Apixaban and rivaroxaban's physiologically-based pharmacokinetic model validation in hospitalized patients: A first step for larger use of a priori modeling approach at bed side.

When used in real-world conditions, substantial interindividual variations in direct oral anticoagulant (DOAC) plasma concentrations are observed for a given dose, leading to a risk of over- or under-exposure and clinically significant adverse events. Physiologically-based pharmacokinetic (PBPK) models could help physicians to tailor DOAC prescriptions in vulnerable patient populations, such as those in the hospital setting. The present study aims to validate prospectively PBPK models for rivaroxaban and apixaban in a large cohort of elderly, polymorbid, and hospitalized patients. In using a model of geriatric population integrating appropriate physiological parameters into models first optimized with healthy volunteer data, observed plasma concentration collected in hospitalized patients on apixaban (n = 100) and rivaroxaban (n = 100) were adequately predicted (ratio predicted/observed area under the concentration curve for a dosing interval [AUCtau ] = 0.97 [0.96-0.99] geometric mean, 90% confidence interval, ratio predicted/observed AUCtau = 1.03 [1.02-1.05]) for apixaban and rivaroxaban, respectively. Validation of the present PBPK models for rivaroxaban and apixaban in in-patients represent an additional step toward the feasibility of bedside use.

Population pharmacokinetics of apixaban in a real-life hospitalized population from the OptimAT study.

This study aimed to characterize apixaban pharmacokinetics (PKs) and its variability in a real-world clinical setting of hospitalized patients using a population PK (PopPK) approach. Model-based simulations helped to identify factors that affect apixaban exposure and their clinical significance. A classic stepwise strategy was applied to determine the best PopPK model for describing typical apixaban PKs in hospitalized patients from the OptimAT study (n = 100) and evaluating the associated variability and influencing factors. Apixaban exposure under specific conditions was assessed using the final model. A two-compartment model with first-order absorption and elimination best described the data. The developed PopPK model revealed a major role of renal function and a minor role of P-glycoprotein phenotypic (P-gp) activity in explaining apixaban variability. The final model indicated that a patient with stage 4 chronic kidney disease (creatinine clearance [CLcr] = 15-29 mL/min) would have a 45% higher drug exposure than a patient with normal renal function (CLcr >90 mL/min), with a further 12% increase if the patient was also a poor metabolizer of P-gp. A high interindividual variability in apixaban PKs was observed in a real-life setting, which was partially explained by renal function and by P-gp phenotypic activity. Target apixaban concentrations are reached under standard dosage regimens, but overexposure can rapidly occur in the presence of cumulative factors warranting the development of a predictive tool for tailoring apixaban exposure and its clinical utility in at-risk patients.

Virulence strategies of an insect herbivore and oomycete plant pathogen converge on host E3 SUMO ligase SIZ1.

Pathogens and pests secrete proteins (effectors) to interfere with plant immunity through modification of host target functions and disruption of immune signalling networks. The extent of convergence between pathogen and herbivorous insect virulence strategies is largely unexplored. We found that effectors from the oomycete pathogen, Phytophthora capsici, and the major aphid pest, Myzus persicae target the host immune regulator SIZ1, an E3 SUMO ligase. We used transient expression assays in Nicotiana benthamiana as well as Arabidopsis mutants to further characterize biological role of effector-SIZ1 interactions in planta. We show that the oomycete and aphid effector, which both contribute to virulence, feature different activities towards SIZ1. While M. persicae effector Mp64 increases SIZ1 protein levels in transient assays, P. capsici effector CRN83_152 enhances SIZ1-E3 SUMO ligase activity in vivo. SIZ1 contributes to host susceptibility to aphids and an oomycete pathogen. Knockout of SIZ1 in Arabidopsis decreased susceptibility to aphids, independent of SNC1, PAD4 and EDS1. Similarly SIZ1 knockdown in N. benthamiana led to reduced P. capsici infection. Our results suggest convergence of distinct pathogen and pest virulence strategies on an E3 SUMO ligase to enhance host susceptibility.

Impact of the Genotype and Phenotype of CYP3A and P-gp on the Apixaban and Rivaroxaban Exposure in a Real-World Setting.

Apixaban and rivaroxaban are the two most prescribed direct factor Xa inhibitors. With the increased use of DOACs in real-world settings, safety and efficacy concerns have emerged, particularly regarding their concomitant use with other drugs. Increasing evidence highlights drug−drug interactions with CYP3A/P-gp modulators leading to adverse events. However, current recommendations for dose adjustment do not consider CYP3A/P-gp genotype and phenotype. We aimed to determine their impact on apixaban and rivaroxaban blood exposure. Three-hundred hospitalized patients were included. CYP3A and P-gp phenotypic activities were assessed by the metabolic ratio of midazolam and AUC0−6h of fexofenadine, respectively. Relevant CYP3A and ABCB1 genetic polymorphisms were also tested. Capillary blood samples collected at four time-points after apixaban or rivaroxaban administration allowed the calculation of pharmacokinetic parameters. According to the developed multivariable linear regression models, P-gp activity (p < 0.001) and creatinine clearance (CrCl) (p = 0.01) significantly affected apixaban AUC0−6h. P-gp activity (p < 0.001) also significantly impacted rivaroxaban AUC0−6h. The phenotypic switch (from normal to poor metabolizer) of P-gp led to an increase of apixaban and rivaroxaban AUC0−6h by 16% and 25%, respectively, equivalent to a decrease of 38 mL/min in CrCl according to the apixaban model. CYP3A phenotype and tested SNPs of CYP3A/P-gp had no significant impact. In conclusion, P-gp phenotypic activity, rather than known CYP3A/P-gp polymorphisms, could be relevant for dose adjustment.

Prediction of cytochromes P450 3A and 2C19 modulation by both inflammation and drug interactions using physiologically based pharmacokinetics.

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 <2 for all observations (ranging from 0.51 to 1.7). The impact of IL-6 and esomeprazole on CYP3A and CYP2C19 activities after a hip surgery were correctly predicted with the developed PBPK models.

Influence of Inflammation on Cytochromes P450 Activity in Adults: A Systematic Review of the Literature.

Background: Available in-vitro and animal studies indicate that inflammation impacts cytochromes P450 (CYP) activity via multiple and complex transcriptional and post-transcriptional mechanisms, depending on the specific CYP isoforms and the nature of inflammation mediators. It is essential to review the current published data on the impact of inflammation on CYP activities in adults to support drug individualization based on comorbidities and diseases in clinical practice. Methods: This systematic review was conducted in PubMed through 7th January 2021 looking for articles that investigated the consequences of inflammation on CYP activities in adults. Information on the source of inflammation, victim drugs (and CYPs involved), effect of disease-drug interaction, number of subjects, and study design were extracted. Results: The search strategy identified 218 studies and case reports that met our inclusion criteria. These articles were divided into fourteen different sources of inflammation (such as infection, autoimmune diseases, cancer, therapies with immunomodulator…). The impact of inflammation on CYP activities appeared to be isoform-specific and dependent on the nature and severity of the underlying disease causing the inflammation. Some of these drug-disease interactions had a significant influence on drug pharmacokinetic parameters and on clinical management. For example, clozapine levels doubled with signs of toxicity during infections and the concentration ratio between clopidogrel's active metabolite and clopidogrel is 48-fold lower in critically ill patients. Infection and CYP3A were the most cited perpetrator of inflammation and the most studied CYP, respectively. Moreover, some data suggest that resolution of inflammation results in a return to baseline CYP activities. Conclusion: Convincing evidence shows that inflammation is a major factor to be taken into account in drug development and in clinical practice to avoid any efficacy or safety issues because inflammation modulates CYP activities and thus drug pharmacokinetics. The impact is different depending on the CYP isoform and the inflammatory disease considered. Moreover, resolution of inflammation appears to result in a normalization of CYP activity. However, some results are still equivocal and further investigations are thus needed.

Impact of SARS-CoV-2 Infection (COVID-19) on Cytochromes P450 Activity Assessed by the Geneva Cocktail.

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 < 0.001) higher during SARS-CoV-2 infection. CYP activity are modulated in an isoform-specific manner by SARS-CoV-2 infection. The pharmacokinetics of CYP substrates, whether used to treat the disease or as the usual treatment of patients, could be therefore clinically impacted.

Impact of Inflammation on Cytochromes P450 Activity in Pediatrics: A Systematic Review.

BACKGROUND AND OBJECTIVE: Cytochromes P450 (CYP) are the major enzymes involved in hepatic metabolism of drugs. Personalization of treatment in pediatrics is a major challenge, as it must not only take into account genetic, environmental, and physiological factors but also ontogeny. Published data in adults show that inflammation had an isoform-specific impact on CYP activities and we aimed to evaluate this impact in the pediatric population. METHODS: Articles listed in PubMed through 7 January, 2021 that studied the impact of inflammation on CYP activities in pediatrics were included in this systematic review. Sources of inflammation, victim drugs (CYP involved), effect of drug-disease interactions, number and age of subjects, and study design were extracted. RESULTS: Twenty-seven studies and case reports were included. The impact of inflammation on CYP activities appeared to be age dependent and isoform-specific, with some drug-disease interactions having significant pharmacokinetic and clinical impact. For example, midazolam clearance decreases by 70%, while immunosuppressant and theophylline concentrations increase three-fold and two-fold with intensive care unit admission and infection. Cytochrome P450 activity appears to return to baseline level when the disease is resolved. CONCLUSIONS: Studies that have assessed the impact of inflammation on CYP activity are lacking in pediatrics, yet it is a major factor to consider to improve drug efficacy or safety. The scarce current data show that the impact of inflammation is isoform and age dependent. An effort must be made to improve the understanding of the impact of inflammation on CYP activities in children to better individualize treatment.

Drug-Drug Interactions Leading to Adverse Drug Reactions with Rivaroxaban: A Systematic Review of the Literature and Analysis of VigiBase.

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.

Impact of Acute Inflammation on Cytochromes P450 Activity Assessed by the Geneva Cocktail.

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-1ß, TNF-α, and IFN-γ) were also measured in blood. CYP1A2 MRs decreased by 53% (P < 0.0001) between baseline and the nadir at D1. CYP2C19 and CYP3A activities (MRs) decreased by 57% (P = 0.0002) and 61% (P < 0.0001), respectively, with the nadir at D3. CYP2B6 and CYP2C9 MRs increased by 120% (P < 0.0001) and 79% (P = 0.018), respectively, and peaked at D1. Surgery did not have a significant impact on CYP2D6 MR. Hip surgery was a good acute inflammation model as CRP, IL-6, and TNF-α peak levels were reached between D1 and day 2 (D2). Acute inflammation modulated CYP activity in an isoform-specific manner, with different magnitudes and kinetics. Acute inflammation may thus have a clinically relevant impact on the pharmacokinetics of these CYP substrates.

Drug interactions with apixaban: A systematic review of the literature and an analysis of VigiBase, the World Health Organization database of spontaneous safety reports.

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.

Outcomes of drug exposition during pregnancy: Analysis from a teratology information service.

OBJECTIVE: We aimed to characterize drug exposures during pregnancy where the outcome was known that had benefited from counselling through our Teratology Information Service (TIS) between 1994-2016. STUDY DESIGN: This observational study analysed data collected through the drug exposures during pregnancy counselling. Data was analysed descriptively. RESULTS: Data from a total of 1'374 pregnant women were collected. Mean age was of 32 years. These women were exposed to more than ten drugs in 1.4 % (N = 19) of cases, with a mean drug intake of two. Analysis of the drugs altogether (N = 3'129) showed that FDA Pregnancy Category C drugs represented 42.9 % (N = 1'342) of drugs and ATC code N (nervous system) represented 36.4 % (N = 1'138). The onset of drug exposure was during the first trimester of pregnancy in 95.1 % (N = 2'982) of patients. Regarding outcomes, the rate of induced abortion was 10.8 % (N = 151), of pregnancy complications was 11.2 % (N = 157) and of malformations was 4.5 % (N = 49). CONCLUSION: Pregnant women counselled by our TIS take a mean of two drugs, ranging from one to 17. Drugs are from FDA Pregnancy Category C and ATC N drugs in most cases, 42.9 % and 36.4 % respectively. The rate of malformation of our cohort was of 4.5 %, close to the estimated spontaneous rate of malformation. This data gives a reassuring aspect of drug exposure in pregnancy but takes into account the outcome at birth only.

Snapshot of proton pump inhibitors prescriptions in a tertiary care hospital in Switzerland: less is more?

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.

Plant immunity in plant-aphid interactions.

Aphids are economically important pests that cause extensive feeding damage and transmit viruses. While some species have a broad host range and cause damage to a variety of crops, others are restricted to only closely related plant species. While probing and feeding aphids secrete saliva, containing effectors, into their hosts to manipulate host cell processes and promote infestation. Aphid effector discovery studies pointed out parallels between infection and infestation strategies of plant pathogens and aphids. Interestingly, resistance to some aphid species is known to involve plant resistance proteins with a typical NB-LRR domain structure. Whether these resistance proteins indeed recognize aphid effectors to trigger ETI remains to be elucidated. In addition, it was recently shown that unknown aphid derived elicitors can initiate reactive oxygen species (ROS) production and callose deposition and that these responses were dependent on BAK1 (BRASSINOSTERIOD INSENSITIVE 1-ASSOCIATED RECEPTOR KINASE 1) which is a key component of the plant immune system. In addition, BAK-1 contributes to non-host resistance to aphids pointing to another parallel between plant-pathogen and - aphid interactions. Understanding the role of plant immunity and non-host resistance to aphids is essential to generate durable and sustainable aphid control strategies. Although insect behavior plays a role in host selection and non-host resistance, an important observation is that aphids interact with non-host plants by probing the leaf surface, but are unable to feed or establish colonization. Therefore, we hypothesize that aphids interact with non-host plants at the molecular level, but are potentially not successful in suppressing plant defenses and/or releasing nutrients.