Medical cannabinoids for painful symptoms in patients with severe dementia: a randomized, double-blind cross-over placebo-controlled trial protocol.

Background: In an observational study in Geneva (Switzerland), we found that administering a standardized THC/CBD oil was feasible, safe, and beneficial in an elderly polymedicated population with severe dementia, behavioral troubles, and pain. Those findings need to be confirmed in a randomized clinical trial. Objectives: The MedCanDem trial is a randomized, double-blind cross-over placebo-controlled trial to study the efficacy of cannabinoids in improving painful symptoms during severe dementia disorders in patients living in long-term care facilities in Geneva. This manuscript describes the MedCanDem trial protocol. Materials and methods: Participants will be patients suffering from severe dementia associated with pain and behavioral troubles and living in long-term care facilities. We selected five facilities specialized in caring for severely demented patients in Geneva (Switzerland). A total of 24 subjects will be randomized 1:1 to the sequence study intervention/placebo or the sequence placebo/study intervention. Patients will receive study intervention treatment or placebo for eight weeks, and then after a one-week wash-out, treatments will be inversed for another eight weeks. The intervention will be a standardized THC/CBD 1:2 oil extract, and the placebo will be a hemp seed oil. The primary outcome is the reduction from the baseline of the Cohen-Mansfield score; secondary outcomes include the reduction in the Doloplus scale, the reduction of rigidity, the monitoring of concomitant drugs prescription and de-prescription, the safety assessment, and a pharmacokinetic evaluation. The primary and secondary outcomes will be assessed at the baseline, after 28 days, and at the end of both study periods. In addition, safety laboratory analysis, pharmacokinetic evaluation, and therapeutic drug monitoring for the cannabinoids will be evaluated through a blood sample analysis conducted at the beginning and the end of both study periods. Discussion and conclusion: This study will allow us to confirm the clinical results observed during the observational study. It represents one of the few studies aiming to prove natural medical cannabis efficacy in a population of non-communicating patients with severe dementia, experimenting with behavioral troubles, pain, and rigidity. Trial registration: The trial has Swissethics authorization (BASEC 2022-00999), and it is registered on clinicaltrials.gov (NCT05432206) and the SNCTP (000005168).

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.

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 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.

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.

Impact of Boosted Antiretroviral Therapy on the Pharmacokinetics and Efficacy of Clopidogrel and Prasugrel Active Metabolites.

BACKGROUND AND OBJECTIVES: Prasugrel and clopidogrel are inhibitors of the ADP-P2Y12 platelet receptor used in acute coronary syndrome patients. They require bioactivation via isoenzymes such as cytochrome P450 (CYP) 3A4, CYP2C19 and CYP2B6. Ritonavir and cobicistat are potent CYP3A inhibitors, prescribed as pharmacokinetic (PK) enhancers in the treatment of human immunodeficiency virus (HIV) infection. METHODS: In this study, the impact of boosted antiretroviral therapies (ARTs) on the PK of clopidogrel and prasugrel active metabolites (AMs), and on the efficacy of prasugrel and clopidogrel, were evaluated in a randomized crossover clinical trial. RESULTS: A significantly lower exposure to clopidogrel AM [3.2-fold lower area under the concentration-time curve (AUC) and maximum plasma concentration (Cmax)] and prasugrel AM (2.1-fold and 1.7-fold lower AUC and Cmax) were demonstrated in HIV-infected patients treated with boosted ARTs compared with healthy controls; however, a differential impact was observed on platelet inhibition between clopidogrel and prasugrel. Clopidogrel 300 mg induced adequate (although modest) platelet inhibition in all healthy subjects, while platelet inhibition was insufficient in 44% of HIV patients. On the contrary, prasugrel 60 mg induced a potent platelet inhibition in both healthy and HIV-infected subjects. CONCLUSION: Prasugrel appears to remain an adequate antiplatelet agent in HIV-infected patients and could be preferred to clopidogrel in this context, regardless of the metabolic interaction and inhibition of its bioactivation pathways.

P-glycoprotein: a clue to vitamin K antagonist stabilization.

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.

Prediction by pharmacogenetics of safety and efficacy of non-steroidal anti- inflammatory drugs: a review.

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.

Role of P-glycoprotein in the uptake/efflux transport of oral vitamin K antagonists and rivaroxaban through the Caco-2 cell model.

Vitamin K antagonists (VKAs) are prescribed worldwide and remain the oral anticoagulant of choice. These drugs are characterized by a narrow therapeutic index and a large inter- and intra-individual variability. P-glycoprotein could contribute to this variability. The aim of this study was to investigate the involvement of P-gp in the transport of acenocoumarol, phenprocoumon and warfarin using an in vitro Caco-2 cell monolayer model. These results were compared with those obtained with rivaroxaban, a new oral anticoagulant known to be a P-gp substrate. The transport of these four drugs was assessed at pH conditions 6.8/7.4 in the presence or absence of the P-gp inhibitor cyclosporine A (10 µM) and the more potent and specific P-gp inhibitor valspodar (5 µM). Analytical quantification was performed by LC/MS. With an efflux ratio of 1.7 and a significant decrease in the efflux (Papp B-A), in the presence of P-gp inhibitors at a concentration of 50 µM, acenocoumarol can be considered as a weak P-gp substrate. Concerning phenprocoumon, the results suggest that this molecule is a poor P-gp substrate. The P-gp inhibitors did not affect significantly the transport of warfarin. The efflux of rivaroxaban was strongly inhibited by the two P-gp inhibitors. In conclusion, none of the three VKAs tested are strong P-gp substrates. However, acenocoumarol can be considered as a weak P-gp substrate and phenprocoumon as a poor P-gp substrate.

Impact of CYP2C9 polymorphisms on the vulnerability to pharmacokinetic drug-drug interactions during acenocoumarol treatment.

AIM: The objective of this study was to investigate the impact of CYP2C9 polymorphisms and drug-drug interactions on the risk of overanticoagulation in patients treated with acenocoumarol, a vitamin K antagonist. MATERIALS & METHODS: A prospective observational study was performed on patients starting acenocoumarol (n = 115). CYP2C9 genotypes were assessed. Data on International Normalized Ratio, comedications and doses of acenocoumarol were collected during the first 35 days of therapy. Overanticoagulation was defined as the occurrence of at least one International Normalized Ratio ≥4. RESULTS: The presence of a CYP2C9 inhibitor or a CYP2C9 polymorphisms statistically increased the risk of overanticoagulation (hazard ratio [HR]: 2.8, p < 0.001 and HR: 1.7, p = 0.04, respectively). The presence of CYP2C9 polymorphisms almost tripled the risk of overanticoagulation (HR: 2.91, p = 0.01) in the presence of a clinically significant drug-drug interaction. CONCLUSION: These findings support the fact that CYP2C9 genotyping could be useful to identify patients requiring closer monitoring, especially when a drug-drug interaction is expected.

Individualizing analgesic prescription Part I: pharmacogenetics of opioid analgesics.

The current 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 processes, and each of these components, in addition to pain perception and processing, seem to 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 usual dose, drug toxicity, as well as inefficacy, can be observed depending on the polymorphism, the analgesic considered and the presence or absence of active metabolites. Thus, cytochrome P450 (CYP)2D6 polymorphism influences codeine and tramadol analgesic effects, CYP2C9 has an impact on the disposition of some nonsteroidal anti-inflammatory drugs, and opioid receptor polymorphism (118A>G) may reduce morphine potency. Moreover, drug interaction mimics genetic deficiency and contributes to the variability in response to analgesics. This two-part review summarizes the available data on the pharmacokinetic-pharmacodynamic consequences of known polymorphisms of drug-metabolizing enzymes (CYP and uridine diphosphate glucuronosyltransferase), drug transporters (multidrug resistance proteins, multidrug resistance-associated proteins, organic anion-transporting polypeptides, and serotonin transporters), relevant drug targets (such as µ-opioid receptor, serotonin receptor and cyclooxygenases) and other nonopioid biological systems, on currently prescribed central and peripheral analgesics.