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Xenobiotics can interact with cytochromes P450 (CYPs), resulting in drug–drug interactions, but CYPs can also contribute to drug–disease interactions, especially in the case of inflammation, which downregulates CYP activities through pretranscriptional and posttranscriptional mechanisms. Interleukin‐6 (IL‐6), a key proinflammatory cytokine, is mainly responsible for this effect. The aim of our study was to develop a physiologically based pharmacokinetic (PBPK) model to foresee the impact of elevated IL‐6 levels in combination with drug interactions with esomeprazole on CYP3A and CYP2C19. Data from a cohort of elective hip surgery patients whose CYP3A and CYP2C19 activities were measured before and after surgery were used to validate the accurate prediction of the developed models. Successive steps were to fit models for IL‐6, esomeprazole, and omeprazole and its metabolite from the literature and to validate them. The models for midazolam and its metabolite were obtained from the literature. When appropriate, a correction factor was applied to convert drug concentrations from whole blood to plasma. Mean ratios between simulated and observed areas under the curve for omeprazole/5‐hydroxy omeprazole, esomeprazole, and IL‐6 were 1.53, 1.06, and 0.69, respectively, indicating an accurate prediction of the developed models. The impact of IL‐6 and esomeprazole on the exposure to CYP3A and CYP2C19 probe substrates and respective metabolites were correctly predicted. Indeed, the ratio between predicted and observed mean concentrations were

Trazodone is indicated for the treatment of major depressive disorder, but more frequently prescribed off-label at lower doses for insomnia in women of childbearing age. The aim of this study was to assess the risks linked to trazodone exposure during pregnancy for which limited safety data are available. This multicenter, observational prospective cohort study compared pregnancy outcomes in women exposed to trazodone in early pregnancy against those in a reference group of women exposed to a selective serotonin reuptake inhibitors (SSRIs) between 1996 and 2021. The sample included 221 trazodone and 869 SSRI-exposed pregnancies. Exposure to trazodone in the first trimester was not associated with a significant difference in the risk of major congenital anomalies (trazodone [1/169, 0.6%]; SSRI [19/730, 2.6%]; adjusted odds ratio, 0.2; 95% confidence interval, 0.03-1.77). The cumulative incidences of live birth were 61% and 73% in the trazodone and reference group, respectively (25% vs 18% for pregnancy loss and 14% vs 10% for pregnancy termination). Trazodone exposure was not associated with a significantly increased risk of pregnancy termination and pregnancy loss. The rate of small for gestational age infants did not differ between the groups. This study did not reveal a significant difference in the risk of major congenital anomalies after first trimester exposure to trazodone, compared with SSRI exposure. Although this study is the largest so far, these results call for confirmation through further studies.

Variation in genes involved in the absorption, distribution, metabolism, and excretion of drugs (ADME) can influence individual response to a therapeutic treatment. The study of ADME genetic diversity in human populations has led to evolutionary hypotheses of adaptation to distinct chemical environments. Population differentiation in measured drug metabolism phenotypes is, however, scarcely documented, often indirectly estimated via genotype-predicted phenotypes. We administered seven probe compounds devised to target six cytochrome P450 enzymes and the P-glycoprotein (P-gp) activity to assess phenotypic variation in four populations along a latitudinal transect spanning over Africa, the Middle East, and Europe (349 healthy Ethiopian, Omani, Greek, and Czech volunteers). We demonstrate significant population differentiation for all phenotypes except the one measuring CYP2D6 activity. Genome-wide association studies (GWAS) evidenced that the variability of phenotypes measuring CYP2B6, CYP2C9, CYP2C19, and CYP2D6 activity was associated with genetic variants linked to the corresponding encoding genes, and additional genes for the latter three. Instead, GWAS did not indicate any association between genetic diversity and the phenotypes measuring CYP1A2, CYP3A4, and P-gp activity. Genome scans of selection highlighted multiple candidate regions, a few of which included ADME genes, but none overlapped with the GWAS candidates. Our results suggest that different mechanisms have been shaping the evolution of these phenotypes, including phenotypic plasticity, and possibly some form of balancing selection. We discuss how these contrasting results highlight the diverse evolutionary trajectories of ADME genes and proteins, consistent with the wide spectrum of both endogenous and exogenous molecules that are their substrates.

We conducted a narrative review of the literature to compare the pharmacological, efficacy and safety profiles of tapentadol and tramadol, and to assess the clinical interest of tapentadol in adult patients. Tapentadol and tramadol share a mixed mechanism of action, including both mu-agonist and monoaminergic properties. Tapentadol is approximately two to three times more potent than tramadol and two to three times less potent than morphine. It has no identified analgesically active metabolite and is not significantly metabolised by cytochrome P450 enzymes, thus overcoming some limitations of tramadol, including the potential for pharmacokinetic drug-drug interactions and interindividual variability due to genetic polymorphisms of cytochrome P450 enzymes. The toxicity profiles of tramadol and tapentadol are similar; however tapentadol is likely to result in less exposure to serotoninergic adverse effects (nausea, vomiting, hypoglycaemia) but cause more opioid adverse effects (constipation, respiratory depression, abuse) than tramadol. The safety of tapentadol in real-world conditions remains poorly documented, particularly in at-risk patient subgroups and also in the ability to assess the risk associated with its residual serotonergic activity (serotonin syndrome, seizures). Because of an earlier market introduction, more real-world safety data are available for tramadol, including data from at-risk patient subgroups. The level of evidence on the efficacy of both tramadol and tapentadol for the treatment of chronic pain is globally low. The trials published to date show overall that tapentadol does not provide a clinically significant analgesic improvement compared to existing treatments, for which the safety profile is much better known. In conclusion, tapentadol is not a first-line opioid but represents an additional analgesic in the therapeutic choices, which some patients may benefit from after careful examination of their clinical situation, co-morbidities and co-medications.

Coronavirus disease 2019 (COVID‐19), caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection, is a severe acute respiratory syndrome with an underlying inflammatory state. We have previously demonstrated that acute inflammation modulates cytochromes P450 (CYPs) activity in an isoform‐specific manner. We therefore hypothesized that COVID‐19 might also impact CYP activity, and thus aimed to evaluate the impact of acute inflammation in the context of SARS‐CoV‐2 infection on the six main human CYPs activity. This prospective observational study was conducted in 28 patients hospitalized at the Geneva University Hospitals (Switzerland) with a diagnosis of moderate to severe COVID‐19. They received the Geneva phenotyping cocktail orally during the first 72 hours of hospitalization and after 3 months. Capillary blood samples were collected 2 hours after cocktail administration to assess the metabolic ratios (MRs) of CYP1A2, 2B6, 2C9, 2C19, 2D6, and 3A. C‐reactive protein (CRP), interleukin 6 (IL‐6), and tumor necrosis factor‐α (TNF‐α) levels were also measured in blood. CYP1A2, CYP2C19, and CYP3A MRs decreased by 52.6% (P = 0.0001), 74.7% (P = 0.0006), and 22.8% (P = 0.045), respectively, in patients with COVID‐19. CYP2B6 and CYP2C9 MRs increased by 101.1% (P = 0.009) and 55.8% (P = 0.0006), respectively. CYP2D6 MR variation did not reach statistical significance (P = 0.072). As expected, COVID‐19 was a good acute inflammation model as mean serum levels of CRP, IL‐6, and TNF‐α were significantly (P

Background Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD) is the most toxic congener of a family of structurally and mechanistically related persistent organic pollutants whose effects are mediated through the aryl hydrocarbon receptor (AhR). Induction of CYP1A1/2 by TCDD through the AhR depends on the magnitude and the duration of exposure. We aimed to assess CYP1A2 activity after acute and chronic exposure to TCDD. The Maincy cohort is a sample population from Melun in the Val-de-Seine region in France that lived for at least 5 years close to a waste incinerator emitting polluted vapours (1974-2002) with high concentrations of dioxins (up to 2000 times the maximal recommended values). Acute exposure to TCDD (Viktor Yushchenko) has been described elsewhere by Sorg et al (Toxicol. Sci. 2012; 125:310-317). Both are rare cases of well-identified source of chronic and acute exposure to TCDD. Methods All subjects underwent a full medical history and physical examination and had a cutaneous examination, and a retro-auricular skin biopsy was taken. A questionnaire was designed and used regarding demographic, personal, environmental and occupational characteristics. CYP1A2 activity was assessed 2 hours after the ingestion of a drink containing caffeine through measurement of the metabolic ratio of paraxanthine (17X) over caffeine (137X) by LC-MS/MS or LC-UV. CYP1A1 expression in skin biopsies was determined by immunohistochemical analysis. Results Forty-seven exposed subjects (age 11-78) and 31 controls were included in the study. Eleven exposed subjects had a history of thyroid disease (23.4%), and 7 (14.8%) had a cancer vs none and 1, respectively, in controls. Nodular skin lesions were found in 13 exposed subjects (27.7%) vs none in controls. Mean CYP1A2 activity of the exposed population was modestly elevated as compared to controls (17X/137X metabolic ratio of 0.475 vs 0.374, P = .051). CYP1A2 was, however, induced (17X/137X, metabolic ratio >0.5) in 27.6% of the exposed cases vs 6.4% of the controls. In contrast, acute dioxin exposure was associated with a strong induction (mean 17X/137X, metabolic ratio of 1.9) still present 29 months after the acute exposure. CYP1A1 was expressed in 59.6% of the skin biopsies (highly expressed in 31.9%) of the Maincy cohort. No correlation between CYP1A2 activity, CYP1A1 expression and clinical manifestations (thyroid disease, cancer, skin lesions) could be demonstrated. Conclusion Higher frequencies of dysthyroidism and cancer were detected in the population exposed chronically to dioxins from a waste incinerator. CYP1A2 was induced in 27.6% of the exposed population, while the magnitude of induction was fourfold higher after acute exposure in the case of Yushchenko.

Background Proton pump inhibitors are among the most widely prescribed drugs in the world, but more than half of the indications for prescription are unjustified. The misuse of this therapeutic class has heavy consequences such as additional health costs, adverse drug reactions following long-term use and gastric acid rebound when the proton pump inhibitor is discontinued. Objective The overprescription of proton pump inhibitors is therefore becoming a public health problem, which led us to evaluate their use within the Geneva University Hospitals. Setting Patients hospitalized in two divisions of the department of internal medicine of the Geneva University Hospitals on a single day. Methods This is a register-based cross-sectional study and it collected data about the prescription pattern of proton pump inhibitors by consulting the electronic records of patients included. Main outcome measure To determine if the proton pump inhibitors prescription is made according to the market authorization and the available guidelines. Results Hundred-eighty patients were included. 54% of patients were on proton pump inhibitors, 29% of whom had their treatment initiated at hospital. Of the indications for treatment, 72% were not justified and 63% of the justified indications did not have an adequate dosage. Therefore, in all patients with a proton pump inhibitor at hospital, only 11% had a justified indication with an adequate dose. Finally, 87% of known home prescriptions were renewed on admission and among them, 71% did not have a justified or possibly justified indication according to the guidelines. Conclusion Indication for treatment inside the hospital was not justified in 72% of patients and only 11% had a justified indication with an adequate dosage. Precise guidelines with evidence-based indications and adequate daily doses would help to correctly prescribe proton pump inhibitors. Moreover, patients should benefit from a thorough evaluation of their treatment.

Rivaroxaban has become an alternative to vitamin K antagonists, which are considered to be at higher risk of drug-drug interactions (DDI) and more difficult to use. However, DDI do occur. We systematically reviewed studies that evaluated them and analysed DDI and subsequent adverse drug reactions (ADR) reported in spontaneous reports and VigiBase. We systematically searched articles that explored DDI with rivaroxaban up to 20 August 2018 via Medline, Embase and Google Scholar. Data from VigiBase came from spontaneous reports recovered up to 2 January 2018, where Omega was used to detect signals and identify potential interactions in terms of triplets with two drugs and one ADR. We identified 31 studies and 28 case reports. Studies showed significant variation in the pharmacokinetic for rivaroxaban, and an increased risk of haemorrhage or thromboembolic events due to DDI was highlighted in case reports. From VigiBase, a total of 21,261 triplets were analysed and the most reported was rivaroxaban–aspirin–gastrointestinal haemorrhage. In VigiBase, only 34.8% of the DDI reported were described or understood, and most were pharmacodynamic DDI. These data suggest that rivaroxaban should be considered to have significant potential for DDI, especially with CYP3A/P-gp modulators or with drugs that impair haemostasis.

Apixaban, a direct oral anticoagulant, has emerged over the past few years because it is considered to have a low risk of drug‐drug interactions compared to vitamin K antagonists. To better characterize these interactions, we systematically reviewed studies evaluating the drug‐drug interactions involving apixaban and analyzed the drug‐drug interactions resulting in an adverse drug reaction reported in case reports and VigiBase. We systematically searched Medline, Embase, and Google Scholar up to 20 August 2018 for articles that investigated the occurrence of an adverse drug reaction due to a potential drug interacting with apixaban. Data from VigiBase came from case reports retrieved up to the 2 January 2018, where identification of potential interactions is performed in terms of two drugs, one adverse drug reaction triplet and potential signal detection using Omega, a three‐way measure of disproportionality. We identified 15 studies and 10 case reports. Studies showed significant variations in the area under the curve for apixaban and case reports highlighted an increased risk of hemorrhage or thromboembolic events due to a drug‐drug interaction. From VigiBase, a total of 1617 two drugs and one adverse drug reaction triplet were analyzed. The most reported triplet were apixaban—aspirin—gastrointestinal hemorrhage. Sixty‐seven percent of the drug‐drug interactions reported in VigiBase were not described or understood. In the remaining 34%, the majority were pharmacodynamic drug‐drug interactions. These data suggest that apixaban has significant potential for drug‐drug interactions, either with CYP3A/P‐gp modulators or with drugs that may impair hemostasis. The most described adverse drug reactions were adverse drug reactions related to hemorrhage or thrombosis, mostly through pharmacodynamic interactions. Pharmacokinetic drug‐drug interactions seem to be poorly detected.

Cytochromes P450 (CYP) are subject to important interindividual variability in their activity due to genetic and environmental factors and some diseases. Limited human data support the idea that inflammation downregulates CYP activities. Our study aimed to evaluate the impact of orthopedic surgery (acute inflammation model) on the activity of six human CYP. This prospective observational study was conducted in 30 patients who underwent elective hip surgery at the Geneva University Hospitals in Switzerland. The Geneva phenotyping cocktail containing caffeine, bupropion, flurbiprofen, omeprazole, dextromethorphan, and midazolam as probe drugs respectively assessing CYP1A2, 2B6, 2C9, 2C19, 2D6, and 3A activities was administered orally before surgery, day 1 (D1) and 3 (D3) postsurgery and at discharge. Capillary blood samples were collected 2 hours after cocktail intake to assess metabolic ratios (MRs). Serum inflammatory markers (CRP, IL‐6, IL‐1β, TNF‐α, and IFN‐γ) were also measured in blood. CYP1A2 MRs decreased by 53% (P

Introduction and Objective Cytochrome P450 enzymes are the major drug-metabolizing enzymes in humans and the importance of drug transport proteins, in particular P-glycoprotein, in the variability of drug response has also been highlighted. Activity of cytochrome P450 enzymes and P-glycoprotein can vary widely between individuals and genotyping and/or phenotyping can help assess their activity. Several phenotyping cocktails have been developed. The Geneva cocktail is composed of a specific probe for six different cytochrome P450 enzymes and one for P-glycoprotein and was used in the context of a research aiming at exploring genotypes and phenotypes in distinct human populations (NCT02789527). The aim of the present study is to solely report the safety results of the Geneva cocktail in the healthy volunteers of these populations. Materials and Methods The Geneva cocktail is composed of caffeine, bupropion, flurbiprofen, omeprazole, dextromethorphan, midazolam, and fexofenadine. The volunteers fasted and avoided drinking caffeine-containing beverages or food and grapefruit juice overnight before receiving the cocktail orally. They provided blood spots for the probes' concentrations at 2, 3, and 6 h after ingestion and were asked about adverse events. Results A total of 265 healthy adult volunteers were included from Ethiopia, Oman, and the Czech Republic. The mean plasma concentrations at the 2-h sampling time of each probe drug in the total sample were: 1663 ng/mL for caffeine, 8 ng/mL for bupropion, 789 ng/mL for flurbiprofen, 6 ng/mL for dextromethorphan, 2 ng/mL for midazolam, 35 ng/mL for fexofenadine, and 103 ng/mL for omeprazole. Four adverse events were observed representing an occurrence of 1.5%. All these events were categorized as mild to moderate, non-serious, and resolved spontaneously. A causal link with the cocktail cannot be excluded because of the temporal relationship but is at most evaluated as possible according to the World Health Organization-Uppsala Monitoring Centre causal assessment system. Conclusions In this research, healthy volunteers from three different human populations were phenotyped with the Geneva cocktail. Four adverse events were observed, confirming the safety of this cocktail that is given at lower than clinically relevant doses and therefore results in concentrations lower than those reported to cause adverse events. Refereed/Peer-reviewed

Clinical trials are usually conducted in a limited time and on a selected population, most often excluding children. These clinical trials provide a first safety profile of the drugs, undeniably essential but often partial, highlighting only the most common adverse drug reactions. In addition in pediatrics, due to growth and physiologic maturation, adverse drug reactions may differ between children and adults and extrapolation of data obtained in adults to children, including safety data, may be inaccurate. Pharmacovigilance, which is based on spontaneous notifications of adverse drug reactions, helps to refine the risk/benefit ratio of drugs and to increase their safety after market launch. This article aims to highlight the importance of pharmacovigilance in general and in particular in the pediatric population and to remind the modalities of reporting in Switzerland.Les essais cliniques sont le plus souvent effectués sur une durée limitée et une population sélectionnée, excluant les enfants. Ils fournissent un premier profil de sécurité des médicaments, souvent partiel, ne mettant en évidence que les effets indésirables les plus fréquents. En pédiatrie, les phénomènes de croissance et de maturation peuvent être à l’origine de réactions aux médicaments différentes que chez l’adulte et empêchent la simple extrapolation à l’enfant des données, notamment de sécurité, obtenues chez l’adulte. La pharmacovigilance repose sur la notification spontanée des effets indésirables. Elle permet d’affiner le rapport risques/bénéfices et d’augmenter la sécurité des médicaments une fois commercialisés. Cet article a pour but de souligner l’importance de la pharmacovigilance, en particulier dans la population pédiatrique, et de rappeler les modalités d’annonces.

This retrospective study evaluates the link between an adverse drug reaction (ADR) or a non-response to treatment and cytochromes P450 (CYP), P-glycoprotein (P-gp) or catechol-O-methyltransferase (COMT) activity in patients taking analgesic drugs for chronic pain. Patients referred to a pain center for an ADR or a non-response to an analgesic drug between January 2005 and November 2014 were included. The genotype and/or phenotype was obtained for assessment of the CYPs, P-gp or COMT activities. The relation between the event and the result of the genotype and/or phenotype was evaluated using a semi-quantitative scale. Our analysis included 243 individual genotypic and/or phenotypic explorations. Genotypes/phenotypes were mainly assessed because of an ADR (n = 145, 59.7%), and the majority of clinical situations were observed with prodrug opioids (n = 148, 60.9%). The probability of a link between an ADR or a non-response and the genotypic/phenotypic status of the patient was evaluated as intermediate to high in 40% and 28.2% of all cases, respectively. The drugs in which the probability of an association was the strongest were the prodrug opioids, with an intermediate to high link in 45.6% of the cases for occurrence of ADRs and 36.0% of the cases for non-response. This study shows that the genotypic and phenotypic approach is useful to understand ADRs or therapeutic resistance to a usual therapeutic dosage, and can be part of the evaluation of chronic pain patients.

Background: Acenocoumarol is a vitamin K antagonist used in some European countries. As warfarin, this drug is characterized by a narrow therapeutic index and a large interindividual variability. Aim: The objective of this study was to assess the involvement of ABCB1 polymorphisms on acenocoumarol treatment. Materials & methods: An observational cohort study was conducted to assess whether there is an association between the presence of the allelic variants of the ABCB1 gene coding for P-glycoprotein and acenocoumarol stabilization and daily doses during the first 35 days of treatment. Results: One hundred and fifteen patients met the inclusion criteria. The results of the clinical study showed that carriers of ABCB1 c.3435TT were more rapidly stabilized than wild-type patients (HR: 2.97, 95% CI: 1.23–7.18; p = 0.02). The same tendency was observed for the ABCB1 c.2677GT and 2677TT genotypes compared with ABCB1 c.2677GG. The ABCB1 c.2677TT genotype was also associated with a significant increase in doses of acenocoumarol (p = 0.03), the same tendency was observed with the ABCB1 c.3435TT genotype compared with the wild-type patients. Conclusion: These data suggest that ABCB1 polymorphisms could be involved in the response to acenocoumarol treatment. Original submitted 6 June 2014; Revision submitted 5 November 2014

Overutilization of proton pump inhibitors (PPI) is obvious despite available recommendations, with clinical and economical issues. This overuse is due to abusive stress ulcer prophylaxis and to automatic represcription, particularly during transitions from intensive care unit to other inhospital units and at hospital discharge. Withdrawal symptoms may contribute to the difficulty of PPI interruption. It is mandatory to limit initiation of PPI treatment outside of appropriate indications and to regularly reassess the need of this treatment.Malgré des indications claires, les inhibiteurs de la pompe à protons (IPP) sont surprescrits, ce qui engendre des conséquences cliniques et économiques. Cette surprescription s’explique principalement par des indications erronées, dominées par la prévention abusive de l’ulcère de stress, et par la poursuite automatique du traitement, en particulier dans les phases de transition entre services hospitaliers ou à la sortie de l’hôpital. Des symptômes de sevrage à l’arrêt du traitement contribuent aussi peut-être à la difficulté d’interrompre les IPP. Il est donc important d’une part de respecter davantage les indications de ce traitement et d’autre part de réévaluer régulièrement la nécessité de le poursuivre.

Overutilization of proton pump inhibitors (PPI) is obvious despite available recommendations, with clinical and economical issues. This overuse is due to abusive stress ulcer prophylaxis and to automatic represcription, particularly during transitions from intensive care unit to other inhospital units and at hospital discharge. Withdrawal symptoms may contribute to the difficulty of PPI interruption. It is mandatory to limit initiation of PPI treatment outside of appropriate indications and to regularly reassess the need of this treatment.

Summary Background Long-term monitoring of white blood cell count is compulsory in patients taking clozapine, although the incidence of drug-induced agranulocytosis is lower than previously expected. The cost-effectiveness of this monitoring is unknown. We aimed to assess the cost-effectiveness of various strategies to monitor white blood cell count in adult patients with schizophrenia taking clozapine. Methods We assessed the cost-effectiveness of four strategies for monitoring white blood cell count (national strategies used in the UK, USA, and European countries, and a hypothetical 8-week strategy) compared with that of no monitoring. We used a semi-Markov model to do the cost–utility analysis from a health-care perspective with a 3-year time horizon, assuming a probability of 0·7% that a patient would develop agranulocytosis. Clinical and resource parameters were based on data from national registries of patients treated with clozapine, study cohorts, and a pharmacovigilance database; we derived estimates of health-related quality of life and mortality from the scientific literature. We assessed model uncertainty, including time horizon, with one-way and probabilistic sensitivity analyses. Findings Compared with no monitoring, all four monitoring strategies increased quality-adjusted survival by less than 1 day per patient; more than 5000 patients would need to be monitored to avoid one death. The incremental cost-effectiveness ratios (ICERs) were at least US$970 000 per quality-adjusted life-year gained for all four strategies compared with no monitoring. The ICERs were highest in the strategies with highest frequencies and longest durations of monitoring. The results remained robust in the one-way and probabilistic sensitivity analyses, suggesting that no monitoring had the highest probability of being cost effective. Interpretation Existing strategies for monitoring white blood cell count in patients taking clozapine, based on divergent national requirements, do not seem to be cost effective. This finding should be taken into account by public health authorities and policy makers in the revision of guidance for clozapine prescription. Funding University Hospitals of Geneva.

La variabilite interindividuelle dans la reponse medicamenteuse est un probleme clinique majeur. La polymedication et les polymorphismes genetiques modulant l’activite des enzymes du metabolisme medicamenteux tels que les cytochromes P450 (CYP) sont une source de variabilite dans la reponse medicamenteuse. De nouvelles techniques diagnostiques rendues plus sures et plus simples a realiser ont ete developpees afin de diagnostiquer les variations dans l’activite metabolique des CYP (tests de phenotypage) ou de rechercher des variantes alleliques specifiques (genotypage). Alors que le genotypage des CYP offre la possibilite de predire le phenotype en fonction des alleles identifies pour autant que le lien entre genotype et phenotype soit etabli, le phenotypage apporte des informations sur l’activite reelle (in vivo) des CYP et est le reflet d’une combinaison de facteurs genetiques, environnementaux et endogenes. Le genotypage et le phenotypage pourraient ainsi etre consideres de maniere prospective afin d’identifier la molecule ideale ou la dose adequate a administrer chez un patient donne, ou de maniere retrospective pour expliquer une reponse medicamenteuse anormale (toxicite ou inefficacite).

Les anti-inflammatoires non steroidiens (AINS) sont la classe de medicaments la plus frequemment utilisee, que ce soit sur prescription medicale ou « over the counter » (OTC). Leur utilisation est basee sur une administration empirique avec un monitoring clinique qui permet de juger de l’efficacite et de la toxicite. La reponse individuelle peut toutefois etre modulee par des facteurs pharmacocinetiques ou pharmacodynamiques parmi lesquels certains facteurs genetiques. Cette revue resume les principales donnees pharmacogenetiques disponibles expliquant en partie la variation interindividuelle d’efficacite et de toxicite des AINS, notamment pour le CYP2C9, les uridine diphosphate glucuronosyltransferase et les cyclooxygenases.

Interindividual variability in drug response is a major clinical problem. Polymedication and genetic polymorphisms modulating drug-metabolising enzyme activities (cytochromes P450, CYP) are identified sources of variability in drug responses. We present here the relevant data on the clinical impact of the major CYP polymorphisms (CYP2D6, CYP2C19 and CYP2C9) on drug therapy where genotyping and phenotyping may be considered, and the guidelines developed when available. CYP2D6 is responsible for the oxidative metabolism of up to 25 % of commonly prescribed drugs such as antidepressants, antipsychotics, opioids, antiarrythmics and tamoxifen. The ultrarapid metaboliser (UM) phenotype is recognised as a cause of therapeutic inefficacy of antidepressant, whereas an increased risk of toxicity has been reported in poor metabolisers (PMs) with several psychotropics (desipramine, venlafaxine, amitriptyline, haloperidol). CYP2D6 polymorphism influences the analgesic response to prodrug opioids (codeine, tramadol and oxycodone). In PMs for CYP2D6, reduced analgesic effects have been observed, whereas in UMs cases of life-threatening toxicity have been reported with tramadol and codeine. CYP2D6 PM phenotype has been associated with an increased risk of toxicity of metoprolol, timolol, carvedilol and propafenone. Although conflicting results have been reported regarding the association between CYP2D6 genotype and tamoxifen effects, CYP2D6 genotyping may be useful in selecting adjuvant hormonal therapy in postmenopausal women. CYP2C19 is responsible for metabolising clopidogrel, proton pump inhibitors (PPIs) and some antidepressants. Carriers of CYP2C19 variant alleles exhibit a reduced capacity to produce the active metabolite of clopidogrel, and are at increased risk of adverse cardiovascular events. For PPIs, it has been shown that the mean intragastric pH values and the Helicobacter pylori eradication rates were higher in carriers of CYP2C19 variant alleles. CYP2C19 is involved in the metabolism of several antidepressants. As a result of an increased risk of adverse effects in CYP2C19 PMs, dose reductions are recommended for some agents (imipramine, sertraline). CYP2C9 is responsible for metabolising vitamin K antagonists (VKAs), non-steroidal anti-inflammatory drugs (NSAIDs), sulfonylureas, angiotensin II receptor antagonists and phenytoin. For VKAs, CYP2C9 polymorphism has been associated with lower doses, longer time to reach treatment stability and higher frequencies of supratherapeutic international normalised ratios (INRs). Prescribing algorithms are available in order to adapt dosing to genotype. Although the existing data are controversial, some studies have suggested an increased risk of NSAID-associated gastrointestinal bleeding in carriers of CYP2C9 variant alleles. A relationship between CYP2C9 polymorphisms and the pharmacokinetics of sulfonylureas and angiotensin II receptor antagonists has also been observed. The clinical impact in terms of hypoglycaemia and blood pressure was, however, modest. Finally, homozygous and heterozygous carriers of CYP2C9 variant alleles require lower doses of phenytoin to reach therapeutic plasma concentrations, and are at increased risk of toxicity. New diagnostic techniques made safer and easier should allow quicker diagnosis of metabolic variations. Genotyping and phenotyping may therefore be considered where dosing guidelines according to CYP genotype have been published, and help identify the right molecule for the right patient.

Outre l’efficacite d’un nouveau medicament, c’est egalement la securite des substances qui est etudiee de maniere aussi approfondie que possible avant que ne soit delivree l’autorisation de mise sur le marche. Cependant, c’est seulement une fois le medicament sur le marche, lorsqu’il a ete administre a un echantillon de population bien plus important et non selectionne, que des effets indesirables plus rares peuvent etre reveles.

The antiplatelet clopidogrel and the proton pump inhibitor esomeprazole demonstrate a pharmacokinetic interaction through CYP2C19 that could translate into clinical inefficacy of clopidogrel. No medical consensus as to their coprescription has been reached, and different guidelines are available. We evaluated the prescribing practices at the Geneva University Hospitals (HUG) by measuring whether the coprescription was staggered as suggested by experts. We estimated the financial impact of different implementation guidelines. We used the HUG electronic patient records to follow the physicians' prescriptions and the administration by nurses from January 2013 to April 2014. We performed a time series analysis to assess 15 years of proton pump inhibitors (PPIs) and antiplatelet drug use. “Extra costs” were calculated assuming that clopidogrel or esomeprazole would replace prasugrel or ticagrelor and pantoprazole or ranitidine, respectively. Only 10.8% of the patient medical orders for the clopidogrel and esomeprazole coprescription specified to stagger the administration, 12.6% specified a concomitant coprescription, and 76.6% had no clear information. A high rate of 49.6% of the nurses staggered the clopidogrel and esomeprazole coprescription when no clear information was given. We found a statistically significant decrease in clopidogrel use after the publication of the OCLA (Omeprazole–CLopidogrel–Aspirin) study and a significant increase in the trend of esomeprazole. Alternative treatments to avoid this interaction are cost ineffective or offer therapeutic options of lesser quality. We observed a high rate of 56.2% of the clopidogrel and esomeprazole coprescription in our hospital and can therefore not ignore the PK/PD interaction. The most common prescription practice was to not specify the time frame of administration, which was translated by nurses in 49.6% of the cases to a scheduled staggered coprescription of clopidogrel and esomeprazole. As long as no consensus has been reached, the medical orders time frame information should be mandatory to allow a clear and harmonious staggering strategy.

Background Bisphosphonate drugs can be used to prevent and treat osteoporosis and to reduce symptoms and complications of metastatic bone disease; however, they are associated with a rare but serious adverse event: osteonecrosis of the maxillary and mandibular bones. This condition is called bisphosphonate-related osteonecrosis of the jaw or BRONJ. BRONJ is diagnosed when people who are taking, or have previously taken, bisphosphonates have exposed bone in the jaw area for more than eight weeks in the absence of radiation treatment. There is currently no "gold standard" of treatment for BRONJ. The three broad categories of intervention are conservative approaches (e.g. mouth rinse, antibiotics), surgical interventions and adjuvant non-surgical strategies (e.g. hyperbaric oxygen therapy, platelet-rich plasma), which can be used in combination. Objectives To determine the efficacy and safety of any intervention aimed at treating BRONJ. Search methods We searched the following databases to 15 December 2015: the Cochrane Oral Health Group Trials Register, the Cochrane Breast Cancer Group Trials Register (20 September 2011), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via Ovid, EMBASE via Ovid, CancerLit via PubMed, CINAHL via EBSCO and AMED via Ovid. We scanned the references cited in retrieved articles and contacted experts in the field, the first authors of included papers, study sponsors, other bisphosphonates investigators and pharmaceutical companies. We searched for ongoing trials through contact with trialists and by searching the US National Institutes of Health Trials Register (clinicaltrials.gov) and the World Health Organization Clinical Trials Registry Platform. We also conducted a grey literature search to September 2015. Selection criteria Randomised controlled trials (RCTs) comparing the effects of any treatment for BRONJ with another treatment or placebo. Data collection and analysis Two review authors independently screened the search results, assessed the risk of bias in the included trials and extracted data. When in dispute, we consulted a third review author. Main results One small trial at high risk of bias met the inclusion criteria. The trial randomised 49 participants, most of whom had cancer. It compared standard care (defined as surgery, antibiotics and oral rinses at the discretion of the oral-maxillofacial surgeon) to standard care plus hyperbaric oxygen therapy (2 atmospheres twice a day for 40 treatments). The trial measured the percentage of participants who improved or healed at three, six, 12 and 18 months and last contact. It also measured mean weekly pain scores. At three months, the study found that the participants in intervention group were more likely to have an improvement in their osteonecrosis than the standard care group participants (risk ratio (RR) 1.94, 95% confidence interval (CI) 1.01 to 3.74). There was no clear difference between the groups for the outcome 'healed' at three months (RR 3.60, 95% CI 0.87 to 14.82). There was no clear difference between the groups for improvement or healing when they were evaluated at six, 12 and 18 months and last contact. The study did not give any information on adverse events. Although the findings suggest adjunctive hyperbaric oxygen improved BRONJ, the quality of the evidence is very low since the only study was underpowered and was at high risk of bias due to lack of blinding, cross-over of participants between groups and very high attrition (50% at 12 months and 80% at 18 months in this study, which was designed for an intended follow-up of 24 months). Authors' conclusions There is a lack of evidence from randomised controlled trials to guide treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ). One small trial at high risk of bias evaluated hyperbaric oxygen therapy (HBO) as an adjunct to "standard" care and could not confirm or refute the effectiveness of HBO. There are two ongoing trials of teriparatide treatment for BRONJ. We found no randomised controlled trials of any other BRONJ treatments. High quality randomised controlled trials are needed. We provide recommendations for their focus and design.

Neben der Wirksamkeit eines neuen Arzneimittels wird auch die Sicherheit von Substanzen vor der Marktzulassung so gut wie moglich untersucht. Jedoch lassen sich erst nach der Marktzulassung, wenn die Arzneimittel bei einer viel grosseren und nicht selektionierten Bevolkerungsgruppe angewendet werden, auch seltenere unerwunschte Arzneimittelwirkungen in Erfahrung bringen.

The use of analgesics is based on the empiric administration of a given drug with clinical monitoring for efficacy and toxicity. However, individual responses to drugs are influenced by a combination of pharmacokinetic and pharmacodynamic factors that can sometimes be regulated by genetic factors. Whereas polymorphic drug-metabolizing enzymes and drug transporters may affect the pharmacokinetics of drugs, polymorphic drug targets and disease-related pathways may influence the pharmacodynamic action of drugs. After a usual dose, variations in drug toxicity and inefficacy can be observed depending on the polymorphism, the analgesic considered and the presence or absence of active metabolites. For opioids, the most studied being morphine, mutations in the ABCB1 gene, coding for P-glycoprotein (P-gp), and in the µ-opioid receptor reduce morphine potency. Cytochrome P450 (CYP) 2D6 mutations influence the analgesic effect of codeine and tramadol, and polymorphism of CYP2C9 is potentially linked to an increase in nonsteroidal anti-inflammatory drug-induced adverse events. Furthermore, drug interactions can mimic genetic deficiency and contribute to the variability in response to analgesics. This review summarizes the available data on the pharmacokinetic and pharmacodynamic consequences of known polymorphisms of drug-metabolizing enzymes, drug transporters, drug targets and other nonopioid biological systems on central and peripheral analgesics.

Skin atrophy is an adverse effect of topical corticosteroids (TCs) which, as an established non-life-threatening effect, has been poorly reported by trials involving these drugs. Atopic dermatitis and psoriasis are example of disorders that require repeated therapies with TCs; however, assessing the atrophogenic activity of TCs is still an issue. This study aims to review clinical data on skin atrophy induced by TCs. Searches of the PubMed, EMBASE, and Cochrane (Central) databases from 1965 to May 2013 were undertaken using the keywords 'corticosteroid', 'skin', and 'atrophy'. Skin and epidermal thickness values were retrieved from trials on healthy skin, and studies including skin atrophy as a safety endpoint in trials testing the efficacy of TCs were analyzed. Overall, 60 articles were retrieved. Whole skin and epidermal thickness were relevant parameters to measure early skin atrophy on healthy skin before it becomes clinically obvious. Epidermis thickness also seems to be more sensitive than whole skin thickness in detecting early atrophy; however, measuring skin atrophy still requires standardization. Further clinical trials on the atrophic effects of each TC are required to better evaluate their respective atrophic risks and their risk/benefit ratios. However, measuring epidermal or whole skin thickness will not be relevant in acute phases of inflammatory skin disorders treated with TCs because of the thickening induced by inflammation. In addition, skin atrophy seems to be induced by chronic TC use rather than by acute treatments. Long-term safety studies may be more relevant to evaluate atrophic activity.

Polypharmacy in the elderly complicates therapy, increases cost, and is a challenge for healthcare agencies. In the context of the evolving role of the pharmacist, this systematic review examines the effectiveness of interventions led by pharmacists in reducing polypharmacy. A computerised search was conducted using Medline, Embase geriatrics and gerontology (2001 edition), the Cochrane Library and International Pharmaceutical Abstracts (IPA) databases. A manual search of articles on polypharmacy and the role of pharmacists in the therapy of the elderly and of the reference sections of all retrieved articles was also carried out. Search terms used were 'polypharmacy', 'elderly', 'aged', 'intervention' and 'pharmacist(s)'. Articles that fulfilled the following criteria were included: only elderly people were included in the study, or all ages were included but the study gave separate results for the elderly; the outcome was expressed as a reduction in the number of medications; a pharmacist participated in the study; and the study was a controlled or a randomised controlled study. We initially identified 106 articles, but only 14 studies met our four inclusion criteria. Reduction in the number of medications was not the major purpose of most selected studies but often a secondary outcome. Objectives differed, the general aim being to enhance the quality of prescribing in elderly patients. These controlled studies argued in favour of the effectiveness of pharmacists' interventions, even though the number of medications eliminated was small. Most studies were not designed to demonstrate the impact of reducing the number of drugs on the clinical consequences of polypharmacy (nonadherence, adverse drug reactions, drug-drug interactions, increased risk of hospitalisation, and medication errors). The most frequently reported outcome related to cost savings. It was therefore difficult to assess whether the interventions benefited the patient. The methodological quality of many identified studies was poor. In particular, the study objectives were often very broad and ill-defined. Polypharmacy itself has been defined in different ways and the appropriate definition may differ according to the patient population and the study setting. Further studies are needed to find the most effective way to reduce polypharmacy, especially in the frail elderly population, and to quantify the real advantages of simplifying their drug regimens in terms of improved quality of life.

Introduction et objectifs Le risque d’erreurs medicamenteuses est accru a l’admission d’un service de soins. L’interface ville/hopital expose a un risque de discontinuite dans la prise en charge medicamenteuse en induisant des divergences non intentionnelles de prescription (DNI) entre traitements habituels et hospitaliers. L’objectif de cette etude etait d’evaluer l’incidence des DNI et de mesurer l’impact d’une reconciliation medicamenteuse a l’admission sur la justesse de la prescription hospitaliere en medecine interne. Methodes Etude interventionnelle de 2 mois realisee a l’admission des patients en medecine interne dans le cadre du projet national « Progress ! La securite de la medication aux interfaces ». Tous les patients admis etaient eligibles et etaient inclus apres la redaction de la prescription initiale hospitaliere (PIH). Un pharmacien realisait la meilleure anamnese medicamenteuse possible (MAMP), puis procedait a l’identification des divergences de prescription par la comparaison de ces donnees aux traitements de la PIH. L’intentionnalite des divergences etait determinee par une concertation avec les prescripteurs et les DNI etaient evaluees pour leur type et les classes therapeutiques qu’elles concernaient. Resultats Vingt-sept patients (59 % femmes) ont ete inclus. L’âge moyen etait de 64,6 ± 17,5 ans. En moyenne, la MAMP durait 1 heure, etait effectuee dans un intervalle de 1,4 jours apres l’admission et permettait l’identification de 7,6 ± 4,9 lignes de traitements par l’exploitation de 2 sources d’information (le plus souvent le patient et son officine). Un total de 54 divergences, dont 42 DNI concernant 17 patients ont ete identifiees (1,6 DNI par patient). Les DNI etaient des omissions de prescription ( n = 32), des erreurs de posologie ( n = 7), des erreurs de modalites d’administration ( n = 2) et une erreur de nom de specialite. Les DNI interessaient 11 classes therapeutiques et 81 % ( n = 34) concernaient 5 classes, (systeme digestif, nerveux, respiratoire, cardiovasculaire et organes sensoriels). La concertation avec le prescripteur a permis la rectification de 52 % des DNI ( n = 22). Discussion et conclusions Les divergences de prescription sont frequentes a l’admission et la reconciliation medicamenteuse peut permettre l’interception et la correction des DNI. L’impact de cette derniere pourra etre mieux estime par une appreciation de la gravite clinique potentielle des DNI par un groupe d’experts independants (medecins, pharmacien clinicien). Un impact positif serait un argument en faveur d’une intervention plus systematique des pharmaciens en amont de la redaction de la PIH, afin de prevenir la survenue des DNI.

Quality therapeutics play an important role in Switzerland's health care and economy. Switzerland holds a key position in the world of research and development, as well as in drug production. Recently, new emphasis has been placed on promoting clinical research and maintaining Switzerland's position as a center of excellence in the field. Recent revisions to the law regarding medical trials in human research allow for better allocation of regulatory resources and simplified procedures for drugs already authorized in Switzerland. The country has its own regulatory agency, the Swiss Agency for Therapeutic Products (Swissmedic), which is a public institution of the Swiss government. Swissmedic is responsible for ensuring safety in medicines, particularly regarding authorizations and market surveillance in the sector of medicinal products and medical devices. Although the centralized authorization procedure of the European Union for medicines does not apply to Switzerland, there are mutual recognition mechanisms between the Swiss medicine regulatory authority and the European Medicines Agency. Swissmedic is also in charge of postmarketing safety and oversees the national pharmacovigilance center, which collaborates closely with the World Health Organization center in Uppsala. In addition, university hospital-based clinical pharmacologists, who are involved in basic science and clinical research, regulatory affairs, ethics committees, and pharmacovigilance, promote quality therapeutics. This article discusses the role of the various stakeholders and the recent efforts made to provide a better allocation of resources aimed at further improving quality therapeutics in Switzerland.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most frequently used drugs, either on prescription or over-thecounter (OTC). Their daily dosage is based on randomised controlled trials and an empirical clinical assessment of their efficacy and toxicity that allows dose adjustment. The individual response can however be altered by environmental and genetic pharmacokinetic and pharmacodynamic factors. This review summarizes the available pharmacogenetic data that explains part of the variability in response and occurrence of adverse drug reactions to NSAIDs treatment, with a thorough focus on CYP2C9, uridine diphosphate glucuronosyltransferases (UGTs) and cyclooxygenases (COX1 and COX2). Other polymorphisms that are currently being studied and could also explain the interindividual variability in the efficacy and safety of NSAIDs will also be considered.

Adverse drug reactions (ADRs) represent an important risk for patients and have a significant economic impact on health systems. ADRs are the fifth most common cause of hospital death, with a burden estimated at 197,000 deaths per year in the EU. This has a societal cost of 79 billion per year. Because of this strong impact in public health, regulatory authorities (RAs) worldwide are implementing new pharmacovigilance legislation to promote and protect public health by reducing the burden of ADRs through the detection of safety signals. Although, traditionally, signal detection activities have mainly been performed based on spontaneous reporting from healthcare professionals and national health RAs, the new pharmacovigilance legislation underlines the relevance of other sources of information (such as scientific literature) for the evaluation of the benefit-risk balance of a certain product. This review aims to highlight the relevance of periodic scientific literature screening in the safety signal detection process. The authors present four practical examples where a safety signal that was detected from a literature report had an impact on the lifecycle of a drug. In addition, based on practical experience of the screening of medical and scientific literature for safety purposes, this article analyses the requirements of the new pharmacovigilance guidelines on literature screening and highlights the need for the implementation of a literature review procedure and the main challenges encountered when performing literature screening for safety aspects.

Our institution's gentamicin dosing and therapeutic drug monitoring (TDM) practices for newborns were suspected to be very heterogeneous. Once-daily dosing (ODD) or extended-interval dosing (EID) and trough concentration measurement were recommended. Clinical decision support guidelines were developed and implemented as clinical decision support in the computerized prescriber order entry system. Impact on dosing, TDM practices, and blood sampling were evaluated.A 1-year retrospective historically controlled study before (April 2008-March 2009) and after the implementation of guidelines (January 2010-December 2010) for newborns (30 days of life) receiving gentamicin. Blood concentrations (% of peak concentrations sampled, % of patients with zero or one concentration sampled, % of trough concentrations ≤1 mg/L) and dose regimen (ODD/EID) were compared between groups. Factors potentially associated with gentamicin concentration were analyzed (multivariate analysis).One hundred thirty-two (postguidelines) versus 102 (preguidelines) patients were included (median gestational age: 34.3 versus 35.8 weeks, P0.05). After implementation of the guidelines, an ODD/EID regimen was almost exclusively used (97.7% versus 61.6%, P0.001), the percentage of peak concentrations (0.9% versus 17.2%, P0.001) and the number of blood samples per patient (87.1% having 0 or 1 concentration measured versus 48.0, P0.001) sharply reduced. A significantly higher percentage of trough concentrations were ≤1 mg/L (68.5% versus 33.0%, P0.001). The probability of a trough concentration ≤1 mg/L increased with an ODD/EID regimen (odds ratio, 7.23; 95% confidence interval: 3.48-15.0, P0.001) and in the postguidelines group (odds ratio, 2.02; 95% confidence interval: 1.01-4.02, P = 0.045).Guideline implementation generated a sharp reduction in blood sampling. Clinical benefits of better gentamicin dosing and TDM practices were evident. Cost-effectiveness and clinical benefit of reduced blood sampling should be evaluated.