Leveraging Clinical Data Warehouses to Measure Impact of Update Prescription Guidelines of Polyvalent Immunoglobulins in 2018 in France.

In France and in other countries, we observed a significant growth in human polyvalent immunoglobulins (PvIg) usage. PvIg is manufactured from plasma collected from numeral donors, and its production is complex. Supply tensions have been observed for several years, and it is necessary to limit their consumption. Therefore, French Health Authority (FHA) provided guidelines in June 2018 to restrict their usage. This research aims to assess the guidelines' impact of the FHA on the use of PvIg. We analyzed data from Rennes University Hospital, where all PvIg prescriptions are reported electronically with quantity, rhythm, and indication. From the clinical data warehouses of RUH, we extracted comorbidities and lab results to evaluate the more complex guidelines. We globally noticed a reduction in the consumption of PvIg after the guidelines. Compliance with the recommended quantities and rhythms have also been observed. By combining two sources of data, we have been able to show an impact of FHA's guidelines on the consumption of PvIg.

Unexpected overdose of oral cyclosporine in a kidney transplant patient: a case report.

Cyclosporine is a widely used immunosuppressive agent to prevent rejection of solid organ transplant. Here, we describe the case of a 71-year-old man who received the prescribed dose of cyclosporine 10 times 6 days after a kidney transplantation because of a concentration miscalculation involving two galenic forms. The patient presented gastrointestinal and neurological disorders. Therapeutic drug monitoring revealed high cyclosporine blood concentrations (693 ng/mL, therapeutic range 100-300 ng/mL). Symptomatic management of digestive disorders was performed, and haemodialysis was started the day after the cyclosporine overdose in the face of acute renal failure. The patient's disorders were quickly resolved. The dosing regimen was adapted in order to administer the most appropriate galenic form and to avoid another administration error. Long-term follow-up showed no failure of renal transplantation. The purpose of this case report is to warn physicians and clinical pharmacists about the vigilance required on cyclosporine prescription, especially when two galenic forms are administered to obtain the prescribed dose.

Involvement of Transporters in Intestinal Drug-Drug Interactions of Oral Targeted Anticancer Drugs Assessed by Changes in Drug Absorption Time.

(1) Background: Oral targeted anticancer drugs are victims of presystemic pharmacokinetic drug−drug interactions (DDI). Identification of the nature of these DDIs, i.e., enzyme-based or/and transporter-based, is challenging, since most of these drugs are substrates of intestinal and/or hepatic cytochrome P-450 enzymes and of intestinal membrane transporters. (2) Methods: Variations in mean absorption time (MAT) between DDIs and control period (MAT ratios < 0.77 or >1.30) have been proposed to implicate transporters in DDIs at the intestinal level. This methodology has been applied to a large set of oral targeted anticancer drugs (n = 54, involved in 77 DDI studies), from DDI studies available either in the international literature and/or in publicly accessible FDA files. (3) Results: Significant variations in MAT were evidenced in 33 DDI studies, 12 of which could be explained by modulation of an efflux transporter. In 21 DDI studies, modulation of efflux transporters could not explain the MAT variation, suggesting a possible relevant role of influx transporters in the intestinal absorption. (4) Conclusions: This methodology allows one to suggest the involvement of intestinal transporters in DDIs, and should be used in conjunction with in vitro methodologies to help understanding the origin of DDIs.

Drug-Drug Interactions with Oral Anticoagulants as Potentially Inappropriate Medications: Prevalence and Outcomes in Elderly Patients in Primary Care and Hospital Settings.

Direct oral anticoagulants and vitamin K antagonists are considered as potentially inappropriate medications (PIM) in several situations according to Beers Criteria. Drug-drug interactions (DDI) occurring specifically with these oral anticoagulants considered PIM (PIM-DDI) is an issue since it could enhance their inappropriate character and lead to adverse drug events, such as bleeding events. The aim of this study was (1) to describe the prevalence of oral anticoagulants as PIM, DDI and PIM-DDI in elderly patients in primary care and during hospitalization and (2) to evaluate their potential impact on the clinical outcomes by predicting hospitalization for bleeding events using machine learning methods. This retrospective study based on the linkage between a primary care database and a hospital data warehouse allowed us to display the oral anticoagulant treatment pathway. The prevalence of PIM was similar between primary care and hospital setting (22.9% and 20.9%), whereas the prevalence of DDI and PIM-DDI were slightly higher during hospitalization (47.2% vs. 58.9% and 19.5% vs. 23.5%). Concerning mechanisms, combined with CYP3A4-P-gp interactions as PIM-DDI, were among the most prevalent in patients with bleeding events. Although PIM, DDI and PIM-DDI did not appeared as major predictors of bleeding events, they should be considered since they are the only factors that can be optimized by pharmacist and clinicians.

Difficulty in Repurposing Selective Serotonin Reuptake Inhibitors and Other Antidepressants with Functional Inhibition of Acid Sphingomyelinase in COVID-19 Infection.

The rapid spread of COVID-19 has become a health emergency causing an urgent need for drug treatments to control the outbreak, especially in more vulnerable individuals. This is reinforced by the fact that prophylactic vaccines and neutralizing monoclonal antibodies may not be fully effective against emerging variants. Despite all efforts made by the scientific community, efficient therapeutic options currently remain scarce, either in the initial, as well as in the advanced forms of the disease. From retrospective observational studies and prospective clinical trials, selective serotonin reuptake inhibitors (SSRIs), and other antidepressants with functional inhibition of acid sphingomyelinase (FIASMAs), have emerged as potential treatments of COVID-19. This has led to some prematurely optimistic points of view, promoting a large prescription of fluvoxamine in patients with COVID-19, that we think should be reasonably tempered.

Association of Amlodipine with the Risk of In-Hospital Death in Patients with COVID-19 and Hypertension: A Reanalysis on 184 COVID-19 Patients with Hypertension.

Association between calcium channel blockers (CCBs) or functional inhibitors of acid sphingomyelinase (FIASMAs) use and decreased mortality in people with COVID-19 has been reported in recent studies. Since amlodipine is both a CCB and a FIASMA, the aim of this study was to investigate the association between chronic amlodipine use and the survival of people with hypertension infected with COVID-19. This retrospective cohort study used data extracted from the medical records of adult inpatients with hypertension and laboratory-confirmed COVID-19 between 1 March 2020 and 31 August 2020 with definite outcomes (discharged from hospital or deceased) from Erasme Hospital (Brussels, Belgium). We re-analyzed the data of the retrospective cohort study using only the 184 patients (103 males, 81 females) with a mean age of 69.54 years (SD = 14.6) with hypertension. The fifty-five participants (29.9%) receiving a chronic prescription of amlodipine were compared with the 129 patients who did not receive a chronic prescription of amlodipine. Univariate and multivariate logistic regressions were used to explore the relationships between mortality and sex, age, comorbidities, smoking, and amlodipine status. Out of the 184 participants, 132 (71.7%) survived and 52 (28.3%) died. The mortality rates were, respectively, 12.73% (n = 7) and 34.88% (n = 45) for the amlodipine and non-amlodipine groups. Multivariate logistic regression was significant (Chi square (5) = 29.11; p < 0.0001). Chronic kidney disease and malignant neoplasm were significant predictors as well as amlodipine status. For chronic kidney disease and malignant neoplasm, the odds ratio with 95% confidence interval (95% CI) were, respectively, 2.16 (95% CI: 1.04−4.5; p = 0.039) and 2.46 (95% CI: 1.01−6.01; p = 0.047). For amlodipine status the odds ratio was 0.29 (95% CI: 0.11−0.74; p = 0.009). The result of the present study suggests that amlodipine may be associated with reduced mortality in people with hypertension infected with COVID-19. Further research and randomized clinical trials are needed to confirm the potential protective effect of amlodipine in people with hypertension infected with COVID-19.

Risk of acute kidney injury by initiation of non-steroidal anti-inflammatory drugs in hospitalised patients treated with diuretics and renin-angiotensin-aldosterone system inhibitors.

OBJECTIVES: Concurrent use of non-steroidal anti-inflammatory drugs (NSAIDs) with diuretics and renin-angiotensin-aldosterone system inhibitors (RAASI) has been associated with an increased risk of developing acute kidney injury (AKI) in the ambulatory setting. There is currently no information on AKI prevalence in hospitalised patients where initiation of NSAID prescription is quite frequent. The aim of our study was to assess the prevalence of AKI in patients treated with diuretics and/or RAASI in the hospital setting when NSAIDs are initiated. METHODS: This was a retrospective single centre study on inpatients receiving triple or dual association treatment. AKI was established according to evidence-based clinical practice guidelines in kidney disease (Kidney Disease Improving Global Outcome, KDIGO) using the following criteria : increase in serum creatinine (SCr) by ≥0.3 mg/dL (or ≥26.5 µmol/L) within 48 hours, or increase in SCr to ≥1.5 times baseline occurring within the last 7 days. RESULTS: AKI was identified in 5 of 151 patients (3.3%) treated with both diuretics and RAASI in whom NSAIDs were initiated, with a 49 µM average increase in SCr within 48 hours compared with baseline. AKI was identified in 2 of 117 (1.7%) patients treated with diuretics and NSAIDs, and in 1 of 427 (0.23%) patients treated with RAASI and NSAIDs. The average increase in SCr within 2 days was 29 µM. No AKI was identified in a control group of 1886 patients treated with diuretics and RAASI but with no initiation of NSAIDs during their hospitalisation. CONCLUSION: Initiation of NSAID therapy in hospitalised patients already being treated with diuretics and RAASI is a risk factor for AKI. The risk of AKI with the triple association appeared higher than with the dual association treatment.

Leveraging National Claims and Hospital Big Data: Cohort Study on a Statin-Drug Interaction Use Case.

BACKGROUND: Linking different sources of medical data is a promising approach to analyze care trajectories. The aim of the INSHARE (Integrating and Sharing Health Big Data for Research) project was to provide the blueprint for a technological platform that facilitates integration, sharing, and reuse of data from 2 sources: the clinical data warehouse (CDW) of the Rennes academic hospital, called eHOP (entrepôt Hôpital), and a data set extracted from the French national claim data warehouse (Système National des Données de Santé [SNDS]). OBJECTIVE: This study aims to demonstrate how the INSHARE platform can support big data analytic tasks in the health field using a pharmacovigilance use case based on statin consumption and statin-drug interactions. METHODS: A Spark distributed cluster-computing framework was used for the record linkage procedure and all analyses. A semideterministic record linkage method based on the common variables between the chosen data sources was developed to identify all patients discharged after at least one hospital stay at the Rennes academic hospital between 2015 and 2017. The use-case study focused on a cohort of patients treated with statins prescribed by their general practitioner or during their hospital stay. RESULTS: The whole process (record linkage procedure and use-case analyses) required 88 minutes. Of the 161,532 and 164,316 patients from the SNDS and eHOP CDW data sets, respectively, 159,495 patients were successfully linked (98.74% and 97.07% of patients from SNDS and eHOP CDW, respectively). Of the 16,806 patients with at least one statin delivery, 8293 patients started the consumption before and continued during the hospital stay, 6382 patients stopped statin consumption at hospital admission, and 2131 patients initiated statins in hospital. Statin-drug interactions occurred more frequently during hospitalization than in the community (3800/10,424, 36.45% and 3253/14,675, 22.17%, respectively; P<.001). Only 121 patients had the most severe level of statin-drug interaction. Hospital stay burden (length of stay and in-hospital mortality) was more severe in patients with statin-drug interactions during hospitalization. CONCLUSIONS: This study demonstrates the added value of combining and reusing clinical and claim data to provide large-scale measures of drug-drug interaction prevalence and care pathways outside hospitals. It builds a path to move the current health care system toward a Learning Health System using knowledge generated from research on real-world health data.

Update on Functional Inhibitors of Acid Sphingomyelinase (FIASMAs) in SARS-CoV-2 Infection.

The SARS-CoV-2 outbreak is characterized by the need of the search for curative drugs for treatment. In this paper, we present an update of knowledge about the interest of the functional inhibitors of acid sphingomyelinase (FIASMAs) in SARS-CoV-2 infection. Forty-nine FIASMAs have been suggested in the treatment of SARS-CoV-2 infection using in silico, in vitro or in vivo studies. Further studies using large-sized, randomized and double-blinded controlled clinical trials are needed to evaluate FIASMAs in SARS-CoV-2 infection as off-label therapy.

Drivers of absolute systemic bioavailability after oral pulmonary inhalation in humans.

There are few studies in humans dealing with the relationship between physico-chemical properties of drugs and their systemic bioavailability after administration via oral inhalation route (Fpulm). Getting further insight in the determinants of Fpulm after oral pulmonary inhalation could be of value for drugs considered for a systemic delivery as a result of poor oral bioavailability, as well as for drugs considered for a local delivery to anticipate their undesirable systemic effects. To better delineate the parameters influencing the systemic delivery after oral pulmonary inhalation in humans, we studied the influence of physico-chemical and permeability properties obtained in silico on the rate and extent of Fpulm in a series of 77 compounds with or without marketing approval for pulmonary delivery, and intended either for local or for systemic delivery. Principal component analysis (PCA) showed mainly that Fpulm was positively correlated with Papp and negatively correlated with %TPSA, without a significant influence of solubility and ionization fraction, and no apparent link with lipophilicity and drug size parameters. As a result of the small sample set, the performance of the different models as predictive of Fpulm were quite average with random forest algorithm displaying the best performance. As a whole, the different models captured between 50 and 60% of the variability with a prediction error of less than 20%. Tmax data suggested a significant positive influence of lipophilicity on absorption rate while charge apparently had no influence. A significant linear relationship between Cmax and dose (R2 = "0.79) highlighted that Cmax was primarily dependent on dose and absorption rate and could be used to estimate Cmax in humans for new inhaled drugs.

Association between Functional Inhibitors of Acid Sphingomyelinase (FIASMAs) and Reduced Risk of Death in COVID-19 Patients: A Retrospective Cohort Study.

Given the current scarcity of curative treatment of COVID-19, the search for an effective treatment modality among all available medications has become a priority. This study aimed at investigating the role of functional inhibitors of acid sphingomyelinase (FIASMAs) on in-hospital COVID-19 mortality. In this retrospective cohort study, we included adult in-patients with laboratory-confirmed COVID-19 between 1 March 2020 and 31 August 2020 with definite outcomes (discharged hospital or deceased) from Erasme Hospital (Brussels, Belgium). We used univariate and multivariate logistic regression models to explore the risk factors associated with in-hospital mortality. We included 350 patients (205 males, 145 females) with a mean age of 63.24 years (SD = 17.4, range: 21-96 years). Seventy-two patients died in the hospital and 278 were discharged. The four most common comorbidities were hypertension (184, 52.6%), chronic cardiac disease (110, 31.4%), obesity (96, 27.8%) and diabetes (95, 27.1%). Ninety-three participants (26.6%) received a long-term prescription for FIASMAs. Among these, 60 (64.5%) received amlodipine. For FIASMAs status, multivariable regression showed increasing odds ratio (OR) for in-hospital deaths associated with older age (OR 1.05, 95% CI: 1.02-1.07; p = 0.00015), and higher prevalence of malignant neoplasm (OR 2.09, 95% CI: 1.03-4.22; p = 0.039). Nonsignificant decreasing OR (0.53, 95% CI: 0.27-1.04; p = 0.064) was reported for FIASMA status. For amlodipine status, multivariable regression revealed increasing OR of in-hospital deaths associated with older age (OR 1.04, 95% CI: 1.02-1.07; p = 0.0009), higher prevalence of hypertension (OR 2.78, 95% CI: 1.33-5.79; p = 0.0062) and higher prevalence of malignant neoplasm (OR 2.71, 95% CI: 1.23-5.97; p = 0.013), then secondarily decreasing OR of in-hospital death associated with long-term treatment with amlodipine (OR 0.24, 95% CI: 0.09-0.62; p = 0.0031). Chronic treatment with amlodipine could be significantly associated with low mortality of COVID-19 in-patients.

Drug-Drug Interactions in Elderly Patients with Potentially Inappropriate Medications in Primary Care, Nursing Home and Hospital Settings: A Systematic Review and a Preliminary Study.

Drug-drug interactions (DDI) occurring with potentially inappropriate medications (PIM) are additional risk factors that may increase the inappropriate character of PIM. The aim of this study was (1) to describe the prevalence and severity of DDI in patients with PIM and (2) to evaluate the DDI specifically regarding PIM. This systematic review is based on a search carried out on PubMed and Web-of-Science from inception to June 30, 2020. We extracted data of original studies that assessed the prevalence of both DDI and PIM in elderly patients in primary care, nursing home and hospital settings. Four hundred and forty unique studies were identified: 91 were included in the qualitative analysis and 66 were included in the quantitative analysis. The prevalence of PIM in primary care, nursing home and hospital were 19.1% (95% confidence intervals (CI): 15.1-23.0%), 29.7% (95% CI: 27.8-31.6%) and 44.6% (95% CI: 28.3-60.9%), respectively. Clinically significant severe risk-rated DDI averaged 28.9% (95% CI: 17.2-40.6), in a hospital setting; and were approximately 7-to-9 lower in primary care and nursing home, respectively. Surprisingly, only four of these studies investigated DDI involving specifically PIM. Hence, given the high prevalence of severe DDI in patients with PIM, further investigations should be carried out on DDI involving specifically PIM which may increase their inappropriate character, and the risk of adverse drug reactions.

Repurposing functional inhibitors of acid sphingomyelinase (fiasmas): an opportunity against SARS-CoV-2 infection?

WHAT IS KNOWN AND OBJECTIVE: Infection by SARS-CoV-2, the virus responsible of COVID-19, is associated with limited treatment options. The purpose of this study was to evaluate the rationale for repurposing functional inhibitors of acid sphingomyelinase (FIASMAs), several of which are approved medicines, for the treatment of SAR-CoV-2 infections. COMMENT: We propose and discuss the FIASMAs' lysosomotropism as a possible explanation for their observed in vitro activities against viruses, and more specifically against infections caused by coronaviruses such as SARS-CoV-2. Successful in vitro-to-in vivo translation of FIASMAs requires that their pharmacokinetics (dosing regimen and drug-drug interactions) are matched with viral kinetics. WHAT IS NEW AND CONCLUSION: Drug repurposing to ensure rapid patient access to effective treatment has garnered much attention in this era of the COVID-19 pandemic. The observed lysosomotropic activity of small-molecule FIASMA compounds suggests that their repurposing as potential drugs against SARS-CoV-2 is promising.

Differential interactions of the ß-lactam cloxacillin with human renal organic anion transporters (OATs).

The ß-lactam penicillin antibiotic cloxacillin (CLX) presents wide inter-individual pharmacokinetics variability. To better understand its molecular basis, the precise identification of the detoxifying actors involved in CLX disposition and elimination would be useful, notably with respect to renal secretion known to play a notable role in CLX elimination. The present study was consequently designed to analyze the interactions of CLX with the solute carrier transporters organic anion transporter (OAT) 1 and OAT3, implicated in tubular secretion through mediating drug entry at the basolateral pole of renal proximal cells. CLX was first shown to block OAT1 and OAT3 activity in cultured OAT-overexpressing HEK293 cells. Half maximal inhibitory concentration (IC50 ) value for OAT3 (13 µm) was however much lower than that for OAT1 (560 µm); clinical inhibition of OAT activity and drug-drug interactions may consequently be predicted for OAT3, but not OAT1. OAT3, unlike OAT1, was next shown to mediate CLX uptake in OAT-overexpressing HEK293 cells. Kinetic parameters for this OAT3-mediated transport of CLX (Km  = 10.7 µm) were consistent with a possible in vivo saturation of this process for high CLX plasma concentrations. OAT3 is consequently likely to play a pivotal role in renal CLX secretion and consequently in total renal CLX elimination, owing to the low plasma unbound fraction of the antibiotic. OAT3 genetic polymorphisms as well as co-administered drugs inhibiting in vivo OAT3 activity may therefore be considered as potential sources of CLX pharmacokinetics variability.

Maternal and Fetal Blood Pharmacokinetics and Organ Distribution of Atrazine, Propazine, Simazine, and Their Metabolites in Pregnant Rats After Chronic Oral Administration.

Environmental contamination by chlorotriazines has been evidenced in mother-child cohort suggesting more detailed risk assessment of these compounds in drinking water. Exposure of rodents to atrazine (ATZ) has been associated with alterations of endocrine and reproductive functions by disrupting neuroendocrine control at hypothalamus level. Perinatal exposure to low doses of ATZ has been associated with reproductive dysfunction, and to behavioral abnormalities in adult exposed during embryogenesis. The objectives of the current investigation were to (1) evaluate the influence of physicochemical properties of chlorotriazines on tissue distribution in pregnant rats and in fetuses and (2) gain a better understanding of fetal distribution of chlorotriazines in specific tissues, particularly in brain. Serial blood samples were obtained from pregnant rats after administration of ATZ, propazine (PRO), and simazine (SIM) via oral route at a dose of 10 mg/kg from day 15 to day 19. Maternal and fetal tissues were harvested at day 20, 24 h after the last dosing. The metabolic extraction ratio was estimated to 87% suggesting a significant first-pass effect explaining the low oral bioavailability. Blood exposure to parent compounds (ATZ, PRO, and SIM) was negligible (lower than 5%) compared with metabolite exposure. The main metabolite exposure involved diamino-s-chlorotriazine, ranging from 60% to 90% depending on the molecules administered. A correlation between tissue-to-blood ratio and physicochemical descriptors was observed for fat and mammary gland tissues but not for brain in adult rats. A more pronounced distribution in fetal brain was observed for ATZ and PRO, the 2 most lipophilic compounds.

Prescriptome analytics: an opportunity for clinical pharmacy.

Clinical pharmacists have unique opportunities to be more involved in prescriptome analytics to expand research horizon in clinical pharmacy as an academic discipline. The development of predictive analytics with machine learning algorithms could have the potential to redesign the way we care for patients in our institutions for a more personalized medication therapy.

Potential drug-drug interactions and nephrotoxicity in hematopoietic stem cell transplant adult recipients during bone marrow transplantation unit stay.

PURPOSE: Studies have documented potential drug-drug interactions (pDDIs) occurring in cancer patients mainly with solid malignancies, either in the ambulatory or hospital settings. While hematopoietic stem cell transplant (HSCT) patients during their bone marrow transplantation unit (BMTU) stay have rather complex medical regimens combining chemotherapy, anti-infectious agents, immunosuppressive agents, and supportive-care drugs, studies on potential DDIs are lacking. Our objective was to evaluate the prevalence and the density of pharmacokinetic and pharmacodynamic potential DDIs, and the evolution of the renal function in hematopoietic stem cell transplant (HSCT) adult recipients during their BMTU stay. METHODS: Retrospective study in 31 adult patients consecutively admitted to the BMTU. RESULTS: Prevalence of pharmacokinetic interactions was ten times lower than the pharmacodynamic interactions. The contraindications were rare, and only of pharmacokinetic origin. The main drugs involved in pharmacokinetic DDIs were ciclosporine, methotrexate, esomeprazole, tramadol, and vincristine. The median number of potential nephrotoxicity-related DDIs per patient was 7 and the median number of days during which nephrotoxicity-related DDIs potentially occurred was 77 days per patient. The decrease in glomerular filtration rate (GFR) throughout the BMTU stay (mean decrease of 13 ml/min) was correlated with the number of days of potential nephrotoxic drug interactions. CONCLUSIONS: Potential DDIs in HCST patients in BMTU were quite common. The DDIs from pharmacokinetic origin were less frequent, but of higher grade, than those of pharmacodynamic origin. The decrease in GFR suggests that the density of potential nephrotoxic drug interactions may be an issue to be considered in these patients.