A Generic Model for Quantitative Prediction of Interactions Mediated by Efflux Transporters and Cytochromes: Application to P-Glycoprotein and Cytochrome 3A4.

BACKGROUND AND OBJECTIVE: The In Vivo Mechanistic Static Model (IMSM) is a powerful method used to predict the magnitude of drug-drug interactions (DDIs) mediated by cytochromes. The objective of this study was to extend the IMSM paradigm to DDIs mediated by efflux transporters and cytochromes. METHODS: First, a generic model for this kind of interaction was devised. A flexible approach was then developed to estimate the characteristic parameters [the contribution ratios (CRs) and inhibition or induction potencies (IXs)] from clinical data by non-linear regression. Next, this approach was applied to the DDIs mediated by P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4/3A5 in a large set of victim drugs and interactors. Lastly, the model and associated parameters were used to identify the DDIs most at risk of overexposure. RESULTS: A total of 25 substrates and 26 interactors (three inducers, 23 inhibitors) could be considered in the regression analysis. The number of observations [area under the plasma concentration-time curve ratios or renal clearance ratios (Robs)] was 138. Fifty CRs and 57 IXs were estimated. The proportions of predictions within 0.67- to 1.5-fold Robs and within 0.5- to 2-fold Robs were 79% and 93% for the internal validation and 76% and 88% for the external validation, respectively. The median fold error was 0.98 (the ideal value is 1) and the interquartile range of the fold error was 0.36. The relative standard error of parameter estimates was a maximum of 15%. CONCLUSIONS: The IMSM approach was successfully extended to DDIs mediated by P-gp and CYP3A4/3A5. The method revealed good predictive performances by internal and external validation.

[Proper use of fluoroquinolones in hospitalized elderly patients: Realisation of a clinical audit in geriatric hospitals of Lyon University Hospital]. / Bon usage des fluoroquinolones chez le sujet âgé hospitalisé : réalisation d'un audit clinique dans les hôpitaux gériatriques des hospices civils de Lyon.

INTRODUCTION: Fluoroquinolones (FQ) are widely used because of their broad spectrum and their ease of use, especially in the elderly. Nevertheless, their misuse is behind the development and the emergence of bacterial resistances. The objective of this study was to evaluate the compliance of FQ prescriptions in the elderly hospitalized, before and after pharmaceutical interventions (PI). METHODS: A prospective clinical audit was conducted for three months in three geriatric hospitals. A pharmacist carried out the evaluation of the prescription's conformity with the help of referent geriatric doctor in infectiology according to the criteria defined by SPILF recommendations (2015). The PIs and their future have been collected and codified. RESULTS: A total of 100 patients were included (mean age: 85.3 years; male female ratio: 1,17). The medical-pharmaceutical collaboration helped to increase the overall compliance rate from 56 to 80%. FQ were used for urinary (72%) or respiratory (20%) infections, first-line (57%), documented (60%) and monotherapy (63%). Our results show that FQ misuse is a not inconsiderable case since in 28% they should not have been prescribed. Thirty-three PI were performed and accepted in 72% cases. CONCLUSION: Actions to promote the FQ proper use have therefore been put in place: communication of the audit results, dissemination of a summary of SPILF recommendations and creation of a tool to assist in the analysis of prescriptions FQ for pharmacists.

[Pharmacokinetic risk factors of beta-blockers overdose in the elderly: Case report and pharmacology approach]. / Facteurs de risque pharmacocinétiques de surdosage en bêta-bloquants chez les patients âgés : cas clinique et rationnel pharmacologique.

Beta-blockers are widely prescribed in elderly patients and may induce severe adverse drug reactions. We report a case of bisoprolol-induced bradycardia in an elderly patient with impaired renal function and use of cytochrome P450 inhibitors. A literature review has been performed in order to analyze pharmacokinetic risk factors of beta-blockers overdosing in geriatrics. Various mechanisms can result in decreased elimination of beta-blockers. These mechanisms vary according to the beta-blocker agent and may be combined in some individuals, especially elderly patients. This can lead to unexpected overexposure. Knowledge about drug interactions and pharmacokinetic elimination pathways is important for preventing overexposure and adverse drug reactions when using beta-blockers.

Risk factors for urinary tract infections in geriatric hospitals.

BACKGROUND: Urinary tract infection (UTI) is the most frequent nosocomial infection in geriatric units. An understanding of risk factors for infection may help to identify prevention strategies. AIM: Identification of the risk factors for UTI in elderly patients. METHODS: Retrospective analysis of three prospective cohorts. All hospitalized patients present in, or admitted to, a geriatric unit from June 1st to June 28th, for the years 2009, 2012, and 2015 were included and followed until discharge or until June 30th of the year concerned. For each patient, type and dates of stay, type and dates of catheter, risk factors, and nosocomial UTI (NUTI) data were collected. Univariate and multivariate (Cox model) analyses were made using SPSS software. FINDINGS: A total of 4669 patients were included and were followed for a total of 83,068 days. There were 189 NUTIs (4.0% patients). NUTIs were significantly more frequent among female patients, in rehabilitation units, in immunosuppressed patients, among those with acute retention, post-void residual, history of urinary tract infection in the previous six months, and in case of dependency. NUTIs were significantly more frequent among those who had a catheter (Z-test, P < 0.001). NUTIs were more frequent among patients with intermittent, indwelling, or suprapubic catheters. They were also more frequent in acute/subacute care or rehabilitation units, in women, in immunosuppressed patients, and in those with a history of previous UTI; they were less frequent in dementia patients. CONCLUSION: The occurrence of NUTI is an important issue in both catheterized and non-catheterized patients; prevention programmes should be widened to include non-catheterized patients.

Factors associated with changes in exposure to anticholinergic and sedative medications in elderly hospitalized patients: multicentre longitudinal study.

BACKGROUND AND PURPOSE: Elderly patients exposed to drugs with anticholinergic or sedative properties may have an increased risk of adverse events. This study aimed to assess the relationship between patient characteristics and changes of exposure to anticholinergic and sedative medications during their hospital stay. METHODS: A multicentre longitudinal study was set up on hospitalized patients (aged ≥65 years) using at least one drug at admission. The primary outcome was change of exposure to anticholinergic and sedative drugs between admission and discharge. Sociodemographic characteristics of the patients, comorbidities, life habits and information about the hospital stay (origin of admission, reasons for hospitalization) were collected. RESULTS: The study included 337 patients (mean age, 85.4 years) with an average hospital stay of 30.1 ± 37.5 days. The drug burden index increased during the hospital stay among males (P = 0.03), patients for whom the reason for hospitalization was either a stroke (P = 0.001) or inability to stay in their own home (P = 0.001), and patients with diabetes mellitus (P = 0.009). In the adjusted model, drug burden index increased among patients hospitalized for stroke, inability to stay in their own home or post-surgery, and for patients with diabetes mellitus or hypertension. CONCLUSIONS: The drug management of elderly patients during hospital stays may increase exposure to anticholinergic and sedative drugs. Although the anticholinergic and sedative properties may be in relation to the therapeutic purpose, they also represent an unexpected risk. Physicians and clinical pharmacists should consider performing optimization of the drug prescriptions for patients at risk.

A Model for Predicting the Interindividual Variability of Drug-Drug Interactions.

Pharmacokinetic drug-drug interactions are frequently characterized and quantified by an AUC ratio (Rauc). The typical value of the AUC ratio in case of cytochrome-mediated interactions may be predicted by several approaches, based on in vitro or in vivo data. Prediction of the interindividual variability of Rauc would help to anticipate more completely the consequences of a drug-drug interaction. We propose and evaluate a simple approach for predicting the standard deviation (sd) of Ln(Rauc), a metric close to the interindividual coefficient of variation of Rauc. First, a model was derived to link sd(Ln Rauc) with the substrate fraction metabolized by each cytochrome and the potency of the interactors, in case of induction or inhibition. Second, the parameters involved in these equations were estimated by a Bayesian hierarchical model, using the data from 56 interaction studies retrieved from the literature. Third, the model was evaluated by several metrics based on the fold prediction error (PE) of sd(Ln Rauc). The median PE was 0.998 (the ideal value is 1) and the interquartile range was 0.96-1.03. The PE was in the acceptable interval (0.5 to 2) in 52 cases out of 56. Fourth, a surface plot of sd(Ln Rauc) as a function of the characteristics of the substrate and the interactor has been built. The minimal value of sd(Ln Rauc) was about 0.08 (obtained for Rauc = 1) while the maximal value, 0.7, was obtained for interactions involving highly metabolized substrates with strong interactors.

Population modeling and simulation study of the pharmacokinetics and antituberculosis pharmacodynamics of isoniazid in lungs.

Among first-line antituberculosis drugs, isoniazid (INH) displays the greatest early bactericidal activity (EBA) and is key to reducing contagiousness in treated patients. The pulmonary pharmacokinetics and pharmacodynamics of INH have not been fully characterized with modeling and simulation approaches. INH concentrations measured in plasma, epithelial lining fluid, and alveolar cells for 89 patients, including fast acetylators (FAs) and slow acetylators (SAs), were modeled by use of population pharmacokinetic modeling. Then the model was used to simulate the EBA of INH in lungs and to investigate the influences of INH dose, acetylator status, and M. tuberculosis MIC on this effect. A three-compartment model adequately described INH concentrations in plasma and lungs. With an MIC of 0.0625 mg/liter, simulations showed that the mean bactericidal effect of a standard 300-mg daily dose of INH was only 11% lower for FA subjects than for SA subjects and that dose increases had little influence on the effects in either FA or SA subjects. With an MIC value of 1 mg/liter, the mean bactericidal effect associated with a 300-mg daily dose of INH in SA subjects was 41% greater than that in FA subjects. With the same MIC, increasing the daily INH dose from 300 mg to 450 mg resulted in a 22% increase in FA subjects. These results suggest that patients infected with M. tuberculosis with low-level resistance, especially FA patients, may benefit from higher INH doses, while dose adjustment for acetylator status has no significant impact on the EBA in patients with low-MIC strains.

New developmental data for Cynomya mortuorum (L., 1761) in Belgium (Diptera: Calliphoridae).

The calliphorid Cynomya mortuorum (L., 1761) is a forensically important species mainly found in the Palearctic region. Knowledge about its biology and ecology is scarce. Thermal constants as well as developmental time were studied at constant and variable regimes of 5 average temperatures: 14, 16, 18, 20 and 22°C, respectively. Total developmental time varied between 15.82±0.40 days at 22°C and 28.67±2.38 days at 14°C, for the constant regime, and between 16.05±0.67 days at 22°C and 32.79±1.77 days at 14°C, for the variable regime. No significant differences were observed between ADD, and threshold at the constant (ADD: 277.39±14.78 DD; lower threshold: 4.72°C) and variable regimes (275.99±14.16 DD; lower threshold: 5.05°C).

Controlling urinary tract infections associated with intermittent bladder catheterization in geriatric hospitals.

BACKGROUND: Controlling urinary tract infections (UTIs) associated with intermittent catheterization in geriatric patients. AIM: After a local epidemiological study identified high rates of UTI, a multi-disciplinary working group implemented and evaluated corrective measures. METHODS: In 2009, a one-month prospective study measured the incidence of UTI, controlled for risk factors and exposure, in six geriatric hospitals. In 2010, a self-administered questionnaire on practices was administered to physicians and nurses working in these geriatric units. In 2011, the working group developed a multi-modal programme to: improve understanding of micturition, measurement of bladder volume and indications for catheter drainage; limit available medical devices; and improve prescription and traceability procedures. Detailed training was provided to all personnel on all sites. The epidemiological study was repeated in 2012 to assess the impact of the programme. FINDINGS: Over 1500 patients were included in the 2009 study. The incidence of acquired infection was 4.8%. The infection rate was higher in patients with intermittent catheters than in patients with indwelling catheters (29.7 vs 9.9 UTI per 100 patients, P = 0.1013) which contradicts the literature. In 2010, the 269 responses to the questionnaire showed that staff did not consider catheterization to place patients at risk of infection, staff had poor knowledge of the recommended indications and techniques, and the equipment varied widely between units. Following implementation of the programme, the study was repeated in 2012 with over 1500 patients. The frequency of UTI in patients with intermittent catheters fell to rates in the published literature. CONCLUSION: Multi-modal programmes are an effective means to control UTI.

Study of relationship between volume of distribution and body weight application to amikacin.

Amikacin use is difficult because of its narrow therapeutic and its pharmacokinetic variability. This variability of amikacin is not well known. To adapt amikacin the physician assumes that there is a linear and continuous relation between the volume of distribution and the body weight. The objective of our study was to evaluate the relationship between the volume of distribution (Vd) and the body weight (BW) using a non parametric statistical analysis of dependence so called Z method. Retrospective pharmacokinetic population study and statistic analysis. 872 patients receiving intravenous amikacin. The volume of distribution was modelled using the Non Parametric Adaptive Grid algorithm (NPAG) for a two-compartment model with intravenous infusion. Z coefficient was performed to evaluate the relationships between Vd and BW. For the 872 patients (mean age of 73 ± 17 years) dispatched as follow 53 % female and 47 % male, the analysis of the statistical relationships by the non parametric Z analysis showed a scattered linkage between Vd and BW. For the whole population, the relationship between Vd and BW was not linear (regression analysis). Z analysis demonstrated that only for 80 % of patients there is a relationship between Vd and BW. For these patients, regression analysis give a significant adjustment of a linear model (r = 0.47, p < 0.001). In the whole studied population there is not a continuous and linear relationship between Vd estimated by NPAG and the BW. These results underline the difficulties to adapt doses of amikacin with only BW information.

[Inter-individual and intra-individual pharmacokinetic variability during teicoplanin therapy in geriatric patients]. / Variabilité pharmacocinétique inter- et intra-individuelle lors de traitements par teicoplanine chez les sujets âgés.

OBJECTIVES: The authors had for aim to assess the inter- and intra-individual variability of teicoplanin pharmacokinetic parameters in geriatric patients. METHODS: A cohort of 90 geriatric patients, treated with teicoplanin, was used to build two models describing the pharmacokinetics of teicoplanin, at the beginning and at the end of treatment respectively. RESULTS: The inter- and intra-individual variability of parameters were important as shown respectively by the coefficients of variation of pharmacokinetic parameters ranging from 125 to 694% and the half-life change during the treatment (by a factor of three to more than 30) for 60% of patients. CONCLUSIONS: The results revealed that elderly patients presented significant variability, which was only partly explained by the renal function. Therapeutic monitoring of teicoplanin in geriatric patients should be undertaken at the end of the loading dose and repeatedly during the maintenance phase to prevent over- or underexposure.

Guidelines for aminoglycoside use and applicability to geriatric patients.

OBJECTIVES: The authors had for objective to evaluate the applicability of AFSSAPS guidelines for aminoglycoside use to geriatric patients. METHODS: Theoretical doses and dosing regimens allowing reaching target concentrations in this population were calculated by applying a pharmacokinetic model to 30 geriatric patients treated by amikacin. RESULTS: The dose allowing reaching a maximum concentration of 60 mg/L was 1.217 mg on average. The time required to reach a blood concentration lower than or equal to 2.5mg/L was 62.5±70.4 hours. Forty-six percent of patients had a trough concentration greater than 2.5 mg/L, 48 hours after administration. For these patients, the time between critical minimum inhibitory concentration (MIC) and toxicity threshold concentration was 21.9±14.9 hours. CONCLUSION: Reaching a target concentration can be problematic in geriatric patients. It is frequently necessary to use dosing intervals greater than 48 hours. The effectiveness and safety of these regimens remain uncertain.

[Calculation of the first dose of amikacine: evaluation of the current dosage recommendations]. / Calcul de la première dose d'amikacine : évaluation des recommandations posologiques actuelles.

Aminoglycosides, including amikacin, are antibiotics with major interest in the management of sepsis, but with a high potential toxicity. The French national recommendations revised in 2011 recommend a dose of amikacin ranging from 15 to 30 mg/kg. The objective was to assess if such a dose interval allows reaching the efficiency target concentrations of 64 mg/L without exceeding the toxic threshold of 2.5mg/L. From a cohort of 100 patients treated with amikacin, the individual pharmacokinetic parameters were estimated using pharmacokinetic software (MM-USCPACK). Peak and residual concentrations obtained after simulated doses ranging from 15 to 30 mg/kg were estimated and compared with the effective and toxic thresholds. The optimum dose to achieve precisely the efficiency target was calculated for each patient. Patients studied had a mean age of 79 years, mean weight of 58 kg, and mean creatinine clearance of 45 mL/min. The dose of 30 mg/kg allows the achievement of an effective peak in 98.7% of patients, but led to a potentially toxic through for 72.4% of them. The optimal dose was at mean of 1264 mg, significantly different than doses calculated with weight (P<0.0001). A weak correlation was found between weight and the optimal dose. A fixed dose of 30 mg/kg seems to be effective for most patients, but often excessive and leads to a toxic residual to 72% of patients, whereas 15 mg/kg was insufficient for most patients. The low correlation between optimal dose and patient weight shows that weight does not explain fully the interindividual variability.

[Practical application of the charter of pharmaceutical sales visit]. / Application pratique de la charte de la visite médicale.

BACKGROUND: Visits from pharmaceutical representatives are controlled in France by regulations, but also by a Charter of good practice. The goal of this study was to measure compliance to the conditions of this charter by participating pharmaceutical companies. MATERIAL AND METHODS: An assessment grid was drafted to determine compliance to interdictions and obligations concerning the information provided during visits from pharmaceutical representatives. RESULTS: We studied 20 visits from pharmaceutical representatives. All of the documents and obligatory information were only provided in 5% of cases. During 80% of these meetings, the pharmaceutical representatives made a comparison with competitor's drugs, which was associated with negative remarks in 44% of cases. The pharmaceutical representatives promoted cases of use outside those, which had received marketing approval in 35%. Gifts or samples were offered at the end of these meetings in 20% of cases. Prohibited practices were observed in a total of 85% of cases. DISCUSSION: This study shows that meetings are respected by pharmaceutical representatives in terms of regulations related to donations. In opposite, there is a very low compliance concerning the proper use of the drug, whether to provide official documentation, to give information respectful of other pharmaceutical companies or to promote the proper use. CONCLUSION: Our results suggest that, at present hospital visits by pharmaceutical representatives do not respect the commitments made by the pharmaceutical industry, and do not make it possible to ensure that honest information is provided to favor the proper use of drugs.

[Relationship between benzodiazepines use and falls in the elderly: a multicenter study in three geriatric centers of a university hospital]. / Relation entre consommation de benzodiazépines et chutes en gériatrie : étude multicentrique dans trois établissements gériatriques d'un CHU.

INTRODUCTION: Benzodiazepines are widely used in the elderly, but may induce potentially severe iatrogenic events like falls. The analysis of their use is difficult because of the numerous molecules and dosages available. The aim of the present study is to build a tool to monitor their consumption and to evaluate the relation between this consumption and patient's falls reported in three geriatric institutions. METHODS: Conversion coefficients found in the literature allowed the expression of benzodiazepine action with a unique comparator: diazepam. Benzodiazepine consumption observed during 20 consecutive months was collected and weighted by hospital activity. A correlation between benzodiazepine consumption and the number of falls reported during the same period was researched. RESULTS: Benzodiazepine consumption expressed in milligrams of diazepam-equivalent per hospitalization day is significantly linked to the number of falls expressed during the same period (R=0.63; p<0.01). However, no statistical bound was found between monthly falls variations and monthly benzodiazepine consumption variations. These results corroborate others published studies: benzodiazepine consumptions are statistically linked to falls, but the reduction of this consumption is of poor predictive value, maybe because of the multifactorial nature of falls. DISCUSSION AND CONCLUSION: The expression of benzodiazepine consumption in diazepam-equivalent enables one to estimate the general exposition of patients and to compare the use of each molecule. The statistical link between this indicator and a major iatrogenic event like falls makes it a tool worth interest for both clinicians and pharmacists.

Stem cell marker (Nanog) and Stat-3 signaling promote MicroRNA-21 expression and chemoresistance in hyaluronan/CD44-activated head and neck squamous cell carcinoma cells.

MicroRNAs are often associated with the pathogenesis of many cancers, including head and neck squamous cell carcinoma (HNSCC). In particular, microRNA-21 (miR-21) appears to have a critical role in tumor cell survival, chemoresistance and HNSCC progression. In this study, we investigated matrix hyaluronan (HA)-induced CD44 (a primary HA receptor) interaction with the stem cell markers, Nanog and Stat-3, in HNSCC cells (HSC-3 cells). Our results indicate that HA binding to CD44 promotes Nanog-Stat-3 (also tyrosine phosphorylated Stat-3) complex formation, nuclear translocation and transcriptional activation. Further analyses reveal that miR-21 is controlled by an upstream promoter containing Stat-3 binding site(s), while chromatin immunoprecipitation assays demonstrate that stimulation of miR-21 expression by HA/CD44 signaling is Nanog/Stat-3-dependent in HNSCC cells. This process results in a decrease of a tumor suppressor protein (PDCD4), and an upregulation of i nhibitors of the apoptosis family of proteins (IAPs) as well as chemoresistance in HSC-3 cells. Treatment of HSC-3 cells with Nanog- and/or Stat-3-specific small interfering RNAs effectively blocks HA-mediated Nanog-Stat-3 signaling events, abrogates miR-21 production and increases PDCD4 expression. Subsequently, this Nanog-Stat-3 signaling inhibition causes downregulation of survival protein (IAP) expression and enhancement of chemosensitivity. To further evaluate the role of miR-21 in tumor cell-specific functions, HSC-3 cells were also transfected with a specific anti-miR-21 inhibitor in order to silence miR-21 expression and block its target functions. Our results demonstrate that anti-miR-21 inhibitor not only upregulates PDCD4 expression but also decreases IAP expression and enhances chemosensitivity in HA-treated HNSCC cells. Together, these findings indicate that the HA-induced CD44 interaction with Nanog and Stat-3 has a pivotal role in miR-21 production leading to PDCD4 reduction, IAP upregulation and chemoresistance in HNSCC cells. This novel Nanog/Stat-3 signaling pathway-specific mechanism involved in miR-21 production is significant for the formation of future intervention strategies in the treatment of HA/CD44-activated HNSCC.

[Interindividual pharmacokinetic variability in long-term antibiotherapy]. / Variabilité pharmacocinétique intra-individuelle et traitement antibiotique prolongé.

OBJECTIVE: The authors wanted to assess intraindividual pharmacokinetic variability, with a case of long-term amikacin therapy. DESIGN: A 92-year-old female patient, weighing 44kg, with renal failure, was treated by amikacin for 52 days. Her individual pharmacokinetic parameters were assessed 12 times in the course of therapy. The intraindividual variability of key parameters was quantified and compared with published interindividual variability. RESULTS: Intraindividual volume and clearance variability was measured at about one fourth to one third of the value observed for interindividual variability. Half-life intraindividual variability was almost equivalent to the interindividual variability: 24.5% versus 32%. CONCLUSIONS: The high pharmacokinetic variability observed has important potential clinical consequences. This case illustrates the need to ensure the effectiveness of treatment, to re-evaluate periodically the patient's status in order to take into account the intraindividual variability of pharmacokinetics parameters.