Hydrocortisone plus fludrocortisone for community acquired pneumonia-related septic shock: a subgroup analysis of the APROCCHSS phase 3 randomised trial.

BACKGROUND: Glucocorticoids probably improve outcomes in patients hospitalised for community acquired pneumonia (CAP). In this a priori planned exploratory subgroup analysis of the phase 3 randomised controlled Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS) trial, we aimed to investigate responses to hydrocortisone plus fludrocortisone between CAP and non-CAP related septic shock. METHODS: APROCCHSS was a randomised controlled trial that investigated the effects of hydrocortisone plus fludrocortisone, drotrecogin-alfa (activated), or both on mortality in septic shock in a two-by-two factorial design; after drotrecogin-alfa was withdrawn on October 2011, from the market, the trial continued on two parallel groups. It was conducted in 34 centres in France. In this subgroup study, patients with CAP were a preselected subgroup for an exploratory secondary analysis of the APROCCHSS trial of hydrocortisone plus fludrocortisone in septic shock. Adults with septic shock were randomised 1:1 to receive, in a double-blind manner, a 7-day treatment with daily administration of intravenous hydrocortisone 50 mg bolus every 6h and a tablet of 50 µg of fludrocortisone via the nasogastric tube, or their placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included all-cause mortality at intensive care unit (ICU) and hospital discharge, 28-day and 180-day mortality, the number of days alive and free of vasopressors, mechanical ventilation, or organ failure, and ICU and hospital free-days to 90-days. Analysis was done in the intention-to-treat population. The trial was registered at ClinicalTrials.gov (NCT00625209). FINDINGS: Of 1241 patients included in the APROCCHSS trial, CAP could not be ruled in or out in 31 patients, 562 had a diagnosis of CAP (279 in the placebo group and 283 in the corticosteroid group), and 648 patients did not have CAP (329 in the placebo group and 319 in the corticosteroid group). In patients with CAP, there were 109 (39%) deaths of 283 patients at day 90 with hydrocortisone plus fludrocortisone and 143 (51%) of 279 patients receiving placebo (odds ratio [OR] 0·60, 95% CI 0·43-0·83). In patients without CAP, there were 148 (46%) deaths of 319 patients at day 90 in the hydrocortisone and fludrocortisone group and 157 (48%) of 329 patients in the placebo group (OR 0·95, 95% CI 0·70-1·29). There was significant heterogeneity in corticosteroid effects on 90-day mortality across subgroups with CAP and without CAP (p=0·046 for both multiplicative and additive interaction tests; moderate credibility). Of 1241 patients included in the APROCCHSS trial, 648 (52%) had ARDS (328 in the placebo group and 320 in the corticosteroid group). There were 155 (48%) deaths of 320 patients at day 90 in the corticosteroid group and 186 (57%) of 328 patients in the placebo group. The OR for death at day 90 was 0·72 (95% CI 0·53-0·98) in patients with ARDS and 0·85 (0·61-1·20) in patients without ARDS (p=0·45 for multiplicative interaction and p=0·42 for additive interaction). The OR for observing at least one serious adverse event (corticosteroid group vs placebo) within 180 days post randomisation was 0·64 (95% CI 0·46-0·89) in the CAP subgroup and 1·02 (0·75-1·39) in the non-CAP subgroup (p=0·044 for multiplicative interaction and p=0·042 for additive interaction). INTERPRETATION: In a pre-specified subgroup analysis of the APROCCHSS trial of patients with CAP and septic shock, hydrocortisone plus fludrocortisone reduced mortality as compared with placebo. Although a large proportion of patients with CAP also met criteria for ARDS, the subgroup analysis was underpowered to fully discriminate between ARDS and CAP modifying effects on mortality reduction with corticosteroids. There was no evidence of a significant treatment effect of corticosteroids in the non-CAP subgroup. FUNDING: Programme Hospitalier de Recherche Clinique of the French Ministry of Health, by Programme d'Investissements d'Avenir, France 2030, and IAHU-ANR-0004.

Can we predict the influence of inflammation on voriconazole exposure? An overview.

Voriconazole is a triazole antifungal indicated for invasive fungal infections that exhibits a high degree of inter-individual and intra-individual pharmacokinetic variability. Voriconazole pharmacokinetics is non-linear, making dosage adjustments more difficult. Therapeutic drug monitoring is recommended by measurement of minimum plasma concentrations. Several factors are responsible for the high pharmacokinetic variability of voriconazole: age, feeding (which decreases absorption), liver function, genetic polymorphism of the CYP2C19 gene, drug interactions and inflammation. Invasive fungal infections are indeed very frequently associated with inflammation, which engenders a risk of voriconazole overexposure. Many studies have reviewed this topic in both the adult and paediatric populations, but few studies have focused on the specific point of the prediction, to evaluate the influence of inflammation on voriconazole pharmacokinetics. Predicting the impact of inflammation on voriconazole pharmacokinetics could help optimize antifungal therapy and improve patient management. This review summarizes the existing data on the influence of inflammation on voriconazole pharmacokinetics in adult populations. We also evaluate the role of C-reactive protein, the impact of inflammation on patient metabolic phenotypes, and the tools that can be used to predict the effect of inflammation on voriconazole pharmacokinetics.

188Re-SSS Lipiodol Radioembolization in HCC Patients: Results of a Phase 1 Trial (Lip-Re-01 Study).

BACKGROUND: Despite the wide development of 90Y-loaded microspheres, 188Re-labeled lipiodol is still being used for radioembolization of hepatocellular carcinoma (HCC). However, the use of this latter compound is limited by in vivo instability. This study sought to evaluate the safety, bio-distribution, and response to 188Re-SSS lipiodol, a new and more stable compound. METHOD: Lip-Re-01 was an activity-escalation Phase 1 study involving HCC patients progressing after sorafenib. The primary endpoint was safety based on Common Terminology Criteria for Adverse Events (AEs) of Grade ≥3 within 2 months. Secondary endpoints included bio-distribution assessed by scintigraphy quantification from 1 to 72 h, tumor to non-tumor uptake ratio (T/NT), as well as blood, urine and feces collection over 72 h, dosimetry, and response evaluation (mRECIST). RESULTS: Overall, 14 heavily pre-treated HCC patients were treated using a whole liver approach. The mean injected activity was 1.5 ± 0.4 GBq for activity Level 1 (n = 6), 3.6 ± 0.3 GBq for Level 2 (n = 6), and 5.0 ± 0.4 GBq for Level 3 (n = 2). Safety was acceptable with only 1/6 of Level 1 and 1/6 of Level 2 patients experiencing limiting toxicity (one liver failure; one lung disease). The study was prematurely discontinued unrelated to clinical outcomes. Uptake occurred in the tumor, liver, and lungs, and only sometimes in the bladder. The T/NT ratio was high with a mean of 24.9 ± 23.4. Cumulative urinary elimination and fecal eliminations at 72 h were very low, 4.8 ± 3.2% and 0.7 ± 0.8%, respectively. Partial response occurred in 21% of patients (0% in the first activity level; 37.5% in the others). CONCLUSION: The high in vivo stability of 188Re-SSS lipiodol was confirmed, resulting in encouraging responses for a Phase 1 study. As the 3.6 GBq activity proved to be safe, it will be used in a future Phase 2 study.

Amoxicillin-Induced Neurotoxicity: Contribution of a Healthcare Data Warehouse to the Determination of a Toxic Concentration Threshold.

BACKGROUND: Amoxicillin (AMX)-induced neurotoxicity is well described and may be associated with AMX overexposure. No neurotoxic concentration threshold has been determined thus far. A better knowledge of maximum tolerable AMX concentrations is of importance to improve the safety of high doses of AMX. METHODS: We conducted a retrospective study using the local hospital data warehouse EhOP® to generate a specific query related to AMX neurotoxicity symptomatology. All patient medical reports containing a mention of neurotoxicity clinical symptoms coupled with AMX plasma concentration measurements were explored. Patients were classified into two groups according to the imputability of AMX in the onset of their neurotoxicity, on the basis of chronological and semiological criteria. A receiver-operating characteristic curve was performed to identify an AMX neurotoxic steady-state concentration (Css) threshold. RESULTS: The query identified 101 patients among 2054 patients benefiting from AMX TDM. Patients received a median daily dose of 9 g AMX, with a median creatinine clearance of 51 mL/min. A total of 17 of the 101 patients exhibited neurotoxicity attributed to AMX. The mean Css was higher for patients with neurotoxicity attributed to AMX (118 ± 62 mg/L) than those without 74 ± 48 mg/L (p = 0.002). A threshold AMX concentration of 109.7 mg/L predicted the occurrence of neurotoxicity. CONCLUSIONS: This study identified, for the first time, an AMX Css threshold of 109.7 mg/L associated with an excess risk of neurotoxicity. This approach needs to be confirmed by a prospective study with systematic neurological evaluation and TDM.

Regulatory assessment of nano-enabled health products in public health interest. Position of the scientific advisory board of the French National Agency for the Safety of Medicines and Health Products.

Nanomaterials are present in a wide variety of health products, drugs and medical devices and their use is constantly increasing, varying in terms of diversity and quantity. The topic is vast because it covers nanodrugs, but also excipients (that includes varying proportions of NMs) and medical devices (with intended or not-intended (by-products of wear) nanoparticles). Although researchers in the field of nanomedicines in clinical research and industry push for clearer definitions and relevant regulations, the endeavor is challenging due to the enormous diversity of NMs in use and their specific properties. In addition, regulatory hurdles and discrepancies are often cited as obstacles to the clinical development of these innovative products. The scientific council of the Agence Nationale de Sécurité du Médicament et des produits de santé (ANSM) undertook a multidisciplinary analysis encompassing fundamental, environmental and societal dimensions with the aim of identifying topics of interest for regulatory assessment and surveillance. This analysis allowed for proposing some recommendations for approximation and harmonization of international regulatory practices for the assessment of the risk/benefit balance of these products, considering as well the public expectations as regards efficacy and safety of nanomaterials used in Health products, in terms of human and environmental health.

Contribution of voriconazole N-oxide plasma concentration measurements to voriconazole therapeutic drug monitoring in patients with invasive fungal infection.

BACKGROUND: Voriconazole (VRC), a widely used triazole antifungal, exhibits significant inter- and intra-individual pharmacokinetic variability. The main metabolite voriconazole N-oxide (NOX) can provide information on the patient's drug metabolism capacity. OBJECTIVES: Our objectives were to implement routine measurement of NOX concentrations and to describe the metabolic ratio (MR), and the contribution of the MR to VRC therapeutic drug monitoring (TDM) by proposing a suggested dosage-adjustment algorithm. PATIENTS AND METHODS: Sixty-one patients treated with VRC were prospectively included in the study, and VRC and NOX levels were assayed by LC-MS/MS. A mixed logistic model on repeated measures was implemented to analyse risk factors for the patient's concentration to be outside the therapeutic range. RESULTS: Based on 225 measurements, the median and interquartile range were 2.4 µg/ml (1.2; 4.2), 2.1 µg/ml (1.5; 3.0) and 1.0 (0.6; 1.9) for VRC, NOX and the MR, respectively. VRC Cmin <2 µg/ml were associated with a higher MR during the previous visit. MR values >1.15 and <0.48 were determined to be the best predictors for having a VRC Cmin lower than 2 µg/ml and above 5.5 µg/ml, respectively, at the next visit. CONCLUSIONS: Measurement of NOX resulted useful for TDM of patients treated with VRC. The MR using NOX informed interpretation and clinical decision-making and is very interesting for complex patients. VRC phenotyping based on the MR is now performed routinely in our institution. A dosing algorithm has been suggested from these results.

Delayed increase of plasma selenoproteins and absence of side effect induced by infusion of pharmacological dose of sodium selenite in septic shock: Secondary analysis of a multicenter, randomized controlled trial.

BACKGROUND: In sepsis, neutrophil respiratory bursts participate in endothelium damage, the first step to multiple organ failure. In plasma two antioxidant selenoenzymes, which protect the endothelium, decrease: selenoprotein-P, and to a lesser extent glutathione peroxidase (GPX3). Sodium selenite (Na2SeO3) is a Se donor, but also an oxidant chemotherapy drug depending on its concentration. In a previous published study, Na2SeO3 continuous infusion in septic shock patients at a pharmacological dose of 4 mg1 Se/day on day-1, followed by a high nutritional dose of 1 mg Se/day during 9 days, showed no beneficial effect on weaning of catecholamine nor on survival. In this ancillary study, we report clinical and biological effects of such continuous infusion of Na2SeO3. METHODS: This was a multicenter, placebo-controlled, double-blind study on 60 patients. Na2SeO3 or placebo in continuous infusion as described above. Evolution with time of plasma Se, selenoprotein-P, GPX3, Organ dysfunction (sequential organ failure assessment SOFA scores, including PaO2/FiO2, for respiratory failure, and plasma lactate) and quality of life at 6 months (by SF36 scores) were analyzed using two-way (time, treatment) non-parametric repeated-measures analysis of variance (Friedman test). MAIN RESULTS: At baseline, plasma Se was about a quarter of reference values. From baseline to day-4 plasma Se, selenoprotein-P and GPX3 significantly increased by 3.9, 2.7 and 1.8 respectively in the Na2SeO3 group as compared with placebo and remained elevated by 2.3, 2.7 and 2.1 at day-14 respectively (p < 0.001). Na2SeO3 did not affect global and organ by organ SOFA Scores and plasma lactate concentration at day-1 and later up to day-14. The evolution of PaO2/FiO2 until day-14 was similar in the two groups. Quality of life in the surviving patients at 6 months was similar between the two groups. CONCLUSION: Continuous infusion of Na2SeO3 at 4 mg Se at day-1 seems to have neither beneficial nor toxic effect at day-1 or later and induces a late increase of selenoprotein-P at day-4. Preclinical studies are required to confirm the use of Na2SeO3 as a cytotoxic drug against neutrophils and protection of the endothelium by selenoprotein-P.

A Robust and Fast/Multiplex Pharmacogenetics Assay to Simultaneously Analyze 17 Clinically Relevant Genetic Polymorphisms in CYP3A4, CYP3A5, CYP1A2, CYP2C9, CYP2C19, CYP2D6, ABCB1, and VKORC1 Genes.

In the field of pharmacogenetics, the trend is to analyze a panel of several actionable genetic polymorphisms. It may require the use of high-throughput sequencing which demands expensive reagents/instruments and specific skills to interpret results. As an alternative, the aim of this work was to validate an easy, fast, and inexpensive multiplex pharmacogenetics assay to simultaneously genotype a panel of 17 clinically actionable variants involved in drug pharmacokinetics/pharmacodynamics. We designed primers to perform a multiplex PCR assay using a single mix. Primers were labeled by two fluorescent dye markers to discriminate alleles, while the size of the PCR fragments analyzed by electrophoresis allowed identifying amplicon. Polymorphisms of interest were CYP3A4*22, CYP3A5*3, CYP1A2*1F, CYP2C9*2-*3, CYP2C19*2-*3-*17, VKORC1-1639G > A, ABCB1 rs1045642-rs1128503-rs2229109-rs2032582, and CYP2D6*3-*4-*6-*9. The assay was repeatable and a minimum quantity of 10 ng of DNA/ sample was needed to obtain accurate results. The method was applied to a validation cohort of 121 samples and genotyping results were consistent with those obtained with reference methods. The assay was fast and cost-effective with results being available within one working-day. This robust assay can easily be implemented in laboratories as an alternative to cumbersome simplex assays or expensive multiplex approaches. Together it should widespread access to pharmacogenetics in clinical routine practice.

Development of a dosing-adjustment tool for fluoroquinolones in osteoarticular infections: The Fluo-pop study.

Fluoroquinolones efficacy depend on both the drug exposure and the level of drug resistance of the bacteria responsible for the infection. Specifically for the Staphylococcus species, which is the microorganism mainly involved in osteoarticular infections (OAI), in-vitro data reported that an AUC/MIC ratio above 115 h maximizes drug efficacy. However, data on OAI patients are lacking and a simple approach to access AUCs is still a clinical issue. We conducted a prospective, single-center study in 30 OAI patients hospitalized in the Rennes University Hospital to model ofloxacin pharmacokinetics and to define a limited sampling strategy (LSS) suitable for ofloxacin and levofloxacin treatments. Modeling was conducted with the Monolix software. The final model was externally validated using levofloxacin data. Monte-Carlo simulations were used to evaluate the probability of target attainment (PTA) of different dosing regimens. Two hundred and ninety-seven (297) ofloxacin concentrations were available for the pharmacokinetic modeling. Ofloxacin pharmacokinetics was best described using a bicompartmental model with a first order elimination, and a transit compartment model absorption. CKD-EPI and sex explained half of ofloxacin pharmacokinetic variability. For LSS, the 0, 1 h and 3 h sampling scheme resulted in the best approach both for BID and TID dosages (R2 adjusted = 91.1% and 95.0%, outliers = 4.8% and 5.0%, respectively). PTA allows choosing the best drug and dosage according to various hypotheses. A simple 3-sample protocol (pre-dose, 1 h after intake and 3 h after intake) to estimate ofloxacin and levofloxacin AUC allows optimal drug dosage for the treatment of osteoarticular infections.

Determination of amoxicillin and cotrimoxazole concentrations in sputum of patients with cystic fibrosis.

In the management of cystic fibrosis, treatments against Staphylococcus aureus and Haemophilus influenzae such as amoxicillin or cotrimoxazole have to be prescribed and the antibiotherapy's efficacy may be linked to the concentration that reaches the infected site. As cystic fibrosis patients present disturbed pharmacokinetics parameters, drug monitoring would be relevant to assess the lung distribution of antibiotics and to optimize dosing regimens. In this context, the aim of the study was to develop and validate HPLC-based methods for the determination of both antibiotics in bronchial sputum from cystic fibrosis patients, in order to assess the distribution of the drugs into the lungs. Plasma proteins were precipitated by acetonitrile and amoxicillin concentrations in sputum were determined by HPLC coupled with tandem-mass spectrometry. Following liquid extraction with ethyl acetate, cotrimoxazole was quantified by HPLC using ultraviolet detection. Both methods were rapid, specific, accurate and reproducible. The method was applied to patient samples. In three treated patients, concentrations of amoxicillin in sputum were similar and below the lower limit of quantification (0.1 µg/g) and in six patients, sputum concentrations up to 11.1 and 6.4 µg/g were measured for sulfamethoxazole and trimethoprim, respectively.

Melatonin: From Pharmacokinetics to Clinical Use in Autism Spectrum Disorder.

The role of melatonin has been extensively investigated in pathophysiological conditions, including autism spectrum disorder (ASD). Reduced melatonin secretion has been reported in ASD and led to many clinical trials using immediate-release and prolonged-release oral formulations of melatonin. However, melatonin's effects in ASD and the choice of formulation type require further study. Therapeutic benefits of melatonin on sleep disorders in ASD were observed, notably on sleep latency and sleep quality. Importantly, melatonin may also have a role in improving autistic behavioral impairments. The objective of this article is to review factors influencing treatment response and possible side effects following melatonin administration. It appears that the effects of exposure to exogenous melatonin are dependent on age, sex, route and time of administration, formulation type, dose, and association with several substances (such as tobacco or contraceptive pills). In addition, no major melatonin-related adverse effect was described in typical development and ASD. In conclusion, melatonin represents currently a well-validated and tolerated treatment for sleep disorders in children and adolescents with ASD. A more thorough consideration of factors influencing melatonin pharmacokinetics could illuminate the best use of melatonin in this population. Future studies are required in ASD to explore further dose-effect relationships of melatonin on sleep problems and autistic behavioral impairments.

Volumetric absorptive microsampling for the quantification of tacrolimus in capillary blood by high performance liquid chromatography-tandem mass spectrometry.

Volumetric absorptive microsampling (VAMS) is an innovative alternative strategy to venipuncture for monitoring tacrolimus levels in transplant recipients. In this study, we aimed to validate a new high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for quantifying tacrolimus in blood collected by VAMS. Tacrolimus was extracted from dried blood tips in an original process involving sonication, protein precipitation and salting out. The assay was validated in accordance with EMA and IATDMCT guidelines. For clinical validation, the tacrolimus concentrations measured in liquid venous whole blood (with the reference method) were compared with those measured in capillary whole blood collected simultaneously with VAMS by a nurse. The assay was then used to monitor tacrolimus exposure in transplant recipients. The method was linear, sensitive and fast. Within-day and between-day precisions and overall bias were within ±15%. No significant hematocrit effect was observed. The matrix effect was negligible and recovery exceeded 80% for every concentration and hematocrit levels. Tacrolimus was stable in blood collected by VAMS for 1 week at room temperature, 48 h at 60 °C and 4 °C and 1 month at -80 °C. Clinical validation (n = 42 paired samples) demonstrated a strong correlation between the two methods (r = 0.97 Pearson correlation). Bland-Altman analysis revealed that more than 90% of the differences between VAMS and liquid blood paired concentrations were within the ±20% acceptable range. The method had a satisfactory analytical performance and fulfilled clinical requirements. This minimally invasive VAMS-based assay appears reliable for the determination of tacrolimus levels in blood from transplanted patients.

Service sanitaire des étudiants en santé : ancrer l'éducation pour la santé dans le cursus des étudiants.

INTRODUCTION: Established in France since 2018, the Student Health Service aims to train students to become actors in health education. METHODS AND RESULTS: A teaching system lasting the equivalent of six weeks full-time has been set up in the third year of medical school in Rennes. The aim is for students to develop the skills needed to carry out interventions based on a project approach, with a variety of audiences, on priority public health themes.New pedagogical approaches have been developed to integrate learning about health promotion and health education into the medical curriculum. Innovations have been implemented: work on the educational posture, tutoring of third-year students by medical interns, a forum for simulation of concrete actions under the supervision of a dual thematic and population-based expertise. Beyond the acquisition of knowledge, the training aims to encourage a reflective approach and is based on peer education.The 240 students of the faculty prepare their project in trinomials throughout the academic year. Their activities take place over ten half-days in more than a hundred establishments in the faculty subdivision and enable them to work with approximately 10,000 people per year. DISCUSSION: Education and health promotion now occupies a central place in the training of third-year students, an essential condition for the sustainable acquisition of this field of expertise by future health professionals.

Simultaneous Versus Delayed Resection for Initially Resectable Synchronous Colorectal Cancer Liver Metastases: A Prospective, Open-label, Randomized, Controlled Trial.

OBJECTIVE: To answer whether synchronous colorectal cancer liver metastases (SLM) should be resected simultaneously with primary cancer or should be delayed. SUMMARY BACKGROUND DATA: Numerous studies have compared both strategies. All were retrospective and conclusions were contradictory. METHODS: Adults with colorectal cancer and resectable SLM were randomly assigned to either simultaneous or delayed resection of the metastases. The primary outcome was the rate of major complications within 60 days following surgery. Secondary outcomes included overall and disease-free survival. RESULTS: A total of 105 patients were recruited. Eighty-five patients (39 and 46 in the simultaneous- and delayed-resection groups, respectively) were analyzed. The percentage of major perioperative complications did not differ between groups (49% and 46% in the simultaneous- and delayed-resection groups, respectively, adjusted OR 0.84, 95% CI 0.35-2.01; P = 0.70, logistic regression). Complications rates were 28% and 13% (P = 0.08, χ2 test) at colorectal site and 15% and 17% (P = 0.80, χ2 test) at liver site, in simultaneous- and delayed-resection groups, respectively. In the delayed-resection group, 8 patients did not reach the liver resection stage, and this was due to disease progression in 6 cases. After 2 years, overall and disease-free survival tended to be improved in simultaneous as compared with delayed-resection groups (P = 0.05), a tendency which persisted for OS after a median follow-up of 47 months. CONCLUSIONS: Complication rates did not appear to differ when colorectal cancer and synchronous liver metastases are resected simultaneously. Delayed resection tended to impair overall survival.

Cumulative Exposure to Infliximab, But Not Trough Concentrations, Correlates With Rate of Infection.

BACKGROUND & AIMS: Infliximab increases the risk of infection in patients with inflammatory bowel diseases (IBD), but there is controversy over the relationship between drug concentration and infections. We aimed to assess factors associated with infection in infliximab-treated patients, including pharmacokinetic features. METHODS: We collected data from 209 patients with IBD (102 men; mean age, 39 y; 159 with Crohn's disease; 54 received combination therapy) who received an infliximab maintenance regimen from November 2016 through April 2017 in France. Data were collected from each infusion visit (total of 640 infusions). Infliximab exposure was estimated based on the area under the curve (AUC) of drug concentration in pharmacokinetic models; individual exposures over the 6-month period were estimated based on the sum of the AUC (ΣAUC). RESULTS: The mean infliximab trough level was 5.46 mg/L, and the mean ΣAUC was 3938 ± 1427 mg.d/L. A total of 215 infections were collected from the 640 infusion visits; 123 patients (59%) had at least 1 infection. Factors independently associated with infection after multivariate analysis were smoking (odds ratio [OR], 2.05; P = .046), IBD flare (OR, 2.71; P = .006), and a high ΣAUC of infliximab (above 3234 mg x d/L) (OR, 2.02; P = .02). The ΣAUC was higher in patients with an occurrence of infection (P = .04) and correlated with the number of infections (P = .04). Trough concentration of infliximab alone was not associated with infection. CONCLUSIONS: Almost two-thirds of patients treated with infliximab developed an infection; risk was individually correlated with cumulative increase in drug exposure, but not infliximab trough level.

Hospital databases for the identification of adverse drug reactions: A 2-year multicentre study in 9 French general hospitals.

AIMS: To estimate the actual number of adverse drug reactions (ADRs), we used the French medical administrative database (PMSI) in addition to ADRs spontaneously reported in the French Pharmacovigilance Database (FPVDB). METHODS: Capture-recapture method was applied to these 2 sources (PMSI and FPVDB), checking their independence via a third data source. The study ran from 1 July 2014 to 30 June 2016 in 9 French general hospitals. From PMSI, all discharge summaries including a selection of 10th International Classification of Diseases codes related to ADRs were analysed. This selection was based on the results of a previous study. All ADRs corresponding to these codes, spontaneously reported in the FPVDB, were included. RESULTS: In PMSI, 56.9% of hospital stays were related to an ADR (628 out of 1104). In the FPVDB, we retained 115 cases. A total of 43 ADRs were common to the 2 databases. In both sources, the most frequently reported ADRs were cutaneous (33.1 and 19.1%) and renal (25.2% and 11.6%). The most frequently suspected drugs were anti-infectives in PMSI (31.1%) and antineoplastic drugs in the FPVDB (30.4%). Using the capture-recapture method, the estimated number of ADRs was 1657 [95% CI: 1273 to 2040]. CONCLUSION: The use of the PMSI could constitute an additional tool for the estimation of the actual number of ADRs in French hospitals. A model involving a third data source enabled the independence of the 2 sources (PMSI and FPVDB) to be checked before applying the capture-recapture method.

A simple and fast liquid chromatography tandem mass spectrometry method to determine cyclosporine A concentrations in endomyocardial biopsies.

Measuring cyclosporine A (CsA), an immunosuppressive drug used to prevent heart transplant rejection, concentrations in myocardial biopsies might be more informative than its measurement in whole blood. Therefore, a fast, accurate and reproductive method to determine CsA concentration in this complex matrix is needed. We report the validation of a liquid chromatography tandem mass spectrometry method to measure CsA concentration in heart parenchyma, applicable to everyday practice. The method was found to be precise, accurate, reproducible, specific of CsA, and without any matrix effect or carry-over. The lower limit of quantification was 50 pg of CsA in myocardium. The method was linear up to 2000 pg of CsA in myocardium. Samples were found stable for one year at - 80 °C. At last, 40 drugs which could be prescribed to heart transplant recipients were tested with the method and showed no interference with CsA signal. The method was suitable to quantify CsA in endomyocardial biopsies from heart transplanted patients. This method allows designing clinical studies aiming at exploring the relationship between CsA intra-graft concentrations and outcome.

Redefining Therapeutic Drug Monitoring of Tacrolimus in Patients Undergoing Liver Transplantation: A Target Trough Concentration of 4-7 ng/mL During the First Month After Liver Transplantation is Safe and Improves Graft and Renal Function.

BACKGROUND: Currently, the recommended tacrolimus (TAC) trough level (Cmin) after liver transplantation (LT) is 6-10 ng/mL (when associated in triple immunosuppressive therapy). However, few studies have achieved the lower limit of this range, especially below 7 ng/mL. This study evaluated the efficacy of a target TAC Cmin of 4-7 ng/mL after LT. METHODS: Of 1677 LTs performed between 2002 and 2017, 904 LT cases were analyzed. The cases were categorized into the following 3 groups and compared: low- (n = 247, 27.3%), intermediate- (n = 344, 37.9%), and high-exposure groups (n = 313, 34.5%) with TAC Cmin of 4-7 ng/mL, 7-10 ng/mL, and >10 ng/mL, respectively. In addition, propensity score matching was performed to reduce heterogeneity and population bias. RESULTS: At months 1 and 3, when compared with the 2 other groups, the low-exposure group had similar grafts (P = 0.75) and patient (P = 0.77) survival, but lower alanine aminotransferase (P < 0.001), bilirubin (P < 0.001), international normalized ratio (P = 0.046), and creatinine (P < 0.001) levels. After propensity score matching, the bilirubin (P < 0.001) and creatinine (P = 0.001) levels in the low-exposure group still improved at months 3, but the graft (P = 0.86) and patient (P = 0.99) survival were still similar. CONCLUSIONS: A TAC Cmin of 4-7 ng/mL seems safe and capable of improving graft and kidney function. This finding should be confirmed in a prospective randomized trial.