses of patients to ELT over time. The Venn diagrams show the number of patients with three series responses at 1 month after ELT onset, A at the time when plasma concentration was determined, and B at the time of the last follow-up
The distribution of ELT concentrations with different genotypes. The influence of gene polymorphisms on ELT concentrations. #p < 0.05 vs. WT; *p < 0.05 vs. others. Data were presented as mean ± SD. WT, wild type; Var: variant
Article
Purpose Eltrombopag (ELT) is an effective drug for relapsed/refractory aplastic anemia (AA). Our previous study showed that ELT concentration was correlated with the effects of ELT. However, the factors affecting ELT concentration in patients with relapsed/refractory AA were not clarified. Therefore, we aimed to evaluate correlations between drug disposition–related gene polymorphisms and the concentration, efficacy, and toxicity of ELT. Methods Forty-five patients who underwent ELT administration from January 2018 to January 2019 at Peking Union Medical Colleague Hospital (PUMCH) were included. The corresponding clinical information was also collected. ELT plasma concentrations were detected by high-performance liquid chromatography-mass spectrometry (HPLC/MS). CYP2C8, (UGT)1A1, and ABCG21 were genotyped by polymerase chain reaction (PCR). The influence of gene polymorphisms on the plasma concentration, efficacy, and toxicity of ELT was analyzed. Results The mean dose required to obtain the optimal effects was significantly lower in the UGT1A1*6 variant carriers than in the UGT1A1*6 WT carriers. There was a significant correlation between the (UGT)1A1*6 polymorphism and higher ELT plasma concentrations (> 11.2 μg/mL). By logistic regression analysis, the efficacy of ELT was related to plasma concentration and a combined genotype of (UGT)1A1*6 and ABCG2. There were no significant associations between genotypes and adverse drug reactions (ADRs) or ELT concentrations and ADRs. Conclusion UGT1A1*6 is a predictor of the ELT plasma concentration and may help to determine the initial therapeutic dose in relapsed/refractory AA patients. Both drug exposure and patient genotype should be considered for better responses to ELT.
 
Measuring persistence with treatment anniversary method
Possible differences in treatment between the 1st and the last dispensation
Article
Purpose Poor persistence to antihypertensive therapy is an important cause of treatment failure. Investigating persistence is especially important in countries with a high cardiovascular mortality, like Lithuania. The aim of this study was to describe the antihypertensive treatment at initiation, to determine the percentage of patients not being persistent with antihypertensive treatment after 1 year and to explore factors associated with non-persistence. Methods In this cohort study, data on dispensed prescription medicines from the Lithuanian National Health Insurance Fund (NHIF) were used. All adult patients with a diagnosis of hypertension having first antihypertensive dispensed in 2018 were included. Descriptive statistics was used to determine the number of patients started with monotherapy and combination therapy. Treatment choice by Anatomical Therapeutic Chemical (ATC) and number of active pharmaceutical ingredient (API) was described. Non-persistence was assessed using the anniversary method. Multivariate logistic regression was used to explore factors associated with non-persistence. Results A total of 72,088 patients were included into the study, 56% started on monotherapy treatment, with 49% being dispensed an angiotensin converting enzyme inhibitor, and 44% started on combination therapy. Overall, 57% of patients were non-persistent after 1 year. Patients’ gender and prescriber qualification showed no association with non-persistence. Younger patients, patients from rural area, patients started with monotherapy, and patients with no medication change had higher odds to become non-persistent. Conclusions The majority of patients were initiated with treatment following hypertension management guidelines, but it is of concern that over half of the patients were non-persistent to antihypertensive therapy in the first year.
 
Study selection
Effects of sodium-glucose co-transporter 2 inhibitors on cardiovascular outcomes. RCT, randomized clinical trial; RWE, real-world evidence; CI, confidence interval; MACE, major adverse cardiac events; MI, myocardial infarction; ACM, all-cause mortality; CVM, cardiovascular mortality; HHF, hospitalization for heart failure; AF, atrial fibrillation; OR, odds ratio; RR, relative ratio. Note: The results of RCT were re-synthesized effect estimates by this umbrella study; on the other hand, RWE was derived from Li [18]’s article
Article
Purpose We aimed to explore possible contributors to discrepancies between randomized controlled trials (RCTs) and real-world observational studies (OS) in cardiovascular benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors in type 2 diabetes (T2D) patients. Methods We searched PubMed and EMBASE to identify meta-analyses of RCTs and OS on cardiovascular effects of SGLT2 inhibitors in T2D patients. Cardiovascular outcomes included major adverse cardiovascular events (MACE), myocardial infarction (MI), stroke, cardiovascular mortality (CVM), all-cause mortality (ACM), hospitalization for heart failure (HHF), and atrial fibrillation (AF). We examined the summary relative risk (RR) and 95% confidence interval (CI) for each endpoint from meta-analyses of RCTs. Results We identified and included 15 eligible meta-analyses, 13 for RCTs and 2 for OS, with moderately strong evidence. The results revealed a significant discrepancy between RCTs and OS for MI (RR, 95% CI 1.05, 0.82–1.38; I = 91.5% versus odds ratio (OR), 95% CI 0.77, 0.73–0.81; I = 15.0%), stroke (RR, 95% CI 0.99, 0.76–1.29; I = 93.4% versus OR, 95% CI 0.75, 0.72–0.78; I = 23.0%), and AF (RR, 95% CI 0.72, 0.62–0.85; I = 0.0% versus OR, 95% CI 0.92, 0.83–1.02; I = 0.0%). Conclusion OS presented significant benefits of SGLT2 inhibitors both on primary and secondary preventions of MACE, MI, stroke, ACM, CVM, and HHF; RCTs did not. Given the spectrum of T2D patient characteristics and the strength of overall evidence, our review underscored the importance of constant integration of all available information and critical interpretation of all inconsistencies to optimize evidence-based diabetes care.
 
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Flowchart of the Systematic Review
Forest plots of included studies
Article
Purpose To conduct a systematic review to identify studies that assessed the association between CYP2C19 polymorphisms and clinical outcomes in peripheral artery disease (PAD) patients who took clopidogrel. Methods We systematically searched Ovid EMBASE, PubMed, and Web of Science from November 1997 (inception) to September 2020. We included observational studies evaluating how CYP2C19 polymorphism is associated with clopidogrel’s effectiveness and safety among patients with PAD. We extracted relevant information details from eligible studies (e.g., study type, patient population, study outcomes). We used the Risk of Bias in Non-randomized Studies-of Interventions (ROBINS-I) Tool to assess the risk of bias for included observational studies. Results The outcomes of interest were the effectiveness and safety of clopidogrel. The effectiveness outcomes included clinical ineffectiveness (e.g., restenosis). The safety outcomes included bleeding and death related to the use of clopidogrel. We identified four observational studies with a sample size ranging from 50 to 278. Outcomes and comparison groups of the studies varied. Three studies (75%) had an overall low risk of bias. All included studies demonstrated that carrying CYP2C19 loss of function (LOF) alleles was significantly associated with reduced clinical effectiveness and safety of clopidogrel. Conclusions Our systematic review showed an association between CYP2C19 LOF alleles and reduced functions of clopidogrel. The use of CYP2C19 testing in PAD patients prescribed clopidogrel may help improve the clinical outcomes. However, based on the limited evidence, there is a need for randomized clinical trials in PAD patients to test both the effectiveness and safety outcomes of clopidogrel.
 
Goodness of fit plot for Pop-PK model of imatinib. A Population-predicted concentrations (μg/ml) and B individual concentrations (μg/ml) versus observed concentrations. C Individual predicted concentrations versus individual weighted residuals (iWRES) and D time (h) versus conditional weighted residuals (CWRES)
Prediction-corrected visual predictive check (pcVPC) plot. The black dots represent observed concentrations, the red line represents the median and the red-shaded area represents the 95% prediction interval around the median; the blue lines are the upper and lower prediction interval and the blue shaded area is the 95% prediction intervals around these limits
Effect of A Albumin and B WBC and C SNP rs1128503 on predicted apparent oral clearance of imatinib (L/h). For the box plot (for SNP rs1128503) the one on the left labelled ‘0’ refers to the wildtype population while the box on the right labelled ‘1’ refers to the combined mutant population (heterozygous and homozygous)
Article
Purpose Imatinib is a substrate of CYP3A4, ABCB1 and ABCG2, and is known to have wide variability in pharmacokinetics (PK). At the same time, a clear relationship between drug levels and response also exists for imatinib in chronic myeloid leukaemia (CML). Therefore, pharmacogenetic-based dosing of imatinib is an attractive proposition. This study aims to characterize the population pharmacokinetics of imatinib in order to identify significant covariates including pharmacogenetic variants. Methods Forty-nine patients with CML were enrolled in the study after being on imatinib for at least 4 consecutive weeks. Steady-state pharmacokinetic sampling was performed either in a sparse (4 samples each, n = 44) or intensive manner (9 samples each, n = 5). An additional pharmacogenetic sample was also collected from all patients. Plasma imatinib levels were estimated using a validated HPLC method. Pharmacogenetic variants were identified using the PharmacoScan array platform. Population pharmacokinetic analysis was carried out using NONMEM v7.2. Seven SNPs within CYP3A4, ABCB1 and ABCG2 genes were evaluated for covariate effect on the clearance of imatinib. Results Imatinib PK was well characterized using a one-compartment model with zero-order absorption. The clearance and volume of distribution were found to be 10.2 L/h and 389 L respectively. Only SNP rs1128503 of the ABCB1 gene had a small but insignificant effect on imatinib clearance, with a 25% reduction in clearance observed in patients carrying the polymorphism. Twenty-three out of forty-nine patients (47%) carried the polymorphic allele, of whom 17 were heterozygous and six were homozygous. Conclusion Our study conclusively proves that genetic polymorphisms in the CYP3A4 and ABC family of transporters do not have any role in the personalized dosing of imatinib in CML.
 
Hepatic CYP3A4 metrics. Correlation between (a) systemic midazolam clearance (CL) and 4βOHC concentrationsa, (b) hepatic CYP3A4 concentrationb and 4βOHC concentrations, and (c) clearance intrinsic for midazolam 1’-hydroxylation in human liver microsomesc and 4βOHC concentrations. Spearman’s rho (ρ) is the correlation coefficient, and the p value is from the Spearman rank correlation analysis. aAvailable in 92 patients (patients with obesity = 74, normal to overweight individiuals = 18). bAvailable in 56 patients (patients with obesity = 38, normal to overweight individuals = 18). cAvailable in 36 patients (RYGB = 20, normal to overweight individuals = 16). Abbreviations: CLint,u, clearance intrinsic unbound; CYP, cytochrome P450; HLM, human liver microsomes; 4βOHC, 4-beta hydroxycholesterol
Intestinal CYP3A4 metrics. Correlation between (a) midazolam absolute bioavailabilitya and 4βOHC concentrations, (b) apparent oral midazolam clearance (CL/F)a and 4βOHC concentrations, (c) jejunum CYP3A4 concentrationb and 4βOHC concentrations, and (d) clearance intrinsic for midazolam 1′-hydroxylation in human intestinal microsomesc and 4βOHC concentrations. Spearman’s rho (ρ) is the correlation coefficient, and the p value is from the Spearman rank correlation analysis. aAvailable in 92 patients (patients with obesity = 74, normal to overweight individuals = 18). bAvailable in 37 RYGB-patients. cAvailable in 20 RYGB-patients. Abbreviations: CLint,u, clearance intrinsic unbound; CYP, cytochrome P450; HIM, human intestinal microsomes; 4βOHC, 4-beta hydroxycholesterol
Clinical variables and 4βOHC. Correlation between (a) BMI and 4βOHC concentrations (n = 96), (b) NAFLD liver fat score and 4βOHC concentrations (n = 95), and (c) hs-CRP and 4βOHC concentrations (n = 96). Spearman’s rho (ρ) is the correlation coefficient, and the p value is from the Spearman rank correlation analysis. Abbreviations: BMI, body mass index; hs-CRP, high-sensitivity C-reactive protein; NAFLD, non-alcoholic fatty liver disease; 4βOHC, 4-beta hydroxycholesterol
Article
Purpose Variability in cytochrome P450 3A4 (CYP3A4) metabolism is mainly caused by non-genetic factors, hence providing a need for accurate phenotype biomarkers. Although 4β-hydroxycholesterol (4βOHC) is a promising endogenous CYP3A4 biomarker, additional investigations are required to evaluate its ability to predict CYP3A4 activity. This study investigated the correlations between 4βOHC concentrations and hepatic and intestinal CYP3A4 protein expression and ex vivo microsomal activity in paired liver and jejunum samples, as well as in vivo CYP3A4 phenotyping (midazolam) in patients with a wide body weight range. Methods The patients ( n = 96; 78 with obesity and 18 normal or overweight individuals) were included from the COCKTAIL-study (NCT02386917). Plasma samples for analysis of 4βOHC and midazolam concentrations, and liver ( n = 56) and jejunal ( n = 38) biopsies were obtained. The biopsies for determination of CYP3A4 protein concentration and microsomal activity were obtained during gastric bypass or cholecystectomy. In vivo CYP3A4 phenotyping was performed using semi-simultaneous oral (1.5 mg) and intravenous (1.0 mg) midazolam. Results 4βOHC concentrations were positively correlated with hepatic microsomal CYP3A4 activity ( ρ = 0.53, p < 0.001), and hepatic CYP3A4 concentrations ( ρ = 0.30, p = 0.027), but not with intestinal CYP3A4 concentrations ( ρ = 0.18, p = 0.28) or intestinal microsomal CYP3A4 activity ( ρ = 0.15, p = 0.53). 4βOHC concentrations correlated weakly with midazolam absolute bioavailability ( ρ = − 0.23, p = 0.027) and apparent oral clearance ( ρ = 0.28, p = 0.008), but not with systemic clearance ( ρ = − 0.03, p = 0.81). Conclusion These findings suggest that 4βOHC concentrations reflect hepatic, but not intestinal, CYP3A4 activity. Further studies should investigate the potential value of 4βOHC as an endogenous biomarker for individual dose requirements of intravenously administered CYP3A4 substrate drugs. Trial registration Clinical.Trials.gov identifier: NCT02386917.
 
Drug treatment assessments. Abbreviations: PIM potentially inappropriate medication, PPO potential prescribing omission. aThree sets of criteria: the European Union (EU)(7)-PIM list, the Screening Tool of Older Persons’ Prescriptions (STOPP)/Screening Tool to Alert to Right Treatment (START), and the Swedish set of criteria developed by the National Board of Health and Welfare. bFrom a medical perspective, taking into account the health condition of the specific patient and medical priorities that have to be made in primary health care. cPIMs/PPOs assessed by both physicians as either clinically relevant, or of uncertain clinical relevance but with a related medical action suggested. dPIMs/PPOs assessed by both physicians as either not clinically relevant, or of uncertain clinical relevance, with no related medical action suggested. eDefined as one or more actions related to the medication being considered medically justified at the individual level, prior to the next regular consultation, according to two physicians in consensus, e.g. a switch or the withdrawal of a drug, ordering of a laboratory test, retrieval of more information about the patient, or arranging an extra visit. fDefined as no action related to the medication being considered medically justified at the individual level, prior to the next regular consultation, according to two physicians in consensus
Article
Purpose To investigate the clinical relevance of potentially inappropriate medications (PIMs) and potential prescribing omissions (PPOs), and to evaluate the association between PIMs/PPOs and inadequate drug treatment. Methods PIMs/PPOs, concordantly identified by two physicians applying the STOPP/START criteria, the EU(7)-PIM list, and a Swedish set in 302 consecutive older primary care patients, were assessed regarding clinical relevance for the specific patient. The physicians determined, in consensus, whether an action related to the medication was medically justified prior to the next regular consultation. If so, the drug treatment was categorised as inadequate, and if not, the treatment was considered adequate. Results In all, 259 (86%) patients had 1010 PIMs/PPOs, 150 (15%) of which, in 81 (27%) patients, were assessed as clinically relevant (kappa: 0.26). A total of 75 (50%) clinically relevant PIMs and PPOs were prioritised for medical action before the next regular consultation. Action-requiring clinically relevant PIMs most often concerned acetylsalicylic acid (ASA) for primary prevention (four out of 68 patients on ASA). The corresponding PPOs concerned beta-blockers in ischaemic heart disease (four out of 61 patients with this condition). When an overall medical perspective was applied, 164 (63%) out of 259 patients with PIMs/PPOs were assessed as having adequate treatment. In adjusted logistic regression, number of PIMs and/or PPOs and number of drugs were associated with inadequate drug treatment. Conclusion One in seven PIMs/PPOs may be clinically relevant, half of these not of priority for medical action. Cautious interpretation is warranted when PIMs/PPOs are used as outcome measures.
 
Study flow chart for selection of the second-generation antipsychotic user cohort
Plot of hazard ratio (HR) and 95% confidence intervals (CI) of the association between second-generation use and incident acute kidney injury
Article
Purpose To investigate the association between acute kidney injury (AKI) and use of second-generation antipsychotics (SGA) in older adults. Methods In a population-based cohort study using Danish national registries, new users of SGAs (aged ≥ 65) were identified during 2005–2015. Each SGA user was matched to 10 population controls on age, sex, and the SGA initiation date. The outcome was incident AKI within 90 days after the index date. Cox regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs), adjusting for potential confounders. Results In the study, 36,581 new SGA users and 365,810 controls were included. The 90-day incidence rate of AKI was 4.38 and 1.70 per 1000 person-years among SGA users and controls, respectively, corresponding to a crude HR of 2.57 (1.79–3.68). The fully adjusted HR (aHR) was 1.43 (0.89–2.27) for all SGAs. The risk differed among individual drugs with aHRs for olanzapine 3.50 (1.20–10.23), quetiapine 1.62 (0.81–3.26), and risperidone 0.68 (0.28–1.64). In sensitivity analyses, the aHR declined to 1.24 (0.95–1.61) at 1-year follow-up. Conclusions Olanzapine use was associated with a significantly increased 90-day AKI risk. For quetiapine, the risk was elevated but not significant, and risperidone had no association. CIs were wide and confounder adjustment largely impacted the estimates. Main limitations included residual confounding and incomplete recording of AKI diagnoses.
 
Associations between adjusted Cpss and combined polymorphism of drug-metabolizing enzyme gene
Correlation between adjusted Cpss and change in TMSE score
Article
Purpose This study aimed to evaluate the influence of genetic polymorphisms of drug-metabolizing enzyme genes, transporter gene, pathological gene (APOE), and non-genetic factors on therapeutic outcomes as well as steady-state plasma concentrations (Cpss) of galantamine in Thai patients with mixed dementia. Methods Fifty-one Thai patients with mixed dementia who received galantamine for at least 6 months were recruited. CYP2D6, CYP3A5, and ABCB1 polymorphisms were detected by TaqMan® Genotyping Assay. UGT1A1 and APOE polymorphism was detected by direct Sanger sequencing technique and restriction fragment length polymorphism technique. Cpss of galantamine was measured by ultra-performance liquid chromatography. Associations of genetic and non-genetic factors with Cpss and clinical outcomes (change in cognitive function as measured by the Thai Mental State Examination (ΔTMSE) scores) were determined by using univariate and multivariate analysis. Results The multivariate regression model revealed that patients who carried one or more detrimental allelic variant (CYP2D6, CYP3A5, and UGT1A1) showed a tendency toward a higher galantamine adjusted Cpss (B = 34.559, 95% CI = 0.741–68.377, p value = 0.045). Logistic regression analysis also revealed CYP2D6*10 carriers were significantly associated with higher ΔTMSE (B = 5.227, 95% CI = 2.395–8.060, p value = 0.001). UGT1A1 mutant alleles and non-genetic factors including concomitant use of statin drugs and higher education level can attenuate therapeutic outcomes of galantamine. Conclusion Pharmacokinetic-related genes including CYP2D6*10 and UGT1A1 mutant alleles were significantly associated with galantamine adjusted Cpss and cognitive function. Determination of Cpss and genotype could be an adjunct examination to provide further explanation in interindividual variability of galantamine therapeutic outcome.
 
Comparison of the mean serum LZD concentrations in critically ill patients; among 3 groups; intermittent GpI, continuous GpII and loading GpIII after intravenous administration of 1200 mg/24 h through 72 h (n = 16)
Article
Purpose Linezolid (LZD) levels are frequently insufficient in intensive care unit (ICU) patients receiving standard dose, which is predictive of a poor prognosis. Alternative dosing regimens are suggested to address these insufficient levels, which are substantial factors contributing to the emergence of multidrug-resistant bacteria, resulting in increased morbidity and mortality among people who are critically ill. Methods Forty-eight patients admitted to the intensive care unit were enrolled in an open-label, prospective, randomized study and assigned to one of three LZD administration modes: intermittent groupI (GpI) (600 mg/12 h), continuous infusion groupII (GpII) (1200 mg/24 h) or continuous infusion with loading dose groupIII (GpIII) (on Day 1, 300 mg intravenously plus 900 mg continuous infusion, followed by 1200 mg/24 h on Day 2). We evaluated serum levels of LZD using a validated ultra-performance liquid chromatography (UPLC) technique. Results Time spent with a drug concentration more than 85% over the minimum inhibitory concentration (T > MIC) was substantially more common in GpII and III than in GpI (P < 0.01). AUC/MIC values greater than 80 were obtained more frequently with continuous infusion GpIII and GpII than with intermittent infusion GpI, at 62.5%, 37.5% and 25%, respectively (P < 0.01). In GpI, the mortality rate was significantly higher than in the other groups. Conclusion In critically ill patients, continuous infusion with a loading dose (GpIII) is obviously superior to continuous infusion without a loading dose (GpII) or intermittent infusion (GpI) for infection therapy. Additionally, it might limit fluctuations in plasma concentrations, which may help overcome LZD resistance.
 
Comparisons of metabolic ratios of tolvaptan between cytochrome P450 (CYP) 3A5 genotypes (n = 28, *1 carriers, and n = 60, *3*3). (A) 4S5S-diol to 5R-tolvaptan (P < 0.01). (B) 4R5S-diol to 5R-tolvaptan (P < 0.01). (C) 3S5R-diol to 5R-tolvaptan (P < 0.01). (D) 4R5R-diol to 5S-tolvaptan (P < 0.01). (E) 4S5R-diol to 5S-tolvaptan (P < 0.01). (F) 3R5S-diol to 5S-tolvaptan (P = 0.04). Box plots represent the median, 25th, and 75th percentiles. The whiskers indicate the range. The differences were compared using the Mann–Whitney U test. *P < 0.05, **P < 0.01
Comparisons of metabolic ratios of tolvaptan between amiodarone( +) (n = 20) and amiodarone( −) (n = 68) patients. (A) 4S5S-diol to 5R-tolvaptan (P < 0.01). (B) 4R5S-diol to 5R-tolvaptan (P = 0.01). (C) 3S5R-diol to 5R-tolvaptan (P = 0.04). (D) 4R5R-diol to 5S-tolvaptan (P = 0.06). (E) 4S5R-diol to 5S-tolvaptan (P = 0.07). (F) 3R5S-diol to 5S-tolvaptan (P = 0.14). Box plots represent the median, 25th, and 75th percentiles. The whiskers indicate the range. The differences were compared using the Mann–Whitney U test. *P < 0.05, **P < 0.01
Article
Purpose The diuretic effect of tolvaptan is largely blood level-dependent although it does exhibit interindividual differences according to cytochrome P450 (CYP) 3A5 genotype. This study aimed to investigate the pharmacokinetic relationship between plasma tolvaptan and its monohydroxylate enantiomers and the factors affecting their metabolism in heart failure patients. Methods Japanese heart failure patients (n = 88) receiving oral tolvaptan (median dosage 7.5 mg/day) were enrolled. Blood samples were collected prior to the dosing on day 6 or later after first administration to determine the plasma concentrations of tolvaptan and its monohydroxylate enantiomers. Gene polymorphisms of CYP3A5, carbonyl reductase (CBR) 1/3, and ATP-binding cassette subfamily B member (ABCB) 1 were analyzed for their impact on tolvaptan pharmacokinetics. Serum laboratory test values and concomitant use of amiodarone were evaluated as factors related to tolvaptan metabolism. Results The median of the sum of the 5S- and 5R-tolvaptan plasma concentrations was 48.9 (range, 15.3–100) ng/mL. CYP3A5 genotypes significantly affected the concentration ratio of all enantiomeric metabolites to tolvaptan, while the other metabolic-related gene polymorphisms had no influence. A negative correlation was found between serum albumin and the enantiomeric ratio of tolvaptan and monohydroxylate DM-4111. Concomitant use of amiodarone increased the plasma levels of whole tolvaptan but significantly decreased the metabolic ratios of 5R-tolvaptan. 5S-tolvaptan was selectively synthesized from ketone MOP-21826 by CBR1 with a substantially smaller reaction velocity compared to tolvaptan monohydroxylation by CYP3A4/5. Conclusion This study clarified the racemic impact of CYP3A5 genotypes on tolvaptan metabolism. Amiodarone may stereoselectively interact with R-forms rather than S-forms of tolvaptan.
 
Correlations between the measured BIS-derived values and the estimated values of A lean tissue mass according to the formula by James et al. [22], B lean tissue mass for kidney transplant recipients according to the formula of Størset et al. [23], and C adipose tissue mass. BIS, bio-impedance spectroscopy; KTR, kidney transplant recipients; r, Spearman’s correlation coefficient
Goodness of fit plots of the final model. A The relationship between the phase angle and the clearance of tacrolimus. B Observed tacrolimus concentrations versus predicted tacrolimus concentrations. C Observed tacrolimus concentrations versus the individual predicted tacrolimus concentrations. D The conditional weighted residuals over the time after transplantation. E The conditional weighted residuals over the predicted tacrolimus concentrations. CWRES, conditional weighted residuals
Visual predictive check showing how well the mean of the observed tacrolimus concentrations (red line) falls within the predicted mean tacrolimus concentration (red area; 95% confidence interval) and how well the variability of the observed tacrolimus concentration (red-dotted line) falls within the predicted variability of the tacrolimus concentration (blue area; 95% confidence interval) over A the phase angle, and B the time after transplantation
QQ plot A and histogram B showing the normality of the normalized prediction distribution errors (NPDEs) distribution for the final model
Boxplot of the estimated tacrolimus concentrations following different dosing strategies. The dark-gray area represents the tacrolimus target range (7.5–12.5 ng/mL), the the light-gray areas represent the areas of moderate underexposure (5.0–7.5 ng/mL) and overexposure (12.5–20.0 ng/mL)
Article
Purpose A population pharmacokinetic (popPK) model may be used to improve tacrolimus dosing and minimize under- and overexposure in kidney transplant recipients. It is unknown how body composition parameters relate to tacrolimus pharmacokinetics and which parameter correlates best with tacrolimus exposure. The aims of this study were to investigate which body composition parameter has the best association with the pharmacokinetics of tacrolimus and to describe this relationship in a popPK model. Methods Body composition was assessed using bio-impedance spectroscopy (BIS). Pharmacokinetic analysis was performed using nonlinear mixed effects modeling (NONMEM). Lean tissue mass, adipose tissue mass, over-hydration, and phase angle were measured with BIS and then evaluated as covariates. The final popPK model was evaluated using goodness-of-fit plots, visual predictive checks, and a bootstrap analysis. Results In 46 kidney transplant recipients, 284 tacrolimus concentrations were measured. The base model without body composition parameters included age, plasma albumin, plasma creatinine, CYP3A4 and CYP3A5 genotypes, and hematocrit as covariates. After full forward inclusion and backward elimination, only the effect of the phase angle on clearance (dOFV = − 13.406; p < 0.01) was included in the final model. Phase angle was positively correlated with tacrolimus clearance. The inter-individual variability decreased from 41.7% in the base model to 34.2% in the final model. The model was successfully validated. Conclusion The phase angle is the bio-impedance spectroscopic parameter that correlates best with tacrolimus pharmacokinetics. Incorporation of the phase angle in a popPK model can improve the prediction of an individual’s tacrolimus dose requirement after transplantation.
 
The goodness-of-fit of the final population pharmacokinetic model of tacrolimus in Chinese renal transplant patients. (A) The population predicted concentration (PRED) vs. the measured concentration (CONC); (B) the individual predicted concentration (IPRE) vs. CONC; (C) the weighted residual error (WRES) vs. PRED; (D) WRES vs. time
The correlation of tacrolimus C0 and AUC0-12h in whole blood and PBMC
The influence of CYP3A5 and ABCB1 genotypes on tacrolimus intracellular AUC0-12h
The correlation between observed and estimated TAC AUC0-12h in models 4, 9, 14, 17 and observed AUC0-12h values
Bland–Altman analysis testing agreement between observed TAC AUC0-12h in models 4, 9, 14, 17 and the estimated values
Article
Purpose Intracellular exposure of tacrolimus (TAC) may be a better marker of therapeutic effect than whole blood exposure. We aimed to evaluate the influence of genetic polymorphism on the pharmacokinetics of TAC in peripheral blood mononuclear cells (PBMCs) and develop limited sampling strategy (LSS) models to estimate the area under the curve (AUC0–12h) in the PBMC of Chinese renal transplant patients. Methods Ten blood samples of each of the 23 renal transplant patients were collected 0–12h after 14 (10–18) days of TAC administration. PBMCs were separated and quantified. The TAC level in PBMCs was determined, and pharmacokinetic parameters were estimated by noncompartmental study. The AUC0–12h of TAC in whole blood was estimated by Bayesian approach based on a population pharmacokinetic model established in 65 renal transplant patients. The influence of CYP3A5 and ABCB1 genotypes on exposure was estimated. By applying multiple stepwise linear regression analysis, LSS equations for TAC AUC0–12h in the PMBC of renal transplant patients were established, and the bias and precision of various equations were identified and compared. Results We found a modest correlation between TAC exposure in whole blood and PBMC (r² = 0.5260). Patients with the CYP3A5 6986GG genotype had a higher AUC0–12h in PBMCs than those with the 6986 AA or GA genotype (P = 0.026). Conversely, patients with the ABCB1 3435TT genotype had a higher AUC0–12h in PBMC than those with the 3435 CC and CT genotypes (P = 0.046). LSS models with 1–4 blood time points were established (r² = 0.570–0.989). The best model for predicting TAC AUC0–12h was C2–C4–C6–C10 (r² = 0.989). The model with C0.5–C6 (r² = 0.849) can be used for outpatients who need monitoring to be performed in a short period. Conclusions The CYP3A5 and ABCB1 genotypes impact TAC exposure in PBMCs, which may further alter the effects of TAC. The LSS model consisting of 2–4 time points is an effective approach for estimating full TAC AUC0–12h in Chinese renal transplant patients. This approach may provide convenience and the possibility for clinical monitoring of TAC intracellular exposure.
 
Comparison of abemaciclib concentrations and treatment-related grade 2 or greater hematotoxicity. The lines within the boxes represent the median values; the upper and lower lines of the boxes represent the 75th and 25th percentiles, respectively; and the upper and lower bars outside the boxes represent the 90th and 10th percentiles, respectively (n = 45)
Article
Purpose Adverse events after the use of the CDK4/6 inhibitor abemaciclib are dose-dependent. However, its pharmacokinetics varies among individuals. Abemaciclib is reportedly transported by P-glycoprotein and breast cancer resistance protein. Therefore, we evaluated whether ABCB1 and ABCG2 polymorphisms are pharmacokinetic predictive factors of abemaciclib. Methods A total of 45 patients with breast cancer taking abemaciclib (150 mg twice per day) for 2 weeks were evaluated to determine the associations among abemaciclib concentration; adverse events; and ABCB1 1236 T > C, 2677G > T/A, 3435C > T, and ABCG2 421C > A gene polymorphisms. Results The trough concentration of abemaciclib was significantly higher in the group with grade 2 or greater neutropenia and thrombocytopenia than in those with grades 0 or 1. For ABCB1 2677G > T/A polymorphisms, the concentration of abemaciclib tended to be higher in the homozygous group (TT + AT) than in the wild-type + heterozygous group (GG + GA + GT) (median [range], 222.8 [80.5–295.8] ng/mL vs. 113.5 [23.6–355.2] ng/mL, P = 0.09), Moreover, the ABCB1 2677G > T/A homozygous group had a higher tendency of abemaciclib withdrawal or dose reduction within 4 weeks than the wild-type + heterozygous group (odds ratio, 4.22; 95% confidence interval, 0.86–20.7; P = 0.08). No significant association was observed among abemaciclib concentration; adverse reactions; and ABCB1 1236 T > C, 3435C > T, and ABCG2 421C > A polymorphisms. Conclusion ABCB1 2677G > T/A polymorphism might be a predictor of the pharmacokinetics and tolerability of abemaciclib.
 
Article inclusion/exclusion process
Forest plots estimating the associations of the IMPDH2 3757 T > C polymorphism with rejection and the corresponding sensitivity analysis (TT vs. TC + CC). a No significant association existed between the genotypes and rejection in the pooled genotype distribution frequency analysis. b No significant association existed between the genotypes and acute rejection within 1 year in the pooled genotype distribution frequency analysis. c The TT genotype showed a 1.61-fold higher risk of rejection than the TC + CC genotypes in pooled OR analysis. d No significant association existed between the genotypes and acute rejection within 1 year in pooled OR analysis. e–h No single study qualitatively altered the results of the meta-analysis
Forest plots estimating the associations of the IMPDH1 125G > A polymorphism with rejection and the corresponding sensitivity analysis. a No significant association existed between the genotypes and rejection in the pooled allele distribution frequency analysis (G allele vs. A allele). b No significant association existed between the genotypes and rejection in the pooled genotype distribution frequency analysis (GG vs. GA + AA). c The GG genotype showed a 1.91-fold higher risk of rejection than the GA + AA genotypes in pooled OR analysis (GG vs. GA + AA). d–f No single study qualitatively altered the results of the meta-analysis
Forest plots estimating the associations of the IMPDH1 106G > A polymorphism with rejection and the corresponding sensitivity analysis (GG vs. GA + AA). a No significant association existed between the genotypes and rejection in the pooled genotype distribution frequency analysis. b The GG genotype showed a 2.12-fold higher risk of acute rejection (1 year) than the GA + AA genotypes in pooled OR analysis. c, d No single study qualitatively altered the results of the meta-analysis
Forest plots estimating the associations of the UGT1A9 275 T > A polymorphism with rejection and the corresponding sensitivity analysis (TT vs. TA + AA). a The TT genotype showed a lower risk of rejection than the TA + AA genotype in the pooled OR analysis. b No single study qualitatively altered the results of the meta-analysis
Article
Purpose To investigate the associations of IMPDH and UGT1A9 polymorphisms with rejection in kidney transplant recipients taking mycophenolic acid (MPA). Methods PubMed, Web of Science, Embase, Cochrane Library, Wanfang Data, and the China Academic Journal Network Publishing Database were systematically searched for studies investigating the associations of IMPDH1, IMPDH2, and UGT1A9 polymorphisms with rejection in kidney transplant recipients taking MPA. Associations were evaluated by pooled odds ratios (ORs) and effect sizes (ESs) with 95% confidence intervals (CIs). Results Twelve studies were included in the analysis, including a total of 2342 kidney transplant recipients. The results showed that compared with the TC + CC variant genotypes, the TT genotype of IMPDH2 3757 T > C was significantly associated with a higher risk of rejection (ES = 1.60, 95% CI = 1.07–2.40, P = 0.021), while there was no significant association of the IMPDH2 3757 T > C polymorphism with acute rejection within 1 year in kidney transplant recipients (OR = 1.49, 95% CI = 0.79–2.80, P = 0.217; ES = 1.44, 95% CI = 0.88–2.36, P = 0.142). The GG genotypes of IMPDH1 125G > A and IMPDH1 106G > A were significantly associated with a higher risk of rejection (ES = 1.91, 95% CI = 1.11–3.28, P = 0.019) and acute rejection within 1 year (ES = 2.12, 95% CI = 1.45–3.10, P < 0.001) than the variant genotypes GA + AA. The TT genotype of UGT1A9 275 T > A showed a decreased risk of rejection compared with the variant genotypes TA + AA (ES = 0.44, 95% CI = 0.23–0.84, P = 0.013). Conclusions IMPDH1, IMPDH2, and UGT1A9 polymorphisms were associated with rejection in kidney transplant recipients, and the genetic backgrounds of patients should be considered when using MPA.
 
Older adults’ responses to the French rPATD questionnaire
Caregivers’ responses to the French rPATD questionnaire
Article
Purpose Successful deprescribing requires understanding the attitudes of older adults and caregivers towards this process. This study aimed to capture these attitudes in four French-speaking countries and to investigate associated factors. Methods A multicenter cross-sectional study was conducted by administrating the French version of the revised Patients’ Attitudes Towards Deprescribing (rPATD) questionnaire in Belgium, Canada, France, and Switzerland. Community-dwelling or nursing home older adults ≥ 65 years taking ≥ 1 prescribed medications and caregivers of older adults with similar characteristics were included. Multivariate logistic regressions were carried out to examine factors associated with willingness to deprescribe. Results A total of 367 older adults (79.3 ± 8.7 years, 63% community-dwelling, 54% ≥ 5 medications) and 255 unrelated caregivers (64.4 ± 12.6 years) of care recipients (83.4 ± 7.9 years, 52% community-dwelling, 69% ≥ 5 medications) answered the questionnaire. Among them, 87.5% older adults and 75.6% caregivers would be willing to stop medications if the physician said it was possible. Reluctance to stop a medication taken for a long time was expressed by 46% of both older adults and caregivers. A low score for the factor “concerns about stopping” (older adults: aOR: 0.21; 95% CI: 0.07–0.59), and a high score for the factor “involvement” (older adults: aOR: 2.66; 95% CI: 1.01–7.07; caregivers: aOR: 11.28; 95% CI: 1.48–85.91) were associated with willingness to deprescribe. Conclusions A significant proportion of older adults and caregivers of French-speaking countries are open to deprescribing. Despite this apparent willingness, deprescribing conversations in clinical practice remains marginal, emphasizing the importance of optimizing the integration of existing tools such as rPATD.
 
Flow chart of study participants
Motives for trial participation among patients and healthy volunteers. Shown is the response distribution to a question worded as, “What were your motives for participating in the study?”
Expected beneficiaries of clinical trials. Shown is the response distribution to a question worded as, “How much do you think the following groups would benefit from clinical trials?”
Concern about the potential consequences of sharing personal information. Shown is the response distribution to a question worded as, “During your participation in clinical trials, you have consented to the disclosure of your personal data to third parties in anonymized form. How concerned are you about the following possible consequences of sharing anonymous clinical trial data?”
Trust in fields of scientific research. Shown is the response distribution to a question worded as, “How great is your trust in...”
Article
Purpose Clinical research relies on data from patients and volunteers, yet the target sample size is often not achieved. Here, we assessed the perception of clinical research among clinical trial participants to improve the recruitment process for future studies. Methods We conducted a single-center descriptive and exploratory study of 300 current or former participants in various phase I–III clinical trials. Questionnaires were either distributed to current clinical trial participants or emailed to former subjects. Results Subjects strongly agreed or agreed that contributing to improving medical care (> 81%), contributing to scientific research (> 79%), and trusting their treating physicians (> 77%) were motives for study participation. Among healthy volunteers, financial motives positively correlated with the number of clinical trials they had participated in (p < 0.05). Higher age positively correlated with expectation of best available treatment during study participation among patients (p < 0.05). Less than 8% of all subjects expressed “great concern” about the potential risks of sharing their personal information as part of the study. Subjects displayed “great trust” or “trust” in medical staff (86.6%) and in government research institutions (76.4%), and “very little trust” or “little trust” in pharmaceutical companies (35.4%) and health insurance companies (16.9%). Conclusion Altruistic motives and trust in treating physicians were predominant motives for clinical trial participation. Older patients expected to receive the best available treatment during participation. Healthy volunteers who reported financial motives had participated in more clinical trials. Consistent with great trust in medical staff and government research institutions, little concern was expressed about the misuse of personal data during the trial.
 
PRISMA flow diagram
of risk of bias assessment based on ROBIS tool P: phase; D: domain; Q: question
Article
Background Alzheimer’s disease (AD) is a neurodegenerative disease and the most common cause of dementia. In this umbrella systematic review (SR), we summarized the efficacy of different pharmacological interventions in improving cognitive function in patients with AD. Methods A systematic search was performed through the PubMed, Scopus, Embase, and Cochrane databases for SRs of studies assessing the efficacy of pharmacological interventions versus placebo in improving cognitive function in AD or mild cognitive impairment due to AD. The risk of bias (RoB) was assessed using the Risk of Bias in SRs (ROBIS) tool. Results Out of 1748 articles found through the database survey, 33 SR articles were included. These studies assessed effects of immunotherapy, cholinesterase inhibitors (ChEIs), memantine, statins, lithium, nonsteroidal anti-inflammatory drugs (NSAIDs), antidiabetic agents, Cerebrolysin, RAS-targeting antihypertensive drugs (ARBs and ACEIs), psychostimulants, glycogen synthase kinase 3 (GSK-3) inhibitors, melatonin, and herbal medications on cognitive function in AD patients. There was no notable overall RoB in 18 studies (54.5%), the RoB in 14 studies (42.4%) was high, and in one study (3.0%) it was unclear. Conclusions The use of ChEIs, including rivastigmine, galantamine, and donepezil, as well as memantine has demonstrated a positive impact on improving cognitive outcomes of AD patients, but no considerable effects were found for immunotherapies. Melatonin, statins, antihypertensive drugs, antidiabetic agents, Cerebrolysin, psychostimulants, and some herbal drugs such as Danggui-Shaoyao-San and Ginkgo biloba seem to be effective in improving cognitive function of AD patients, but the evidence in this regard is limited.
 
Flowchart of included patients co-prescribed beta-blockers and antidepressants in each of the three study years 2007, 2012, and 2017
Article
Purpose To compare the co-prescription of metoprolol and potent CYP2D6-inhibiting antidepressants before and during a 10-year period after implementation of an optimized drug interaction database into clinical decision support systems in Norway. Methods The study was a retrospective, cross-sequential nationwide analysis of drug-dispensing data retrieved from the Norwegian Prescription Database over a 1-year period before (2007) and two 1-year periods after (2012 and 2017) implementation of a drug interaction database providing recommendations on non-interacting alternative medications. Primary outcome was changes in co-prescription rates of metoprolol and the potent CYP2D6-inhibiting antidepressants fluoxetine, paroxetine, or bupropion relative to alternative antidepressants with no or limited CYP2D6 inhibitory potential. To control for potential secular trend bias, a comparison group consisting of atenolol/bisoprolol users was included. Results The co-prescription rate of metoprolol with potent CYP2D6 inhibitors declined following implementation of the optimized database, by 21% ( P < 0.001) after 5 years and by 40% ( P < 0.001) after 10 years. Compared with atenolol/bisoprolol users, patients treated with metoprolol had significantly reduced likelihood of being prescribed a CYP2D6-inhibiting antidepressant in the two post-implementation periods (OR 0.61 (95% CI 0.54–0.69) and OR 0.45 (95% CI 0.40–0.51), respectively, versus OR 0.84 (95% CI 0.74–0.94) prior to implementation). Small and mostly insignificant differences in average daily metoprolol dosage were found between patients treated with the various antidepressants. Conclusion The present study suggests that implementation of a drug interaction database providing recommendations on non-interacting drug alternatives contributes to reduced co-prescribing of drug combinations associated with potentially serious adverse effects.
 
A simplified depiction of coagulation cascade and LMWHs sites of action
Article
Purpose Low molecular weight heparins (LMWHs) are a group of heterogenous moieties, long used in the prevention and treatment of thrombosis. They derive from heparin and since they are prepared by different methods of depolymerization, they differ in pharmacokinetic properties and anticoagulant profiles, and thus are not clinically interchangeable. Methods In this review we provide an overview of tinzaparin's main characteristics and uses. Results Tinzaparin which is produced by the enzymatic depolymerization of unfractionated heparin (UFH) can be used for the treatment and prevention of deep venous thrombosis (DVT) and pulmonary embolism (PE); it has been also used in special populations such as elders, obese, pregnant women, and patients with renal impairment and/or cancer with favorable outcomes in both safety and efficacy, with a once daily dose regimen. Furthermore, LMWHs are extensively used in clinical practice for both thromboprophylaxis and thrombosis treatment of COVID-19 patients. Conclusion Tinzaparin features support the hypothesis for having a role in immunothrombosis treatment (i.e. in the context of cancer ,COVID-19), interfering not only with coagulation cascade but also exhibiting anti-inflammatory potency.
 
PRISMA flow diagram showing the literature search and selection of isoniazid PopPK studies in TB patients. NAT2 N-acetyltransferase 2, PopPK population pharmacokinetics, SNP singlenucleotide polymorphism, TB tuberculosis
Bar chart integrating NAT2 genotype distribution and corresponding clearance across isoniazid PopPK studies. NAT2 N-acetyltransferase 2. *The clearance of isoniazid for NAT2 rapid and intermediate acetylators were clubbed as one category. The proportion of TB patients with unknown genotype in any study is not represented in the bar chart
Article
Purpose Significant pharmacokinetic variabilities have been reported for isoniazid across various populations. We aimed to summarize population pharmacokinetic studies of isoniazid in tuberculosis (TB) patients with a specific focus on the influence of N-acetyltransferase 2 ( NAT2 ) genotype/single-nucleotide polymorphism (SNP) on clearance of isoniazid. Methods A systematic search was conducted in PubMed and Embase for articles published in the English language from inception till February 2022 to identify population pharmacokinetic (PopPK) studies of isoniazid. Studies were included if patient population had TB and received isoniazid therapy, non-linear mixed effects modelling, and parametric approach was used for building isoniazid PopPK model and NAT2 genotype/SNP was tested as a covariate for model development. Results A total of 12 articles were identified from PubMed, Embase, and hand searching of articles. Isoniazid disposition was described using a two-compartment model with first-order absorption and linear elimination in most of the studies. Significant covariates influencing the pharmacokinetics of isoniazid were NAT2 genotype, body weight, lean body weight, body mass index, fat-free mass, efavirenz, formulation, CD4 cell count, and gender. Majority of studies conducted in adult TB population have reported a twofold or threefold increase in isoniazid clearance for NAT2 rapid acetylators compared to slow acetylators. Conclusion The variability in disposition of isoniazid can be majorly attributed to NAT2 genotype. This results in a trimodal clearance pattern with a multi-fold increase in clearance of NAT2 rapid acetylators compared to slow acetylators. Further studies exploring the generalizability/adaptability of developed PopPK models in different clinical settings are required.
 
1 Definition of the treatment cycle from drug dispensing data *For each assisted woman in the Lazio region, therapeutic cycles are identified based on the dates of drug delivery in a 21-day mobile window. The drugs assigned to each window allow to associate one of the following formulations to each cycle: recombinant, extractive, combined (recombinant + extractive)
Flow-chart of the study cohort: women, cycles, and drug dispensing
Pathway analysis: treatment patterns and transition between treatments and pregnancy (abortion and pregnancy)
Association between exposure to the three exposure categories and infantile outcomes
Association between exposure to the three exposure categories and infantile outcomes
Article
Purpose Infertility is a topic of growing interest, and female infertility is often treated with gonadotropins. Evidence regarding comparative safety and efficacy of different gonadotropin formulations is available from clinical studies, while real-world data are missing. The present study aims to investigate effectiveness and safety of treatment with different gonadotropin formulations in women undergoing medically assisted procreation treatments in Latium, a region in central Italy, through a real-world data approach. Methods A retrospective population-based cohort study in women between the ages of 18 and 45 years who were prescribed with at least one gonadotropin between 2007 and 2019 was conducted. Women were enrolled from the regional drug dispense registry, and data on their clinical history, exposure to therapeutic cycles (based on recombinant “REC” or extractives “EXT” gonadotropin, or combined protocol “CMD” (REC + EXT)), and maternal/infantile outcomes were linked from the regional healthcare administrative databases. Multivariate logistic regression models were applied to estimate the association between exposure and outcomes. Results Overall, 90,292 therapeutic cycles prescribed to 35,899 women were linked to pregnancies. Overall, 15.8% of cycles successfully led to pregnancy. Compared to extractives, recombinant and combined treatments showed a stronger association with conception rate (RR REC adj = 1.06, 95% CI: 1.01–1.12; RR CBD adj = 1.17, 95% CI: 1.11–1.24). Maternal outcomes occurred in less than 5% of deliveries, and no significant differences between treatments were observed (REC vs EXT, pre-eclampsia: RR adj = 1.24, 95% CI: 0.86–1.79, ovarian hyperstimulation syndrome: RR adj = 1.25, 95% CI: 0.59–2.65, gestational diabetes: RR adj = 1.06, 95% CI: 0.84–1.35). Regarding infantile outcomes, similar results were obtained for different gonadotropin formulations (REC vs EXT: low birth weight: RR adj = 0.98, 95% CI: 0.83–1.26, multiple births: RR adj = 1.06, 95% CI: 0.92–1.23, preterm birth: RR adj = 1.03, 95% CI: 0.92–1.26). Conclusions Efficacy and safety profiles of REC proved to be similar to those of EXT. Regarding the efficacy in terms of conception rate and birth rate, protocols using the combined approach performed slightly better. Outcomes related to maternal and infantile safety were generally very rare, and safety features were overlapping between gonadotropin formulations.
 
Article
Purpose Gemcitabine and nab-paclitaxel association can be used in first- or second-line treatment for metastatic pancreatic adenocarcinoma. Here, we report five cases of supposed gemcitabine-induced thrombotic microangiopathy (G-TMA), four of them with nab-paclitaxel. We assumed that nab-paclitaxel could be responsible for a potential drug interaction with gemcitabine, increasing the risk of thrombotic microangiopathy occurrence. Methods Clinicians reported cases of supposed G-TMA that were declared to the Pharmacovigilance center. We collected the patients’ data (clinical and biological characteristics), calculated an incidence rate of G-TMA in our center, and a Naranjo score for each patient. We also reviewed literature on a potential drug interaction between nab-paclitaxel and gemcitabine. Results Four patients were treated with nab-paclitaxel/gemcitabine and one with gemcitabine alone. The time onset of supposed G-TMA was 2 to 11 months. Patients developed anemia, thrombocytopenia, and renal failure. The incidence rate of supposed G-TMA was 2.7% in our center compared to 0.31% (Meyler’s Side Effect of Drugs) and 0.01% in the gemcitabine’s summary of product characteristics. Literature review outlined an increase of gemcitabine’s plasmatic concentrations induced by nab-paclitaxel (Drugs® website) and a potentiation of gemcitabine’s effect by nab-paclitaxel in murine models. This study showed that nab-paclitaxel inhibits cytidine deaminase’s activity (responsible for gemcitabine’s metabolism) and increases gemcitabine’s active metabolite concentrations (gemcitabine triphosphate) in tumor tissues. Conclusion High incidence rate of G-TMA was observed in our cohort due to a potential drug interaction between nab-paclitaxel and gemcitabine with an increased risk of developing G-TMA. Additional pharmacological and pharmaco-epidemiological investigations are mandatory to explore this hypothesis.
 
Boxplot showing the distribution of opinion of each expert on the conventional meta-analysis (CMA) and semi-automated meta-analysis (SAMA)
Time spent conducting the conventional meta-analysis (total time: 24.7 working days) and the semi-automated meta-analysis (total time: 14 working days)
Article
Purpose To assess the feasibility and acceptance of the semi-automated meta-analysis (SAMA). The objectives are twofold, namely (1) to compare expert opinion on the quality of protocols, methods, and results of one conventional meta-analysis (CMA) and one SAMA and (2) to compare the time to execute the CMA and the SAMA. Methods Experts evaluated the protocols and manuscripts/reports of the CMA and SAMA conducted independently on the safety of metronidazole in pregnancy. Expert opinion was collected using AMSTAR 2 checklist. Time spent was recorded using case report forms. Results The overall scores of the opinion of all experts for protocols, methods, and results for SAMA (6.75) and CMA (6.87) were not statistically different (p = 0.88). The experts’ confidence in the results of each MA was 7.89 ± 1.17 and 8.11 ± 0.92, respectively. The time to completion was 14 working days for SAMA and 24.7 for CMA. MA tasks such as calculation of effect estimates, subgroup/sensitivity analysis, and publication bias investigation required no investment in time for SAMA. Conclusion In conclusion, our study demonstrated the feasibility of SAMA and suggests acceptance for risk assessment by an expert committee. Our results suggest that SAMA reduces the time required for a MA without altering expert confidence in the methodological and scientific rigor. As our study was limited to one example, the generalization of our results requires confirmation by other studies.
 
Response of treatments in heterozygous carriers of common SNPs in ADHD presentations Predominantly Inattentive Type (ADHD-PI), Combined Type (ADHD-C), Single-nucleotide polymorphisms (SNPs)
Receiver operating characteristic (ROC) curve. A ROC curve of BDNF levels for ATX treatment resistance
Article
Objective Although several genes have previously been studied about the treatment of Attention Deficit Hyperactivity Disorder (ADHD), the number of studies investigating the effects of genes on atomoxetine (ATX) treatment is very limited. In this study, we aimed to investigate the effect of CYP2C19 polymorphisms, which have a role in ATX biotransformation, on the treatment response and also to assess whether there is a relationship between BDNF and treatment response in children and adolescents with ADHD. Methods One hundred children with ADHD and 100 healthy controls (HCs) were included in this study. The treatment response was assessed 2 months after the start of the ATX treatment. DNA samples from peripheral venous blood were replicated using PCR and analyzed using the ILLUMINA next-generation sequencing method. The resulting fastqs were analyzed using Basespace’s Variant Interpreter Program. Plasma BDNF levels were evaluated with ELISA kits. Results Treatment response was found to be lower in both heterozygous and homozygous carriers of the c.681G > A (CYP2C19*2) polymorphism. When the BDNF level was compared, it was found to be significantly higher in the ADHD group compared to HCs. Also, BDNF has a stronger predictive value for assessing resistance to ATX treatment. Conclusions To our knowledge, this is the first study to assess the effects of CYP2C19 polymorphisms and BDNF levels together on ATX treatment in children. Further studies with an extensive population are needed to better understand the effects of CYP2C19 polymorphisms on treatment and side effects, as well as the effects of BDNF levels.
 
Kaplan–Meier curves of time to disease progression (MMSE < 10) according to a) treatment with AChEIs, b) treatment with memantine and c) use AChEIs + memantine in combination; results from log-rank test on the top of the curves
Article
Purpose To assess the impact of long-term use of different drugs commonly prescribed in Alzheimer’s disease (AD) on its clinical course and to identify clinical and therapeutic factors associated with a delay in AD progression. Methods We retrospectively enrolled 50 patients visited at the Neurology Unit, Careggi University Hospital (Florence), followed for at least 24 months. AD diagnosis was made according to clinical diagnostic criteria for probable/possible AD dementia, always supported at least by one biomarker. Clinical features, MMSE scores evaluated at diagnosis and every 6 months, and AD drugs used for at least 6 months, were recorded. Cox regression analysis was performed to estimate the hazard ratio (HR) for AD progression, assuming as the “final event,” the progression to a more severe disease stage, defined as the achievement of an MMSE score less than 10. Results At baseline, the median MMSE score was 22. During follow-up (median of 41 months), 56% of patients progressed to a more severe disease stage. The use of memantine, either alone (HR 0.24; 95% CI 0.09–0.60) or combined with acetylcholinesterase inhibitors (HR 0.35; 95% CI 0.14–0.88) and a higher MMSE score at baseline (HR 0.82; 95% CI 0.70–0.96) were associated with a significantly lower risk of AD progression. Conclusion Nowadays, effective disease-modifying therapy for AD is missing. Nevertheless, when the diagnosis is established, our results support the advantage of long-term use of available pharmacological treatments, especially in combination, in delaying AD progression to its more severe disease stage.
 
Percentage of patients for whom a distinct complexity factor was identified in the medication regimen (prevalence) and percentage of patients that indeed experience difficulties by the complexity factor (relevance) in the intervention group (N = 48); only complexity factors identified at least once in the intervention group considered. (a) Occasional, episodic drug treatment. (b) Dermatological preparations (prescription-only). (c) Administration every two days or less frequently. (d) Administration at fixed times of the day. (e) Complex measurements (self-performed). (f) Once weekly administration. (g) Injection devices (non-prefilled). (h) The same active ingredient in different preparations. (i) Meal-dependent administration. (j) Inhalers. (k) Use of multiple doses concurrently. (l) Different doses of the same active ingredient at different times of day. (m) Liquid oral dosage forms. (n) Potentially patient-unfriendly nature of liquid oral dosage forms. (o) Injection devices (prefilled). (p) Administration more than two times daily. (q) Potentially increased need for training in dosage form use. (r) Medication on demand. (s) Only one drug at one specific point in time. (t) Administration at lunch time. (u) Tablet splitting. (v) Total number of drugs
Article
Purpose To describe the prevalence of complexity factors in the medication regimens of community-dwelling patients with more than five drugs and to evaluate the relevance of these factors for individual patients. Methods Data were derived from the HIOPP-6 trial, a controlled study conducted in 9 general practices which evaluated an electronic tool to detect and reduce complexity of drug treatment. The prevalence of complexity factors was based on the results of the automated analysis of 139 patients’ medication data. The relevance assessment was based on the patients’ rating of each factor in an interview (48 patients included for analysis). Results A median of 5 (range 0–21) complexity factors per medication regimen were detected and at least one factor was observed in 131 of 139 patients. Almost half of these patients found no complexity factor in their medication regimen relevant. Conclusion In most medication regimens, complexity factors could be identified automatically, yet less than 15% of factors were indeed relevant for patients as judged by themselves. When assessing complexity of medication regimens, one should especially consider factors that are both particularly frequent and often challenging for patients, such as use of inhalers or tablet splitting. Trial registration The HIOPP-6 trial was registered retrospectively on May 17, 2021, in the German Clinical Trials register under DRKS-ID DRKS00025257.
 
Top-cited authors
Roger K Verbeeck
  • University of Namibia
Roberto Raschetti
  • Istituto Superiore di Sanità
Klaus T Olkkola
  • University of Helsinki
Francesca Menniti-Ippolito
  • Istituto Superiore di Sanità
Simin Dashti-Khavidaki
  • Tehran University of Medical Sciences