ABSTRACT
BACKGROUND: The European post-authorisation study (EU PAS) register is a repository launched in 2010 by the European Medicines Agency (EMA). All EMA-requested PAS, commonly observational studies, must be recorded in this register. Multi-database studies (MDS) leveraging secondary data have become an important strategy to conduct PAS in recent years, as reflected by the type of studies registered in the EU PAS register. OBJECTIVES: To analyse and describe PAS in the EU PAS register, with focus on MDS. METHODS: Studies in the EU PAS register from inception to 31st December 2018 were described concerning transparency, regulatory obligations, scope, study type (e.g., observational study, clinical trial, survey, systematic review/meta-analysis), study design, type of data collection and target population. MDS were defined as studies conducted through secondary use of >1 data source not linked at patient-level. Data extraction was carried out independently by 14 centres with expertise in pharmacoepidemiology, using publicly available information in the EU PAS register including study protocol, whenever available, using a standardised data collection form. For validation purposes, a second revision of key fields for a 15% random sample of studies was carried out by a different centre. The inter-rater reliability (IRR) was then calculated. Finally, to identify predictors of primary data collection-based studies/versus those based on secondary use of healthcare databases) or MDS (vs. non-MDS), odds ratios (OR) and 95% confidence intervals (CI) were calculated fitting univariate logistic regression models. RESULTS: Overall, 1426 studies were identified. Clinical trials (N = 30; 2%), systematic reviews/meta-analyses (N = 16; 1%) and miscellaneous study designs (N = 46; 3%) were much less common than observational studies (N = 1227; 86%). The protocol was available for 63% (N = 360) of 572 observational studies requested by a competent authority. Overall, 36% (N = 446) of observational studies were based fully or partially on primary data collection. Of 757 observational studies based on secondary use of data alone, 282 (37%) were MDS. Drug utilisation was significantly more common as a study scope in MDS compared to non-MDS studies. The overall percentage agreement among collaborating centres that collected the data concerning study variables was highest for study type (93.5%) and lowest for type of secondary data (67.8%). CONCLUSIONS: Observational studies were the most common type of studies in the EU PAS register, but 30% used primary data, which is more resource-intensive. Almost half of observational studies using secondary data were MDS. Data recording in the EU PAS register may be improved further, including more widespread availability of study protocols to improve transparency.
Subject(s)
Pharmacoepidemiology , Research Design , Databases, Factual , Humans , Observational Studies as Topic , Reproducibility of Results , Surveys and QuestionnairesABSTRACT
Motivation: Medications can have unexpected effects on disease, including not only harmful drug side effects, but also beneficial drug repurposing. These effects on disease may result from hidden influences of drugs on disease gene networks. Then, discovering how biological effects of drugs relate to disease biology can both provide insight into the mechanism of latent drug effects, and can help predict new effects. Results: Here, we develop Draphnet, a model that integrates molecular data on 429 drugs and gene associations of nearly 200 common phenotypes to learn a network that explains drug effects on disease in terms of these molecular signals. We present evidence that our method can both predict drug effects, and can provide insight into the biology of unexpected drug effects on disease. Using Draphnet to map a drug's known molecular effects to downstream effects on the disease genome, we put forward disease genes impacted by drugs, and we suggest a new grouping of drugs based on shared effects on the disease genome. Our approach has multiple applications, including predicting drug uses and learning drug biology, with implications for personalized medicine. Availability and implementation: Code to reproduce the analysis is available at https://github.com/RDMelamed/drug-phenome.
ABSTRACT
BACKGROUND AND OBJECTIVE: The gold standard treatment of established cytomegalovirus infection or prevention in solid organ transplantation is the intravenous administration of ganciclovir (GCV) or oral administration of valganciclovir (VGCV), both adjusted to the renal function. In both instances, there is a high interindividual pharmacokinetic variability, mainly owing to the wide range of variation of both the renal function and body weight. Therefore, accurate estimation of the renal function is crucial for GCV/VGCV dose optimization. This study aimed to compare three different formulas for estimating the renal function in solid organ transplantation patients with cytomegalovirus infection, for individualizing antiviral therapy with GCV/VGCV, using a population approach. METHODS: A population pharmacokinetic analysis was performed using NONMEM 7.4. A total of 650 plasma concentrations obtained after intravenous GCV and oral VGCV administrations were analyzed, from intensive and sparse sampling designs. Three different population pharmacokinetic models were built with the renal function given by Cockcroft-Gault, Modification of Diet in Renal Disease, or Chronic Kidney Disease EPIdemiology Collaboration (CKD-EPI) formulas. Pharmacokinetic parameters were allometrically scaled to body weight. RESULTS: The CKD-EPI formula was identified as the best predictor of between-patient variability in GCV clearance. Internal and external validation techniques showed that the CKD-EPI model had better stability and performed better compared with the others. CONCLUSIONS: The model based on the more accurate estimation of the renal function with the CKD-EPI formula and body weight as a size metric most used in the clinical practice can refine initial dose recommendations and contribute to GCV and VGCV dose individualization when required in the prevention or treatment of cytomegalovirus infection in solid organ transplantation patients.
Subject(s)
Cytomegalovirus Infections , Organ Transplantation , Renal Insufficiency, Chronic , Humans , Ganciclovir/pharmacokinetics , Ganciclovir/therapeutic use , Valganciclovir , Antiviral Agents/pharmacokinetics , Cytomegalovirus Infections/drug therapy , Cytomegalovirus Infections/prevention & control , Renal Insufficiency, Chronic/drug therapy , Kidney/physiologyABSTRACT
Type 2 diabetes mellitus is a serious health disorder with a global prevalence of 6059 cases per 100,000 in 2017. By analyzing real-world data, our study found an increasing prevalence of type 2 diabetes in Greece, with the peak being 7,40 individuals per 100,000 in 2016.
Subject(s)
Diabetes Mellitus, Type 2 , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/epidemiology , Greece/epidemiology , Humans , PrevalenceABSTRACT
OBJECTIVES: To determine the frequency of use, sources of information, and selection criteria of Greek residents regarding over-the-counter (OTC) drugs, as well as their opinion about their dispensing in nonpharmacy settings. METHODS: This was a survey study in which an anonymous cross-sectional questionnaire was used to assess the knowledge, habits, and attitudes about OTC drugs. Data were collected from March 2017 to July 2017 in Thessaloniki, the second largest city in Greece. Logistic regression was used to investigate significant factors that affect the participants' behavior. RESULTS: A total of 782 participants completed the questionnaire. The population had a mean (SD) age of 46 (17) years and 55.1% were females. About one-third (32.5%) of the participants used nonsteroidal anti-inflammatory drugs more than once per week. OTC drugs acting on the gastrointestinal tract were used to a lower extent (13.2%). The majority (84%) of the respondents consult a healthcare professional about the information on OTC drugs. Furthermore, when not sure about which OTC drug to use, 510 participants (65.6%) valued their physician's advice, whereas 480 participants (60.2%) valued their pharmacist's advice. Most participants (61.2%) were negatively inclined toward the purchase of OTC drugs in nonpharmacy settings, with younger participants being more receptive to out-of-pharmacy OTC drug purchase than older ones (odds ratio 2.20; 95% confidence interval 1.37-3.54). CONCLUSIONS: Healthcare professionals play an important role in providing people information on their selection of OTC drugs. This could be the main reason why participants prefer to buy OTC drugs from community pharmacies rather than retail shops.
Subject(s)
Nonprescription Drugs , Pharmacists , Attitude , Cross-Sectional Studies , Female , Greece , Habits , Humans , Middle Aged , Nonprescription Drugs/therapeutic useABSTRACT
INTRODUCTION: A large proportion of medicine product labels lack information on safety in pregnancy and breastfeeding. To address this gap, pharmaceutical companies are requested to develop post-approval studies regarding the use of drugs by pregnant and breastfeeding women. OBJECTIVE: Our study aims to review key features of observational studies in pregnancy and breastfeeding and their impact on the respective medicine product labels. METHODS: Observational studies focusing on the safety evaluation of medicines used during pregnancy and breastfeeding were selected from the European Union Register of Post-Authorization Studies (EU PAS register) and ClinicalTrials.gov. We extracted information on the variables of interest and performed an impact assessment on the respective label. RESULTS: A total of 141 observational studies were eligible. Of these, 63 studies (45%) were based on primary data collection and 55 studies (39%) on secondary use of health data. A small number of studies (8%) aimed to evaluate drug safety during breastfeeding. Studies using secondary data collection lasted around 2.9 years as opposed to 7.5 years' duration for studies using primary data collection. Only two product labels were updated based on the study results. CONCLUSION: The duration is significantly longer for studies based on primary data collection, and these are also smaller in size (less power), whereas outcomes of interest are similar. For completed studies, the impact on the label was very low. Given the gap in adequate pregnancy information on product labels, the current process of generating evidence in pregnancy and breastfeeding seems neither efficient nor impactful. To support evidence-based decision making by prescribers, this current process might be redesigned.
Subject(s)
Breast Feeding , Pregnancy Outcome , Female , Humans , Marketing , PregnancyABSTRACT
BACKGROUND: The prevalence of potential drug-drug interactions (pDDIs) is indicative of the prevalence of actual drug-drug interactions and prescription quality. However, they are significantly understudied in Greece. OBJECTIVE: The objective of the study was to determine the prevalence of pDDIs among outpatients and identify factors associated with their occurrence. METHODS: Anonymous e-prescription data between 2012 and 2017 were obtained from community pharmacies in Thessaloniki, Greece. Patients taking more than one medication for at least three months were included. pDDIs were identified and categorized depending on their clinical significance using Drug Interactions Checker. Crude and adjusted odds ratios (ORs) with accompanying 95% confidence intervals (CIs) of risk factors of pDDIs occurrence were identified using multivariable logistic regression. RESULTS: During the study period, 6,000 anonymous e-prescriptions (1,000 per year) satisfying the inclusion criteria were collected. The overall prevalence of major pDDIs was 17.4% (63.0% for moderate pDDIs). The most common major pDDIs were between amlodipine and simvastatin (22.8% of major interactions), followed by clopidogrel and omeprazole (6.4% of major interactions). Polypharmacy (≥5 concomitantly received medications) was associated with an increased risk of major pDDIs (adjusted OR, 5.72; 95% CI, 4.87-6.72); no associations were observed regarding age, sex, and number of prescribing physicians. CONCLUSION: The prevalence of pDDIs in this study was higher than previously reported in other European countries, with polypharmacy being a potential risk factor. Those results argue for a need for improvement in the area of prescribing in Greece.
Subject(s)
Electronic Prescribing , Drug Interactions , Greece/epidemiology , Humans , Polypharmacy , PrevalenceABSTRACT
INTRODUCTION: Recent case reports suggested that concomitant use of sodium-glucose co-transporter 2 (SGLT2) inhibitors with statins could lead to increased statin toxicity. We provide a comprehensive overview of the available pharmacological and clinical evidence on this potential drug-drug interaction (DDI). AREAS COVERED: We searched MEDLINE PubMed until November 2020 for (i) pharmacokinetic studies on SGLT2 inhibitors, statins, and their potential interaction, and (ii) case reports and clinical studies assessing the safety of concomitant use of SGLT2 inhibitors and statins. We also searched regulatory documents submitted to the United States Food and Drug Administration for unpublished data on this potential DDI. EXPERT OPINION: SGLT2 inhibitors are increasingly used for type 2 diabetes, chronic heart failure, and chronic kidney disease, and concomitant use with statins is common given the comorbidity of indications. While pharmacokinetic studies in healthy subjects showed no clinically relevant changes in statin levels during SGLT2 inhibitor co-administration, the published case reports and pharmacologic reasoning support the possibility of an interaction. Underlying mechanisms could be pharmacokinetic or pharmacodynamic, and canagliflozin appears to be the SGLT2 inhibitor with the highest interaction potential. Further research including 'real-world' pharmacoepidemiologic studies is needed to better understand the clinical significance of this DDI.