Low Interaction Potential Research Articles

Tailoring Synthetic Polypeptide Design for Directed Fibril Superstructure Formation and Enhanced Hydrogel Properties.

The biological significance of self-assembled protein filament networks and their unique mechanical properties have sparked interest in the development of synthetic filament networks that mimic these attributes. Building on the recent advancement of autoaccelerated ring-opening polymerization of amino acid N-carboxyanhydrides (NCAs), this study strategically explores a series of random copolymers comprising multiple amino acids, aiming to elucidate the core principles governing gelation pathways of these purpose-designed copolypeptides. Utilizing glutamate (Glu) as the primary component of copolypeptides, two targeted pathways were pursued: first, achieving a fast fibrillation rate with lower interaction potential using serine (Ser) as a comonomer, facilitating the creation of homogeneous fibril networks; and second, creating more rigid networks of fibril clusters by incorporating alanine (Ala) and valine (Val) as comonomers. The selection of amino acids played a pivotal role in steering both the morphology of fibril superstructures and their assembly kinetics, subsequently determining their potential to form sample-spanning networks. Importantly, the viscoelastic properties of the resulting supramolecular hydrogels can be tailored according to the specific copolypeptide composition through modulations in filament densities and lengths. The findings enhance our understanding of directed self-assembly in high molecular weight synthetic copolypeptides, offering valuable insights for the development of synthetic fibrous networks and biomimetic supramolecular materials with custom-designed properties.

Investigation of Drug-Interaction Potential for Arthritis Dietary Supplements: Chondroitin Sulfate, Glucosamine, and Methylsulfonylmethane.

Osteoarthritis is one of the leading conditions that promote the consumption of these dietary supplements. Chondroitin sulfate, glucosamine, and methylsulfonylmethane are among the prominent alternative treatments for osteoarthritis. In this study, these dietary supplements were incubated with cytochrome P450 isozyme-specific substrates in human liver microsomes, and the formation of marker metabolites was measured to investigate their inhibitory potential on cytochrome P450 enzyme activities. The results revealed no significant inhibitory effects on seven CYPs, consistent with established related research data. Therefore, these substances are anticipated to have a low potential for cytochrome P450-mediated drug interactions with osteoarthritis medications that are likely to be co-administered. However, given the previous reports of interaction cases involving glucosamine, caution is advised regarding dietary supplement-drug interactions.

Absence of Clinically Meaningful Drug-Drug Interactions with Rezafungin: Outcome of Investigations.

Rezafungin is a novel once-weekly echinocandin for intravenous injection currently in development for the treatment of Candida infections and the prevention of Candida, Aspergillus, and Pneumocystis infections in allogeneic blood and marrow transplant recipients. While in vitro data indicated that rezafungin exposure was unlikely to be affected by commonly prescribed medicines, interactions resulting in the altered systemic exposure of some drugs coadministered with rezafungin could not be excluded. Two phase 1 open label crossover studies, conducted in healthy subjects, examined drug interactions between rezafungin and multiple drug probe cytochrome P450 (CYP) substrates and/or transporter proteins, immunosuppressants, and cancer therapies. Statistical analysis compared the outcomes for drugs coadministered with rezafungin to those for the drugs administered alone. The geometric mean ratio was reported, and a default 90% confidence interval (CI) no-effect equivalence range of 80 to 125% was used for the maximal plasma concentration (Cmax), the area under the curve from time zero to the final sampling time point (AUC0-t), and the AUC from time zero to infinity (AUC0-∞). Most probes and concomitant drugs were within the equivalence range. For tacrolimus, ibrutinib, mycophenolic acid, and venetoclax, the AUC or Cmax was reduced (10 to 19%), with lower bounds of the 90% CI values falling outside the no-effect range. The rosuvastatin AUC and Cmax and the repaglinide AUC0-∞ were increased (12 to 16%), with the 90% CI being marginally above the upper bound. Overall, the in vitro and in vivo data demonstrated a low drug interaction potential with rezafungin via CYP substrate/transporter pathways and commonly prescribed comedications, suggesting that coadministration was unlikely to result in clinically significant effects. Treatment-emergent adverse events were typically mild, and rezafungin was generally well tolerated. IMPORTANCE Antifungal agents used to treat life-threatening infections are often associated with severe drug-drug interactions (DDIs) that may limit their usefulness. Rezafungin, a newly approved once-weekly echinocandin, has been shown to be free of DDIs based on extensive nonclinical and clinical testing described in this study.

Expanded profiling of Remdesivir as a broad-spectrum antiviral and low potential for interaction with other medications in vitro

Remdesivir (GS-5734; VEKLURY) is a single diastereomer monophosphoramidate prodrug of an adenosine analog (GS-441524). Remdesivir is taken up by target cells and metabolized in multiple steps to form the active nucleoside triphosphate (GS-443902), which acts as a potent inhibitor of viral RNA-dependent RNA polymerases. Remdesivir and GS-441524 have antiviral activity against multiple RNA viruses. Here, we expand the evaluation of remdesivir’s antiviral activity to members of the families Flaviviridae, Picornaviridae, Filoviridae, Orthomyxoviridae, and Hepadnaviridae. Using cell-based assays, we show that remdesivir can inhibit infection of flaviviruses (such as dengue 1–4, West Nile, yellow fever, Zika viruses), picornaviruses (such as enterovirus and rhinovirus), and filoviruses (such as various Ebola, Marburg, and Sudan virus isolates, including novel geographic isolates), but is ineffective or is significantly less effective against orthomyxoviruses (influenza A and B viruses), or hepadnaviruses B, D, and E. In addition, remdesivir shows no antagonistic effect when combined with favipiravir, another broadly acting antiviral nucleoside analog, and has minimal interaction with a panel of concomitant medications. Our data further support remdesivir as a broad-spectrum antiviral agent that has the potential to address multiple unmet medical needs, including those related to antiviral pandemic preparedness.

Рабепразол в лечении кислотозависимых заболеваний

Proton-pump inhibitors (PPIs) are widely used to treat acid-related disorders (ARD). Rabeprazole is a potent inhibitor of gastric H+/K+-ATPase, and it is indicated for the treatment of gastroesophageal reflux disease, Zollinger-Ellison syndrome, gastric and duodenal ulcers and for Helicobacter pylori eradication (in combination with antibiotics), as well as for the treatment of ARD described in this article. Pharmacokinetic and pharmacodynamic data show that rabeprazole provides a marked acid inhibition from the first administration, which persists with repeated use. Due to the predominantly non-enzymatic metabolism, rabeprazole has a lower interaction potential between drugs. Besides, rabeprazole maintains a high intragastric pH and achieves maximum acid inhibition in 24 hours. Rabeprazole is characterized by linearity of pharmacokinetics, which remains unchanged in renal and hepatic insufficiency. Rabeprazole is available in the dosage form of enteric capsules due to the PPIs instability in an acidic environment. Rabeprazole is generally well-tolerated by patients. Besides several minor side effects, rabeprazole is safe to be widely used in the treatment of ARD. KEYWORDS: proton pump inhibitors, antisecretory drugs, rabeprazole, efficacy, safety, expediency, acid-related disorders, gastroesophageal reflux disease, peptic ulcer, gastropathy, dyspepsia. FOR CITATION: Tsukanov V.V. Rabeprazole in the treatment of acid-related disorders. Russian Medical Inquiry. 2023;7(5):264–273 (in Russ.). DOI: 10.32364/2587-6821-2023-7-5-4.

Thrombocytopenia Induced by Direct Oral Anticoagulants: a Clinical Case and Literature Review

The last decade has dramatically changed the strategy of anticoagulant therapy in patients with atrial fibrillation. Direct oral anticoagulants have replaced vitamin K antagonists: either direct thrombin blockers (dabigatran) or factor IIa blockers (apixaban, rivaroxaban, edoxaban). According to the regulatory domestic and foreign documents, the use of direct oral anticoagulants in patients with atrial fibrillation has priority in comparison with vitamin K antagonists, since they have a predictable anticoagulant effect, the possibility of taking fixed doses without the need for routine anticoagulant monitoring, rapid onset and termination of action, relatively low potential for food and drug interactions. Direct oral anticoagulants are used for the prevention of thromboembolic complications in patients with atrial fibrillation, for the prevention of deep vein thrombosis in patients who have undergone surgery on the knee or hip joints, for emergency treatment and secondary prevention of deep vein thrombosis and pulmonary embolism. Alertness to side effects tends to focus on the likelihood of bleeding, with the possibility of other side effects of direct oral anticoagulants receiving less attention or going unnoticed. These mainly include liver damage, kidney damage and a number of other rare adverse reactions. The finding of isolated thrombocytopenia in patients taking direct oral anticoagulants may be associated with a high risk of life-threatening bleeding. The article analyzes published data on the occurrence of thrombocytopenia associated with the intake of direct oral anticoagulants, and presents a clinical case of thrombocytopenia while taking apixaban.

Findings on In Vitro Transporter-Mediated Drug Interactions and Their Follow-Up Actions for Labeling: Analysis of Drugs Approved by US FDA between 2017 and 2021.

Understanding possible follow-up actions on in vitro findings helps determine the necessity of labeling for drug interactions. We analyzed information for in vitro findings on transporter-mediated interactions of drugs approved by the U.S. Food and Drug Administration’s Center for Drug Evaluation and Research for the last five years (i.e., 2017–2021) and their follow-up actions for labeling. Higher R values than the pre-defined cut-off were observed with 3.7–39.1% inhibitor drugs in a simple prediction. Among these drugs, 16–41.7% were labeled with their potential drug interactions, while results of supporting studies or scientific rationales were submitted for the other drugs leading to no interaction labeling. In vitro transporter substrates were reported with 1.7–67.6% of drugs. The interaction labels for these substrate drugs were observed in up to 40% of drugs, while the other drugs were not labeled on the drug interactions with claims for their low interaction potential, evidenced by clinical studies or scientific rationales. The systematic and comprehensive analysis in this study will provide insight into the management of in vitro findings for transporter substrate or inhibitor drugs.

Assessment of drug-drug interaction potential with EDP-305, a farnesoid X receptor agonist, in healthy subjects.

EDP‐305 is a farnesoid X receptor (FXR) agonist that selectively activates FXR and is a potential treatment for patients with nonalcoholic steatohepatitis (NASH) with liver fibrosis. Results from preclinical studies indicate that CYP3A4 is the primary enzyme involved in EDP‐305 metabolism and that EDP‐305 has low potential to inhibit or induce cytochrome (CYP) isoenzymes and drug transporters. Four studies were conducted in healthy volunteers to evaluate the drug–drug interaction (DDI) potential of EDP‐305 co‐administered with drugs known to be substrates for drug metabolizing enzymes or transporters, and to assess the effect of inhibitors and inducers of CYP3A4 on EDP‐305. Results suggest caution when substrates of CYP3A4 are administered concomitantly with EDP‐305. A potential for increased exposure is apparent when CYP1A2 substrates with a narrow therapeutic index are administered with EDP‐305. In contrast, substrates of drug transporters can be administered concomitantly with EDP‐305 with a low potential for interactions. Coadministration of EDP‐305 and a combined OC had no relevant effects on plasma concentrations of the combined OC. Co‐administration of EDP‐305 with strong or moderate inhibitors and inducers of CYP3A4 is not recommended. These results indicate low overall likelihood of interaction of EDP‐305 and other substrates through CYP mediated interactions. The interaction potential of EDP‐305 with drug transporters was low and of unlikely clinical significance. The EDP‐305 DDI profile allows for convenient administration in patients with NASH and other patient populations with comorbidities, with minimal dose modification of concomitant medications.

Mianseryna a depresja, lęk, bezsenność

Mianserin is a drug that has been used for many years to reduce symptoms of depression such as depression, anxiety and insomnia. Which seriously impair the functioning of the patient and, if are untreated, may lead to recurrence of depression. A beneficial feature of the drug is its low potential for adverse interactions with other drugs. For this reason, using of mianserin should be considered in the elderly and patients with comorbidities.

Perampanel as first add-on antiseizure medication: Italian consensus clinical practice statements

BackgroundWhen use of a single antiseizure medication (ASM) fails to induce seizure remission, add-on therapy is justified. Perampanel (PER) is approved in Europe as adjunctive therapy for focal, focal to bilateral tonic-clonic seizures and generalized tonic-clonic seizures. Aim of the study was to establish whether PER is suitable for first add-on use.MethodsA Delphi methodology was adopted to assess consensus on a list of 39 statements produced by an Expert Board of 5 epileptologists. Using an iterative process, statements were finalized by a Delphi Panel of 84 Italian pediatric and adult neurologists. Each statement was rated anonymously to determine level of agreement on a 9-point Likert scale. Consensus was established as agreement by at least 80% of the panelists. The relevance of each statement was also assessed on a 3-point scale.ResultsConsensus was achieved for 37 statements. Characteristics of PER considered to justify its use as first add-on include evidence of a positive impact on quality of life based on long term retention data, efficacy, tolerability, and ease of use; no worsening of cognitive functions and sleep quality; a low potential for drug interactions; a unique mechanism of action. Potential unfavorable factors are the need for a relatively slow dose titration; the potential occurrence of behavioral adverse effects; lack of information on safety when used in pregnancy; limited access to plasma PER levels.ConclusionPerampanel has many features which justify its use as a first add-on. Choice of an ASM as first add-on should be tailored to individual characteristics.

Prevalence of potential drug-drug interactions among nonmetastatic castration-resistant prostate cancer patients treated with apalutamide and enzalutamide.

e18690 Background: Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) are often treated with concurrent medications for the management of comorbid conditions. This increases the risk of drug interactions which may lead to compromised efficacy and safety of nmCRPC therapies. This study aimed to characterize potential drug-drug interactions (pDDIs) with the novel anti-androgen (AA) agents enzalutamide (Enza) and apalutamide (Apa) in a real-world nmCRPC population. Methods: We analyzed Optum Clinformatics Data Mart, a large claims database from January 1, 2017, through March 31, 2020. The study population included adult males with prostate cancer, evidence of castration, >1 pharmacy claim for Apa or Enza (index date defined as drug initiation), and without codes for metastases. Darolutamide, a more recently approved AA, was not included due to lack of data. Concomitant medications were defined as therapy with at least 1 day overlap with Apa and Enza. The top concomitant medications covering 99% of Apa and Enza population were assessed for pDDI using Micromedex, Lexicomp, and Drugs.com compendia. Results: We identified 149 Apa and 319 Enza patients with mean age 77 years across groups. The study population was primarily white (56.3% Apa; 56.7% Enza) and had Medicare insurance (81.0% Apa; 82.2% Enza). Mean Charlson comorbidity index scores were similar for each group (Apa: 2.3 [SD: 4.1]; Enza: 2.4 [SD: 2.4]). Polypharmacy was common in both groups, with the majority taking ≥5 medications (Apa: 79.8%; Enza: 75.9%). Of the co-medications included in this analysis, Micromedex, Lexicomp and Drugs.com flagged 12, 38 and 53 pDDIs for Apa, and 7, 35 and 49 pDDIs for Enza, respectively. A pDDI was identified for 35% Apa and 21% Enza patients using Micromedex and >80% of Apa and Enza patients using other compendia. The pDDIs by severity and risk rating as defined by the respective compendia are shown in Table. Specifically, 4 interactions for Apa and 1 for Enza were rated X (i.e., avoid combination). Conclusions: This study finds a high prevalence of pDDIs among Apa and Enza patients signifying the need for strict monitoring while initiating these therapies. Given the high prevalence of polypharmacy and comorbidities among nmCRPC, these patients may benefit from drugs with lower interaction potential. Future real-world analyses should be conducted to characterize the clinical and economic impact of these pDDIs as well as to assess pDDI for darolutamide. [Table: see text]

Centella asiatica Water Extract Shows Low Potential for Cytochrome P450-Mediated Drug Interactions.

Centella asiatica (CA) shows considerable promise for development as a botanical drug for cognitive decline. Its primary bioactive components include triterpene glycosides asiaticoside and madecassoside and their corresponding aglycones asiatic acid and madecassic acid. Exploration of the bioactivity of CA's caffeoylquinic acids is ongoing. In this study, an aqueous extract of CA (CAW-R61J) was evaluated for drug interaction potential through inhibition or induction of P450 enzymes, as required by the US Food and Drug Administration. CAW-R61J was assessed for induction potential of CYP1A2, CYP2B6, and CYP3A4 using transporter-certified cryopreserved human hepatocytes in sandwich culture. Gene expression of these target P450s was quantified, and enzyme activities were determined to confirm gene expression results. No induction was observed up to 16.7 µg/ml CAW-R61J (equivalent to 1.1 µM asiaticoside, 0.8 µM madecassoside, 0.09 µM asiatic acid, and 0.12 µM madecassic acid). Reversible and time-dependent inhibitory effects of CAW-R61J on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 were evaluated using human liver microsomes. CAW-R61J showed weak reversible inhibition of most of the P450 forms tested, with the strongest being CYP2C9 (IC50 of 330 µg/ml). CAW-R61J (≤1000 µg/ml) was not a time-dependent inhibitor of any of these P450 enzymes. In summary, CAW-R61J had no, or only a weak impact, on P450 induction and inhibition in vitro. The clinical relevance of these results will depend on the in vivo concentration of CAW-R61J components achieved in humans. Plasma triterpene concentrations measured in our recent clinical studies suggest minimal risk of P450-mediated drug interactions by these components. SIGNIFICANCE STATEMENT: A preparation of Centella asiatica is currently under clinical development for the prevention or treatment of cognitive decline. The US Food and Drug Administration required an evaluation of its potential for drug interactions mediated through drug-metabolizing enzymes. This in vitro study revealed minimal induction or inhibition of a range of P450 enzymes, including CYP3A4, by the C. asiatica extract, suggesting a low potential for drug interactions modulated by P450 metabolism.

Pharmacokinetics, Pharmacodynamics, and Exposure-Response of Lanadelumab for Hereditary Angioedema.

Hereditary angioedema (HAE) with C1 inhibitor deficiency is a rare disorder characterized by unpredictable, potentially life‐threatening recurrent angioedema attacks. Lanadelumab is a fully human monoclonal antibody with selective binding to active plasma kallikrein, and prevents the formation of cleaved high molecular weight kininogen (cHMWK) and bradykinin, thereby preventing HAE attacks. The clinical pharmacology of lanadelumab was characterized following subcutaneous administration in 257 subjects (24 healthy subjects and 233 patients with HAE). The pharmacokinetics of lanadelumab were described using a one‐compartment model with first‐order rate of absorption and linear clearance, showing slow absorption and a long half‐life (14.8 days). A covariate analysis retained body weight and health status on apparent clearance (CL/F) and body weight on volume of distribution (V/F). Population estimates of CL/F and V/F were 0.0249 L/hour (0.586 L/day) and 12.8 L, respectively. An indirect‐response Imax model showed 53.7% maximum suppression in cHMWK formation with a low potential for interactions with concomitant medications (analgesic, anti‐inflammatory, and antirheumatic medications). A 300 mg dose administered Q2W was associated with a mean steady‐state minimum concentration (Cmin,ss; 25.4 μg/mL) that was ~ 4.5‐fold higher than the half‐maximal inhibitory concentration for cHMWK reduction (5.71 μg/mL). Exposure‐response analyses suggest that 300 mg Q2W dosing was associated with a significantly reduced HAE attack rate, prolonged time to first attack after treatment initiation, and lower need for concomitant medications. The response was comparable across patient body weight groups. Findings from this analysis support the dosing rationale for lanadelumab to prevent attacks in patients with HAE.

Metabolism and Pharmacokinetic Drug-Drug Interaction Profile of Vericiguat, A Soluble Guanylate Cyclase Stimulator: Results From Preclinical and Phase I Healthy Volunteer Studies.

BackgroundVericiguat is a stimulator of soluble guanylate cyclase currently under investigation as a first-in-class therapy for worsening chronic heart failure (NCT02861534). Patients with heart failure often require polypharmacy because of comorbidities. Hence, understanding the clearance mechanisms, elimination, and potential for pharmacokinetic drug–drug interactions of vericiguat is important for dose recommendations in this patient population.MethodsBiotransformation and perpetrator properties of vericiguat were characterized in vitro using human hepatocytes, liver microsomes, and recombinant enzymes. This was complemented by a human mass balance study and ten drug–drug interaction studies in healthy volunteers wherein vericiguat was co-administered orally with omeprazole, magnesium/aluminum hydroxide, ketoconazole, rifampicin, mefenamic acid, midazolam, warfarin, digoxin, sacubitril/valsartan, aspirin, or sildenafil.ResultsIn the human mass balance study, mean total radioactivity recovered was 98.3% of the dose administered (53.1% and 45.2% excreted via urine and feces, respectively). The main metabolic pathway of vericiguat is glucuronidation via uridine diphosphate-glucuronosyltransferase 1A9 and 1A1. In vitro studies revealed a low risk of vericiguat acting as a perpetrator by inhibiting cytochrome P450s, uridine diphosphate-glucuronosyltransferase isoforms, or major transport proteins, or by inducing cytochrome P450s. These observations were supported by phase I drug–drug interaction studies. Phase I studies that assessed the propensity of vericiguat as a victim drug showed changes in the range that did not warrant recommendations for dose adjustment in phase III.ConclusionsA low pharmacokinetic interaction potential of vericiguat was estimated from in vitro data and confirmed in vivo. Thus, vericiguat is suitable for a patient population with multiple comorbidities requiring polypharmacy.Electronic supplementary materialThe online version of this article (10.1007/s40262-020-00895-x) contains supplementary material, which is available to authorized users.

Fevipiprant has a low risk of influencing co-medication pharmacokinetics: Impact on simvastatin and rosuvastatin in different SLCO1B1 genotypes

Fevipiprant, a prostaglandin D2 receptor 2 antagonist, is in clinical development as a treatment for asthma. The goal of this study was to assess the potential of fevipiprant to cause drug-drug interactions (DDI) as a perpetrator, that is, by altering the pharmacokinetics (PK) of co-medications.In vitro drug interaction studies of clinically relevant drug metabolizing enzymes and transporters were conducted for fevipiprant and its acyl glucuronide (AG) metabolite. Comparison of Ki values with unbound systemic or portal vein steady-state plasma exposure of fevipiprant and its AG metabolite revealed the potential for inhibition of organic anion transporting polypeptide 1B1 (OATP1B1) transporters (R-value of 5.99), while other targets including cytochrome P450 enzymes were not, or only marginally, inhibited.Consequently, an open-label, two-part, two-period, single-sequence clinical study assessed the effect of fevipiprant 450 mg QD on the pharmacokinetics of simvastatin 20 mg and rosuvastatin 20 mg, two statins with different dependency in OATP1B1-mediated hepatic uptake, in healthy adult volunteers. The study also assessed the pharmacogenetics of the SLCO1B1 gene, which encodes OATP1B1. Clinically, fevipiprant 450 mg QD showed a low potential for interaction and increased the peak concentrations of simvastatin acid and rosuvastatin by 2.23- and 1.87-fold, respectively, with little or no impact on total exposure.Genotype analysis confirmed that SLCO1B1 genotype influences statin pharmacokinetics to a similar extent either with or without fevipiprant co-administration. In summary, fevipiprant at 450 mg QD has only minor liabilities as a perpetrator for DDI.

HIV treatment regimens and adherence to national guidelines in Australia: an analysis of dispensing data from the Australian pharmaceutical benefits scheme

BackgroundTreatment guidelines for antiretroviral therapy (ART) have evolved to emphasize newer regimens that address ageing-related comorbidities. Using national Australian dispensing data we compare ART regimens with Australian HIV treatment guidelines in the context of treated comorbidities.MethodsThe study population included all individuals in a 10% sample of national data from the Australian Pharmaceutical Benefits Scheme (PBS) who purchased a prescription of ART during 2016. We defined each patient’s most recently dispensed ART regimen and characterized them to evaluate regimen complexity and adherence to national HIV treatment guidelines. We then analyzed ART regimens in the context of other co-prescriptions purchased for defined comorbidities.ResultsThe 1995 patients in our sample purchased 212 different ART regimens during 2016; 1524 (76.4%) purchased one of the top ten most common regimens of which 62.3% were integrase strand transfer inhibitor-based. Among the 1786 (90%) patients that purchased the most common regimens, 83.7% purchased a regimen recommended by the guidelines for initial antiretroviral therapy and 11.4% purchased antiretrovirals that are not recommended for initial therapy; < 1% of the entire cohort purchased medications not recommended for use. While most patients purchased optimal ART regimens with low potential for significant drug interactions, regimen choices in the setting of risk factors for heart disease, renal disease and low bone mineral density appeared suboptimal.ConclusionsAustralian HIV providers are prescribing ART regimens in accordance with updated treatment guidelines, but could further optimize regimens in the setting of important medical comorbidities.

Potential protein-binding displacement interactions with perampanel: An in vitro analysis

Plasma protein binding and effects on volume of distribution and pharmacologically active, circulating-drug concentrations are complex issues. Protein-binding displacement often underlies drug–drug interactions. Perampanel is a once-daily oral anti-seizure drug for focal seizures and primary generalized tonic-clonic seizures. Perampanel is also indicated for monotherapy use for focal seizures in the United States. Perampanel is extensively but slowly metabolized via CYP3A4. Its elimination t½ is about 100 h, and it displays substantial plasma protein binding (>95%). Here, we examine perampanel’s potential to displace highly bound anti-seizure drugs and the ability of warfarin, a standard highly protein-bound drug, to displace perampanel. Protein binding of perampanel, phenytoin, valproate, and warfarin was assessed using equilibrium dialysis. Plasma samples containing each compound were dialyzed against phosphate buffered saline. For phenytoin, valproate, and warfarin, plasma samples were also dialyzed in the presence of perampanel. After 24 h equilibrium dialysis, amounts of test compounds were analyzed to calculate plasma protein binding. At clinically relevant concentrations, perampanel did not displace other highly bound drugs or vice versa. Protein-binding displacement may confound therapeutic drug monitoring of extensively protein-bound medications. Without empirical data, clinicians might be concerned that addition of perampanel could alter unbound concentrations of other medications, resulting in adverse effects. Our data indicate perampanel has low potential for drug interactions resulting from protein-binding displacement.

Top New Drug Approvals of 2018

Top New Drug Approvals of 2018

Guidelines for seizure management in palliative care: proposal for an updated clinical practice model based on a systematic literature review

IntroductionVery little has been written on seizure management in palliative care (PC). Given this situation, and considering the forthcoming setting up of the Palliative Care Unit at our neurorehabilitation centre, the Clínica San Vicente, we decided to establish a series of guidelines on the use of antiepileptic drugs (AEDs) for handling seizures in PC. MethodsWe conducted a literature search in PubMed to identify articles, recent manuals, and clinical practice guidelines on seizure management in PC published by the most relevant scientific societies. ResultsClinical practice guidelines are essential to identify patients eligible for PC, manage seizures adequately, and avoid unnecessary distress to these patients and their families. Given the profile of these patients, we recommend choosing AEDs with a low interaction potential and which can be administered by the parenteral route, preferably intravenously. Diazepam and midazolam appear to be the most suitable AEDs during the acute phase whereas levetiracetam, valproic acid, and lacosamide are recommended for refractory cases and long-term treatment. ConclusionsThese guidelines provide general recommendations that must be adapted to each particular clinical case. Nevertheless, we will require further well-designed randomised controlled clinical trials including large samples of patients eligible for PC to draft a consensus document recommending adequate, rational, and effective use of AEDs, based on a high level of evidence, in this highly complex area of medical care.

New anticonvulsants in everyday clinical use

New anticonvulsants in everyday clinical use Abstract. In summary, the armamentarium of the clinically active epileptologist is constantly expanding. The newer substances often show a better tolerability and a lower interaction potential than the older substances, but they are not more effective. The selection of the anticonvulsant depends on the individual situation and takes into account the type of epilepsy, age, comorbidities and, in the case of women, any desire to have children. Because epilepsies are often still refractory to therapy, new substances are urgently needed and several promising preparations are currently under development. Epilepsy surgery is also making great progress, so it is recommended that, after the unsuccessful use of two adequate anticonvulsants, this often very successful option be considered, which ideally leads to a cure from epilepsy, and that patients be referred to an appropriate centre.