A pharmacovigilance study of pharmacokinetic drug interactions using a translational informatics discovery approach.

BACKGROUND: While the pharmacokinetic (PK) mechanisms for many drug interactions (DDIs) have been established, pharmacovigilance studies related to these PK DDIs are limited. Using a large surveillance database, a translational informatics approach can systematically screen adverse drug events (ADEs) for many DDIs with known PK mechanisms. METHODS: We collected a set of substrates and inhibitors related to the cytochrome P450 (CYP) isoforms, as recommended by the United States Food and Drug Administration (FDA) and Drug Interactions Flockhart table™. The FDA's Adverse Events Reporting System (FAERS) was used to obtain ADE reports from 2004 to 2018. The substrate and inhibitor information were used to form PK DDI pairs for each of the CYP isoforms and Medical Dictionary for Regulatory Activities (MedDRA) preferred terms used for ADEs in FAERS. A shrinkage observed-to-expected ratio (Ω) analysis was performed to screen for potential PK DDI and ADE associations. RESULTS: We identified 149 CYP substrates and 62 CYP inhibitors from the FDA and Flockhart tables. Using FAERS data, only those DDI-ADE associations were considered that met the disproportionality threshold of Ω > 0 for a CYP substrate when paired with at least two inhibitors. In total, 590 ADEs were associated with 2085 PK DDI pairs and 38 individual substrates, with ADEs overlapping across different CYP substrates. More importantly, we were able to find clinical and experimental evidence for the paclitaxel-clopidogrel interaction associated with peripheral neuropathy in our study. CONCLUSION: In this study, we utilized a translational informatics approach to discover potentially novel CYP-related substrate-inhibitor and ADE associations using FAERS. Future clinical, population-based and experimental studies are needed to confirm our findings.

Association of CYP1A1 and CYP1B1 inhibition in in vitro assays with drug-induced liver injury.

Drug-induced liver injury (DILI) is one of the major causes for the discontinuation of drug development and withdrawal of drugs from the market. Since it is known that reactive metabolite formation and being substrates or inhibitors of cytochrome P450s (P450s) are associated with DILI, we systematically investigated the association between human P450 inhibition and DILI. The inhibitory activity of 266 DILI-positive drugs (DILI drugs) and 92 DILI-negative drugs (no-DILI drugs), which were selected from Liver Toxicity Knowledge Base (US Food and Drug Administration), against 8 human P450 forms was assessed using recombinant enzymes and luminescent substrates, and the threshold values showing the highest balanced accuracy for DILI discrimination were determined for each P450 enzyme using receiver operating characteristic analyses. The results showed that among the P450s tested, CYP1A1 and CYP1B1 were inhibited by DILI drugs more than no-DILI drugs with a statistical significance. We found that 91% of drugs that showed inhibitory activity greater than the threshold values against CYP1A1 or CYP1B1 were DILI drugs. The results of internal 5-fold cross-validation confirmed the usefulness of CYP1A1 and CYP1B1 inhibition data for the threshold-based discrimination of DILI drugs. Although the contribution of these P450s to drug metabolism in the liver is considered minimal, our present findings suggest that the assessment of CYP1A1 and CYP1B1 inhibition is useful for screening DILI risk of drug candidates at the early stage of drug development.

The Complex Management of Atrial Fibrillation and Cancer in the COVID-19 Era: Drug Interactions, Thromboembolic Risk, and Proarrhythmia.

PURPOSE OF REVIEW: Cardiotoxicity by anticancer agents has emerged as a multifaceted issue and is expected to affect both mortality and morbidity. This review summarizes clinical challenges in the management of oncological patients requiring anticoagulants for atrial fibrillation (AF) also considering the current outbreak of the COVID-19 (coronavirus disease 2019) pandemic, since this infection can add challenges to the management of both conditions. Specifically, the aims are manyfold: (1) describe the evolving use of direct oral anticoagulants (DOACs) in AF patients with cancer; (2) critically appraise the risk of clinically important drug-drug interactions (DDIs) between DOACs and oral targeted anticancer agents; (3) address expected DDIs between DOACs and candidate anti-COVID drugs, with implications on management of the underlying thrombotic risk; and (4) characterize the proarrhythmic liability in cardio-oncology in the setting of COVID-19, focusing on QT prolongation. RECENT FINDINGS: AF in cardio-oncology poses diagnostic and management challenges, also due to the number of anticancer drugs recently associated with AF onset/worsening. Oral targeted drugs can potentially interact with DOACs, with increased bleeding risk mainly due to pharmacokinetic DDIs. Moreover, the vast majority of oral anticancer agents cause QT prolongation with direct and indirect mechanisms, potentially resulting in the occurrence of torsade de pointes, especially in susceptible patients with COVID-19 receiving additional drugs with QT liability. Oncologists and cardiologists must be aware of the increased bleeding risk and arrhythmic susceptibility of patients with AF and cancer due to DDIs. High-risk individuals with COVID-19 should be prioritized to target preventive strategies, including optimal antithrombotic management, medication review, and stringent monitoring.

Cannabis and Cannabinoids: Kinetics and Interactions.

Cannabis sativa and related products are widely used, but their potential to cause significant clinical interactions remains unclear, particularly for cannabinoid-enriched or otherwise concentrated products. The pharmacokinetics of most cannabis products is not known. Where information is known, there is wide variation. Extrapolation of limited clinical data is complicated by the complexity and variability of cannabis products as well as their delivery through various routes of administration. In vitro evidence shows that the major cannabinoids are substrates for numerous metabolic enzymes, including the cytochrome P450 metabolizing enzymes. Whereas many consumers consider cannabis products to be safe relative to alternative prescription or narcotic drugs, clinical reports of cannabis-related drug interactions and adverse events are increasing in frequency. Patients using these products, whether for medical or nonmedical purposes, together with conventional therapeutic agents may be at increased risk of adverse events, including therapeutic failure, and require enhanced monitoring.

Administration of a long-acting antipsychotic injection to a child while managing contraindicated polypharmacy interactions and transition between services.

Second-generation antipsychotics are used to treat a variety of psychiatric symptoms and illnesses as well as the behavioural aspects of various neurodevelopmental disorders. However, there is reluctance in using second-generation long-acting injectable antipsychotics in child psychiatry services. We present a case of a 12-year-old child whose presentation and medication regime warranted the use of aripiprazole long-acting injection against a backdrop of potential CYP P450 enzyme interactions as a consequence of polypharmacy. The case also describes the difficulties encountered working across different health sectors and agencies and highlights the ongoing need for skills-based Continuous Professional Development for Child and Adolescent Mental Health Services-based nursing staff.

Expert consensus on the management of breakthrough cancer pain in older patients. A Delphi study.

OBJECTIVES: We aimed to generate expert-based recommendations on the management of breakthrough cancer pain (BTcP) in older patients with cancer. MATERIAL AND METHODS: A two-round multidisciplinary Delphi study. Specialists rated their agreement with a set of statements using a nine-point Likert scale (one = totally disagree and nine = totally agree). Statements were classified as appropriate (median ranged from seven to nine), irrelevant (median ranged from four to six) or inappropriate (median ranged from one to three). Consensus was established when at least two thirds of the panel scored within any of the ranges. RESULTS: A total of 64 specialists from pain units (44.4%), palliative care units (25.4%), medical oncology (19.1%), geriatric medicine (7.9%) and others (3.2%), participated in two consultation rounds. Specialists agreed that effective coordination between the different specialties and levels of care is essential for proper management of BTcP. Most participants (81.3%) supported the assessment of frailty and resolved (96.8%) that frailty status is a better indicator of patient needs than biological age. Participants agreed (75.8%) in the application of the Davies algorithm for diagnosis of BTcP in older patients. A strong consensus was achieved regarding which pharmacological treatment (transmucosal fentanyl) and dosing method (start low and go slow) are the most suitable for the older population. No agreement was reached on how interventionist techniques should be integrated into the therapeutic strategy for BTcP. CONCLUSIONS: The present Delphi has generated a set of recommendations that will help healthcare professionals in the management of BTcP in older patients.

The current understanding of the interactions between nanoparticles and cytochrome P450 enzymes - a literature-based review.

Nanoparticles (NPs) have wide spectrum applications in the areas of industry and biomedicine. However, concerns about their toxic and negative impacts on the environments as well as human health have been raised. Cytochrome P450s (CYPs) are involved in endogenous and exogenous metabolism. Modulations of CYP can adversely damage drug metabolism, detoxification of xenobiotics and animal physiology functions. This article focused on NPs-CYP interactions for humans and animals available in the literature. It was found that different NPs process specific inhibitory potencies against CYPs involved in drug metabolism. Moreover, NPs were able to modify the expression of CYPs genes or protein in humans and other animals, which highlighted their detoxification functions. Nonetheless, changes of CYPs responsible for hormone synthesis and metabolism resulted in endocrine disturbances. Hence, there is a need to screen newly developed NPs to evaluate their interactions with CYPs. The future studies should further strategize the in vitro approaches to reveal the molecular mechanisms behind interactions by taking full considerations of the interference of co-factors, buffers, substrates and metabolites with NPs. Moreover, in vivo studies should compare the influences of NPs via different administration routes and different duration of treatments to reveal the physiological significance.

Predicting the need for a reduced drug dose, at first prescription.

Prescribing the right drug with the right dose is a central tenet of precision medicine. We examined the use of patients' prior Electronic Health Records to predict a reduction in drug dosage. We focus on drugs that interact with the P450 enzyme family, because their dosage is known to be sensitive and variable. We extracted diagnostic codes, conditions reported in clinical notes, and laboratory orders from Stanford's clinical data warehouse to construct cohorts of patients that either did or did not need a dose change. After feature selection, we trained models to predict the patients who will (or will not) require a dose change after being prescribed one of 34 drugs across 23 drug classes. Overall, we can predict (AUC ≥ 0.70-0.95) a dose reduction for 23 drugs and 22 drug classes. Several of these drugs are associated with clinical guidelines that recommend dose reduction exclusively in the case of adverse reaction. For these cases, a reduction in dosage may be considered as a surrogate for an adverse reaction, which our system could indirectly help predict and prevent. Our study illustrates the role machine learning may take in providing guidance in setting the starting dose for drugs associated with response variability.

Effect of valproic acid on perampanel pharmacokinetics in patients with epilepsy.

We prospectively examined the effect of antiepileptic (AED) cotherapy on steady state plasma concentrations of perampanel (PMP) in epileptic patients. We classified AEDs as strong enzyme inducers (carbamazepine, phenobarbital, phenytoin, oxcarbazepine), not strong enzyme inducers/not inhibitors (levetiracetam, lamotrigine, topiramate, rufinamide, lacosamide, zonisamide, clobazam), and enzyme inhibitors (valproic acid [VPA]). The main outcome was the comparison of PMP plasma concentration to weight-adjusted dose ratio (C/D; [µg/mL]/mg kg-1  d-1 ) among comedication subgroups. From 79 patients (42 females, 37 males) aged (mean ± standard deviation) 33 ± 13 years (range = 12-66 years), 114 plasma samples were collected. Twenty-eight patients (44 samples) were cotreated with enzyme inducers (group A), 21 (27 samples) with not strong enzyme inducers/not inhibitors (group B), 21 (31 samples) with not strong enzyme inducers/not inhibitors + VPA (group C), and 9 (12 samples) with enzyme inducers + VPA (group D). PMP C/D was reduced (-56%, P < .001) in group A (1.79 ± 0.80) versus group B (4.05 ± 2.16) and increased (P < .001) in group C (6.72 ± 4.04) compared with groups A (+275%), B (+66%), and D (2.76 ± 2.00, +143%). Our study documents the unpublished higher PMP C/D in patients cotreated with VPA. These findings have both theoretical relevance, suggesting better characterization of PMP metabolic pathways with ad hoc studies, and clinical usefulness in managing patients on AED polytherapy.

Drinking Ethanol Has Few Acute Effects on CYP2C9, CYP2C19, NAT2, and P-Glycoprotein Activities but Somewhat Inhibits CYP1A2, CYP2D6, and Intestinal CYP3A: So What?

We quantified the effect of acute ethanol exposure (initial blood concentrations 0.7 g/L) on major drug metabolizing enzymes and p-glycoprotein. Sixteen healthy Caucasians participated in a randomized crossover study with repeated administration of either vodka or water. Enzyme/transporter activity was assessed by a cocktail of probe substrates, including caffeine (CYP1A2/NAT2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and digoxin (P-glycoprotein). The ratio of AUC0-t of dextromethorphan for ethanol/water coadministration was 1.95 (90% confidence interval (CI) 1.48-2.58). The effect was strongest in individuals with a CYP2D6 genotype predicting high activity (n = 7, ratio 2.66, 90% CI 1.65-4.27). Ethanol increased caffeine AUC0-t 1.38-fold (90% CI 1.25-1.52) and reduced intestinal midazolam extraction 0.77-fold (90% CI 0.69-0.86). The other probe drugs were not affected by ethanol. The results suggest that acute ethanol intake typically has no clinically important effect on the enzymes/transporters tested.

Drug-drug interactions as a result of co-administering Δ9-THC and CBD with other psychotropic agents.

INTRODUCTION: To determine, via narrative, non-systematic review of pre-clinical and clinical studies, whether the effect of cannabis on hepatic biotransformation pathways would be predicted to result in clinically significant drug-drug interactions (DDIs) with commonly prescribed psychotropic agents. AREAS COVERED: A non-systematic literature search was conducted using the following databases: PubMed, PsycInfo, and Scopus from inception to January 2017. The search term cannabis was cross-referenced with the terms drug interactions, cytochrome, cannabinoids, cannabidiol, and medical marijuana. Pharmacological, molecular, and physiologic studies evaluating the pharmacokinetics of Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), both in vitro and in vivo, were included. Bibliographies were also manually searched for additional citations that were relevant to the overarching aim of this paper. EXPERT OPINION: Δ9-Tetrahydrocannabinol and CBD are substrates and inhibitors of cytochrome P450 enzymatic pathways relevant to the biotransformation of commonly prescribed psychotropic agents. The high frequency and increasing use of cannabis invites the need for healthcare providers to familiarize themselves with potential DDIs in persons receiving select psychotropic agents, and additionally consuming medical marijuana and/or recreational marijuana.

Steroidogenic disruptive effects of the serotonin-noradrenaline reuptake inhibitors duloxetine, venlafaxine and tramadol in the H295R cell assay and in a recombinant CYP17 assay.

The aim of this study was to determine the steroidogenic endocrine disrupting effect of three widely used serotonin-noradrenaline reuptake inhibitors duloxetine, venlafaxine and tramadol, using two in vitro models, the H295R assay and a recombinant CYP17 enzyme assay. Steroid hormones were quantified using LC-MS/MS. Duloxetine showed endocrine disrupting effects at 5-20µM with CYP17 being the main target. Venlafaxine also affected the steroidogenesis, mainly by affecting the CYP17 lyase reaction, although at much higher concentrations i.e. 100µM. Tramadol only exerted minor effects on the steroidogenesis with the lowest observed effect at 314µM. Based on the H295R results, the inhibition of CYP17 by duloxetine and venlafaxine was investigated in a recombinant CYP17 assay with the use of the 4 major CYP17 substrates pregnenolone, progesterone, 17α-hydroxypregnenolone and 17α-hydroxyprogesterone. Both duloxetine and venlafaxine inhibited CYP17 enzyme activity, but duloxetine was most potent. IC50-values were in the range 5.3-21µM for duloxetine and 1318-2750µM for venlafaxine. Overall, results from the recombinant CYP17 assay confirmed the results from the H295R cell assay. Using testosterone as end point, the margin of safety (defined as NOAEL/Cmax) for duloxetine was 1.6 indicating that duloxetine may have endocrine disrupting effects. In contrast, venlafaxine and tramadol showed higher margins of safety (venlafaxine: 24; tramadol: 157) indicating a lower potential to disrupt the human steroidogenesis.

Cytochrome P450 interactions are common and consequential in Massachusetts hospital discharges.

Despite the recognition that drug-drug interactions contribute substantially to preventable health-care costs, the prevalence of such interactions related to the cytochrome P450 system in clinical practice remains poorly characterized. This study drew retrospective hospital discharge cohorts from a large health claims data set and a large health system data set. For every hospital discharge, frequency of co-occurrence of substrates and inducers or inhibitors at cytochrome P450 2D6, 2C19, 3A4 and 1A2 were determined. A total of 124 520 individuals in the state of Massachusetts (health claims cohort) and 77 026 individuals in two large academic medical centers (electronic health record (EHR) cohort) were examined. In the claims cohort, 35 157 (28.2%) exhibited at least one CYP450 drug-drug interaction at hospital discharge, whereas in the EHR cohort, 36 750 (47.7%) had at least one interaction. The most commonly affected CYP450 systems were 2C19 and 2D6, with putative interactions observed in at least 10% of individuals at discharge in each cohort. Odds of hospital readmission within 90 days among those discharged with at least one interaction were 10-16% greater, with mean health-care cost $574/month greater over the subsequent year, after adjusting for age, sex, insurance type, total number of medications prescribed, Charlson comorbidity score and presence or absence of a psychiatric diagnosis. These two distinct clinical data types show that CYP450 drug-drug interactions are prevalent and associated with greater probability of early hospital readmission and greater health-care cost, despite the widespread availability and application of drug-drug interaction checking software.

Pharmacogenomics of triazole antifungal agents: implications for safety, tolerability and efficacy.

INTRODUCTION: Triazole antifungal agents are prescribed to treat invasive fungal infections in neutropenic and non-neutropenic patients. These antifungal agents are substrates and inhibitors of cytochrome P450 (CYP). Genetic polymorphisms in CYP2C9, CYP2C19 and CYP3A5 can lead to large population-specific variations in drug efficacy and safety, optimal dosing, or contribute to drug interactions associated with this class. Areas covered: This manuscript reviews the pharmacogenomics (i.e. the influence of genetics on drug disposition) of triazole antifungal agents related to their CYP-mediated metabolism and summarizes their implications on triazole efficacy, safety, and tolerability. A search of English language original research, and scholarly reviews describing the pharmacogenomics of triazole antifungal agents and their impact on drug efficacy, safety, and tolerability published from 1980 to present was undertaken using PubMed. Expert opinion: Currently studies demonstrating the pharmacogenomic influences on itraconazole, posaconazole and isavuconazole are minimal and limited to their inhibitory effects on CYP3A4 in expressors of CYP3A5 variants. Conversely, there are significant pharmacogenomic considerations for voriconazole because it interacts with several polymorphic CYPs, most notably CYP2C19. Pharmacogenomics of CYP2C9 do not appear to effect fluconazole safety and efficacy. However, genetic polymorphisms may influence its drug interactions but this needs further study.

A Chemoproteomic Platform To Assess Bioactivation Potential of Drugs.

Reactive metabolites (RM) formed from bioactivation of drugs can covalently modify liver proteins and cause mechanism-based inactivation of major cytochrome P450 (CYP450) enzymes. Risk of bioactivation of a test compound is routinely examined as part of lead optimization efforts in drug discovery. Here we described a chemoproteomic platform to assess in vitro and in vivo bioactivation potential of drugs. This platform enabled us to determine reactivity of thousands of proteomic cysteines toward RMs of diclofenac formed in human liver microsomes and living animals. We pinpointed numerous reactive cysteines as the targets of RMs of diclofenac, including the active (heme-binding) sites on several key CYP450 isoforms (1A2, 2E1 and 3A4 for human, 2C39 and 3A11 for mouse). This general platform should be applied to other drugs, drug candidates, and xenobiotics with potential hepatoxicity, including environmental organic substances, bioactive natural products, and traditional Chinese medicine.

Population pharmacokinetics of ospemifene and safety evaluation of pharmacokinetic alterations caused by intrinsic and extrinsic factors
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PURPOSE: To develop a population pharmacokinetic (PPK) model to assess factors influencing ospemifene pharmacokinetics and to assess safety for pharmacokinetic alteration observed in drug development. METHOD: A PPK model was constructed using pooled ospemifene concentrations. Covariates considered before start of the analysis were: age, race, body weight, BMI, albumin, alanine amino-transferase, bilirubin, and creatinine clearance. The expected distribution of ospemifene concentration was derived for the 4 cases in phase-1 studies that increased ospemifene exposure: administration to severe renal impairment subjects (case 1), administration to moderate hepatic impairment subjects (case 2), coadministration with ketoconazole (case 3), or coadministration with fluconazole (case 4). Safety information in a long-term safety trial was used to assess the potential changes in risk of adverse events with ospemifene-exposure increase. RESULTS: The PPK parameter estimates were 9.16 L/h for CL/F, 34.3 L for V2/F, 16.4 L/h for Q/F, 250 L for V3/F, and 0.522 h-1 for ka, based on the final model. Distributions of estimated AUC in a phase-3 study largely covered the expected distribution for case 1, case 2, or case 3, but did not overlap the expected distribution for case 4. The incidences of adverse events were not associated with ospemifene exposure in the long-term safety study. CONCLUSIONS: We developed an ospemifene PPK model and identified no relevant covariate in the PPK analysis. The drug appears safe to use in renal impairment, moderate hepatic impairment, and when coadministered with ketoconazole. Ospemifene should not be administered with fluconazole.
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Study on influence of piperine treatment on the pharmacokinetics of diclofenac in healthy volunteers.

1. Diclofenac sodium (DIC) is a widely used anti-inflammatory drug and its administration in humans receiving long-term therapy with herbal drugs containing piperine (PIP) may occur, which leads to drug-phytochemical interactions. The purpose of the present study was to investigate the influence of PIP treatment on the pharmacokinetics of DIC in healthy volunteers. 2. The open-label, two period, sequential study was conducted in 12 healthy volunteers. PIP 20 mg was administered once daily for 10 days during treatment phase. A single dose of DIC 100 mg was administered during control and after treatment phases under fasting conditions. The blood samples were collected after DIC dosing at predetermined time intervals and analyzed by HPLC. 3. Treatment with PIP significantly enhanced maximum plasma concentration (Cmax) (2.24-3.68 µg/mL, p < 0.05), area under the curve (AUC) (7.09-11.81 µg h/mL, p < 0.05), half-life (T1/2) (1.23-1.65 h, p < 0.05) and significantly decreased elimination rate constant (Kel) (0.62-0.41 h-1, p < 0.05), apparent oral clearance (CL/F) (7.57-4.52 L/h, p < 0.05) of DIC as compared to that of control phase. 4. The results suggest that the altered pharmacokinetics of DIC might be attributed to PIP mediated inhibition of CYP2C9 enzyme, which indicates the clinically significant interaction present between DIC and PIP. Therefore, the combination therapy of DIC along with PIP may represent a novel approach to reduce dosage and result in reduced incidence of gastrointestinal side effects seen with DIC alone at higher doses.