An Investigation of O-Demethyl Tramadol/Tramadol Ratio for Cytochrome P450 2D6 Phenotyping: The CYTRAM Study.

Cytochrome P450 2D6 (CYP2D6) gene polymorphisms influence the exposure to tramadol (T) and its pharmacologically active metabolite, O-demethyl tramadol (O-dT). Tramadol has been considered as a candidate probe drug for CYP2D6 phenotyping. The objective of the CYTRAM study was to investigate the value of plasma O-dT/T ratio for CYP2D6 phenotyping. European adult patients who received IV tramadol after surgery were included. CYP2D6 genotyping was performed and subjects were classified as extensive (EM), intermediate (IM), poor (PM), or ultra-rapid (UM) CYP2D6 metabolizers. Plasma concentrations of tramadol and O-dT were determined at 24 h and 48 h. The relationship between O-dT/T ratio and CYP2D6 phenotype was examined in both a learning and a validation group. Genotype data were obtained in 301 patients, including 23 PM (8%), 117 IM (39%), 154 EM (51%), and 7 UM (2%). Tramadol trough concentrations at 24 h were available in 297 patients. Mean value of O-dT/T ratio was significantly lower in PM than in non-PM individuals (0.061 ± 0.031 versus 0.178 ± 0.09, p < 0.01). However, large overlap was observed in the distributions of O-dT/T ratio between groups. Statistical models based on O-dT/T ratio failed to identify CYP2D6 phenotype with acceptable sensitivity and specificity. Those results suggest that tramadol is not an adequate probe drug for CYP2D6 phenotyping.

REview of potentially inappropriate MEDIcation pr[e]scribing in Seniors (REMEDI[e]S): French implicit and explicit criteria.

PURPOSE: To establish a consensus on both explicit and implicit criteria in order to identify potentially inappropriate prescribing (PIP) in French older people aged 75 years and over or 65 years and over with multimorbidity. METHODS: Fifteen experts in geriatrics, general practice, pharmacy, and clinical pharmacology were involved in a two-round Delphi survey to assess preliminary explicit and implicit criteria based on an extensive literature review and up-to-date evidence data. Experts were asked to rate their level of agreement using a 5-level Likert scale for inclusion of criteria and also for rationale and therapeutic alternatives. A consensus was considered as reached if at least 75% of the experts rated criteria as "strongly agreed" or "agreed." RESULTS: The new tool included a seven-step algorithm (implicit criteria) encompassing the three main domains that define PIP (i.e. overprescribing, underprescribing, and misprescribing) and 104 explicit criteria. Explicit criteria were divided into 6 tables related to inappropriate drug duplications (n = 7 criteria), omissions of medications and/or medication associations (n = 16), medications with an unfavourable benefit/risk ratio and/or a questionable efficacy (n = 39), medications with an unsuitable dose (n = 4) or duration (n = 6), drug-disease (n = 13), and drug-drug interactions (n = 19). CONCLUSION: The REMEDI[e]S tool (REview of potentially inappropriate MEDIcation pr[e]scribing in Seniors) is an original mixed tool, adapted to French medical practices, aimed at preventing PIP both at the individual level in clinical practice and the population level in large-scale studies. Therefore, its use could contribute to an improvement in healthcare professionals' prescribing practices and safer care in older adults.

[Evaluation of direct oral anticoagulants (DOACs) prescriptions in geriatric hospital over 3 years]. / Évaluation des prescriptions d'anticoagulants oraux directs (AOD) en gériatrie hospitalière sur 3 ans.

INTRODUCTION: Direct oral anticoagulants (DOACs) are an attractive choice for patients in need of anticoagulant therapy, but available data on their specific use in real life conditions in elderly patients are limited. The purpose of this study is to describe the characteristics and evolution of the prescriptions in geriatric hospital. PATIENTS AND METHODS: The prescriptions of patients treated with DOACs in two university geriatric hospitals were analyzed retrospectively over 3 years. Co-treatment and hemorrhagic and thrombotic complications were studied. RESULTS: A total of 399 patients were included, including 10 in 2015, 110 in 2016 and 279 in 2017. The average age was 85 years old, 40% of patients had a weight of less than 60kg, and more than 50% had an estimated creatinine clearance of less than 50mL/min. The most common indication was atrial fibrillation in 85%. In 32% of cases, the dosage of DOACs was not adapted to official recommendations. Underdosages accounted for approximately 60% of dosage errors. Twelve patients (3% of the cohort) had a thrombotic event under DOACs, associated with an underdosing in 50% of them. 41 patients, or 10% of the cohort, had a hemorrhagic event under DOACs, with 12 patients (29%) having a pharmacologic risk factor (10 overdoses and 2 drug interactions). CONCLUSION: The prescription of DOACs in elderly patients has increased considerably in recent years. However, dosing errors remain frequent (overdoses as underdoses), associated with hemorrhagic or thrombotic events. Similarly, drug interactions should be known as they are a risk factor for avoidable under- or overdose. Improving prescriptions of DOACs in geriatrics needs to respect the rules of good practice, to regularly reassess renal function, and to transmit observations of adverse effects to pharmacovigilance centers.

Prevalence and Risk Factors of Drug-Associated Corrected QT Prolongation in Elderly Hospitalized Patients: Results of a Retrospective Analysis of Data Obtained Over 6 Months.

OBJECTIVES: Little information exists on the frequency and determinants of drug-associated long QT syndrome in older adults. The objectives of this study were to assess the prevalence and identify risk factors of drug-associated long QT syndrome in a population of elderly hospitalized patients. METHODS: This was a retrospective study performed over 6 months in hospital geriatric medicine. Various QT-correction equations were fitted to the individual QT-RR data to evaluate the most appropriate equation. Long QT syndrome was defined as corrected QT ≥450 ms. Available data were compared in patients with and without long QT syndrome. Logistic regression and classification and regression tree analysis were performed to identify determinants of long QT syndrome. RESULTS: Thirty-three of 152 patients (22%) exhibited corrected QT ≥450 ms. The different QT correction equations provided similar results, except the Bazett equation. In patients with long QT syndrome, there was a higher proportion of male subjects (58 vs. 33%, p = 0.009) and a higher number of QT-prolonging drugs than in patients without long QT syndrome. Male sex (odds ratio, 3.25) and the number of prescribed QT-prolonging agents (odds ratio, 1.77) were significantly associated with the probability of long QT syndrome. The number of QT-prolonging drugs had a stronger influence on the risk of long QT syndrome in men than in women. CONCLUSION: Male sex was found to be a significant risk factor of corrected QT prolongation in elderly hospitalized patients. The risk also increased with the number of QT-prolonging agents, especially in men. Those findings may help to mitigate the risk of long QT syndrome in elderly patients in clinical practice.

Implications of using the MDRD or CKD-EPI equation instead of the Cockcroft-Gault equation for estimating renal function and drug dosage adjustment in elderly patients.

The objectives of this study were to compare the estimations of renal function obtained with six equations, including the Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations and to evaluate the implication of using other equations for drug dosing in elderly patients in place of CG. An observational prospective study was conducted over 6 months in two geriatric hospitals with inclusions of all hospitalized inpatients. A list of 36 drugs for which recommendations of dosage adjustment for renal function were mentioned in the manufacturer dosing guidelines was used to compare the implications of using the various equations for drug dosing. A total of 249 patients with a mean age of 83.6 years were included. Mean estimates of renal function from the CG, MDRD, and CKD-EPI equations were 51.3 ± 23.5 mL/min, 72.2 ± 35.2, and 64.3 ± 22.5 mL/min/1.73 m2 , respectively (P < 0.001). Twenty percent of patients had at least one drug for which the dose was not appropriately adjusted to renal function. The use of the MDRD and CKD-EPI equations in place of the CG equation was associated with dosage discrepancy in 20-25% of patients and 15% of drug orders, resulting in potential overdosage in 95% of cases. Use of MDRD or CKD-EPI equations results in higher estimates of renal function and may have important implications for drug dosing decision and drug safety in elderly patients. The best way is to directly measure the drug effect or its concentration when it is possible to do so.

[Moderate potentially drug-induced hyponatremia in older adults: benefit in drug reduction]. / L'hyponatrémie modérée potentiellement médicamenteuse du sujet âgé : bénéfice de la réduction des médicaments.

OBJECTIVE: This study aimed at evaluating the benefit of changing drug therapy in elderly patients with moderate, potentially drug-induced hyponatremia. METHODS: Hospitalized older adults, with moderate hyponatremia, potentially induced by drugs, were randomized into two arms: an interventional group, whose drug therapy was changed, and a reference group, which received standard care. The effectiveness of the intervention was evaluated by the normalization of serum sodium after four weeks and by the incidence of falls three months later. RESULTS: Nineteen patients were randomized, fourteen evaluated at 4 weeks. Serum sodium was normalized more frequently in the interventional group than in the reference group: 75% (6/8) IC95% [35-97] versus 0% (0/6) IC95% [0-46]; p=0.01. A greater reduction in falls occurred in the therapeutic intervention group 75% (3/4) IC95% [19-99] versus 0% (0/5) IC95% [0-52]; p=0.048. CONCLUSION: This study showed the biological and clinical benefit of a pharmalogical intervention. Registration number of the study: ID RCB 2010-A00778-31.