Drug Interactions Research Articles

Virologically suppressed switch to Dolutegravir/Lamivudine 2-Drug regimen versus switch to commonly prescribed 3-Drug regimens in the United States

BackgroundTwo-drug regimens (2DRs) have been introduced in recent years to potentially reduce antiretroviral therapy (ART) toxicities and drug-drug interactions while demonstrating comparable efficacy to three-drug regimens (3DRs) for people with HIV (PWH). The objective of this study was to compare the real-world effectiveness and durability of a single-tablet 2DR of dolutegravir/lamivudine (DTG/3TC) with that of commonly prescribed 3DRs in ART-experienced, virologically suppressed PWH during the first 24 months of DTG/3TC availability in the United States.MethodsVirologically suppressed (viral load [VL] < 200 copies/mL) adult PWH initiating DTG/3TC 2DR, bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF), or a DTG-based 3DR between 01MAY2019 and 31OCT2020 were identified in the OPERA® cohort and followed through 30APR2021. Univariate Poisson regression (incidence rates) and marginal structural Cox proportional hazards models with inverse probability of treatment weights (hazard ratios) were used to quantify relationships between regimen type and confirmed virologic failure (2 consecutive VLs ≥ 200 copies/mL) or regimen discontinuation. Reasons for discontinuation were examined.ResultsA total of 8,037 ART-experienced, virologically suppressed PWH met the inclusion criteria and switched to DTG/3TC (n = 1,450), BIC/FTC/TAF (n = 5,691), or a DTG-based 3DR (n = 896). Incidence rates of confirmed virologic failure were low for all groups, at 0.66 (DTG/3TC), 0.84 (BIC/FTC/TAF), and 1.78 (DTG 3DR) per 100 person-years (py). Compared to DTG/3TC, only the DTG 3DRs were associated with a statistically significant increased hazard of confirmed virologic failure (hazard ratio: 5.21, 95% confidence interval: 1.85, 14.67). Discontinuation rates per 100 py were highest in the DTG 3DR group (24.90), followed by the DTG/3TC group (17.69) and the BIC/FTC/TAF group (8.30). Regardless of regimen, discontinuations were infrequently attributed to effectiveness (VL ≥ 200 copies/mL; 4%) or tolerability (adverse diagnoses, side effects, or lab abnormalities; 6%).ConclusionsAmong virologically suppressed PWH initiating a new regimen, few individuals experienced virologic failure in real-world clinical care. While rates of regimen discontinuation were high, most discontinuations could not be attributed to a lack of virologic control or poor tolerability. These findings suggest that DTG/3TC is an effective option for ART-experienced, virologically suppressed PWH.

Alligamycin A, an antifungal β-lactone spiroketal macrolide from Streptomyces iranensis

Fungal infections pose a great threat to public health and there are only four main types of antifungal drugs, which are often limited with toxicity, drug-drug interactions and antibiotic resistance. Streptomyces is an important source of antibiotics, represented by the clinical drug amphotericin B. Here we report the discovery of alligamycin A (1) as an antifungal compound from the rapamycin-producer Streptomyces iranensis through genome-mining, genetics and natural product chemistry approaches. Alligamycin A harbors a unique chemical scaffold with 13 chiral centers, featuring a β-lactone moiety, a [6,6]-spiroketal ring, and an unreported 7-oxo-octylmalonyl-CoA extender unit incorporated by a potential crotonyl-CoA carboxylase/reductase. It is biosynthesized by a type I polyketide synthase which is confirmed through CRISPR-based gene editing. Alligamycin A displayed potent antifungal effects against numerous clinically relevant filamentous fungi, including resistant Aspergillus and Talaromyces species. β-Lactone ring is essential for the antifungal activity since alligamycin B (2) with disruption in the ring abolished the antifungal effect. Proteomics analysis revealed alligamycin A potentially disrupts the integrity of fungal cell walls and induces the expression of stress-response proteins in Aspergillus niger. Discovery of the potent antifungal candidate alligamycin A expands the limited antifungal chemical space.

Knowledge graph driven medicine recommendation system using graph neural networks on longitudinal medical records

Medicine recommendation systems are designed to aid healthcare professionals by analysing a patient’s admission data to recommend safe and effective medications. These systems are categorised into two types: instance-based and longitudinal-based. Instance-based models only consider the current admission, while longitudinal models consider the patient’s medical history. Electronic Health Records are used to incorporate medical history into longitudinal models. This project proposes a novel Knowledge Graph-Driven Medicine Recommendation System using Graph Neural Networks, KGDNet, that utilises longitudinal EHR data along with ontologies and Drug-Drug Interaction knowledge to construct admission-wise clinical and medicine Knowledge Graphs for every patient. Recurrent Neural Networks are employed to model a patient’s historical data, and Graph Neural Networks are used to learn embeddings from the Knowledge Graphs. A Transformer-based Attention mechanism is then used to generate medication recommendations for the patient, considering their current clinical state, medication history, and joint medical records. The model is evaluated on the MIMIC-IV EHR data and outperforms existing methods in terms of precision, recall, F1 score, Jaccard score, and Drug-Drug Interaction control. An ablation study on our models various inputs and components to provide evidence for the importance of each component in providing the best performance. Case study is also performed to demonstrate the real-world effectiveness of KGDNet.

Bempedoic Acid, the First-in-Class Oral ATP Citrate Lyase Inhibitor with Hypocholesterolemic Activity: Clinical Pharmacology and Drug–Drug Interactions

Bempedoic acid is a new drug that improves the control of cholesterol levels, either as monotherapy or in combination with existing lipid-lowering therapies, and shows clinical efficacy in cardiovascular disease patients. Thus, patients with comorbidities and under multiple therapies may be eligible for bempedoic acid, thus facing the potential problem of drug–drug interactions (DDIs). Bempedoic acid is a prodrug administered orally at a fixed daily dose of 180 mg. The dicarboxylic acid is enzymatically activated by conjugation with coenzyme A (CoA) to form the pharmacologically active thioester (bempedoic acid–CoA). This process is catalyzed by very-long-chain acyl-CoA synthetase 1 (ACSVL1), expressed almost exclusively at the hepatic level. Bempedoic acid–CoA is a potent and selective inhibitor of ATP citrate lyase (ACL), a key enzyme in the biosynthetic pathway of cholesterol and fatty acids. The drug reduces low-density lipoprotein–cholesterol (LDL-C) (20–25%), non-high-density lipoprotein–cholesterol (HDL-C) (19%), apolipoprotein B (apoB) (15%), and total cholesterol (16%) in patients with hypercholesterolemia or mixed dyslipidemia. The drug has a favorable pharmacokinetics profile. Bempedoic acid and its metabolites are not substrates or inhibitors/inducers of cytochrome P450 (CYP450) involved in drug metabolism. On the other hand, bempedoic acid–glucuronide is a substrate for organic anion transporter 3 (OAT3). Bempedoic acid and its glucuronide are weak inhibitors of the OAT2, OAT3, and organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3). Thus, bempedoic acid could inhibit (perpetrator) the hepatic uptake of OATP1B1/3 substrate drugs and the renal elimination of OAT2 and OAT3 substrates and could suffer (victim) the effect of OAT3 transporter inhibitors, reducing its renal elimination. Based on these pharmacological characteristics, here, we describe the potential DDIs of bempedoic acid with concomitant medications and the possible clinical implications.

Mechanistic insights into the interaction of anxiolytic drugs with human serum albumin in a ternary system utilizing spectroscopic and molecular modeling approaches

In recent years, buspirone has been co-administered with sertraline to resolve sexual disorders caused by sertraline. Therefore, the present study was conducted to investigate the interaction effect of two antidepressants and anxiolytic drugs, sertraline and buspirone, on human serum albumin (HSA) using spectroscopic and molecular docking techniques. Fluorescence emission spectroscopy and molecular docking were used to calculate the binding affinity and determine the best binding sites for these two drugs. Additionally, UV-visible and circular dichroism spectroscopy were performed to investigate the effect of these drugs on the conformational changes of HSA. The results showed that both drugs have a strong ability to quench the fluorescence of HSA through a static mechanism, and cause structural changes in HSA. It was also found that binding of sertraline and buspirone to HSA is spontaneous (ΔG° <) and hydrophobic interactions, van der Waals forces and hydrogen bonds play a significant role in these interactions in the ternary system. In addition, molecular docking data showed that both drugs bind with high affinity to the Trp residue in subdomain IIA. The binding constants (Kb) for (HSA-SRH)-BSH and (HSA-BSH)-SRH were equal to 6.30 and 3.99, respectively, at 298 K. This study demonstrates that the presence of the second drug (buspirone/sertraline) affects the interaction and binding affinity of the first drug (sertraline/buspirone) to human serum albumin.

The effect of polygenic risk score and childhood adversity on transdiagnostic symptom dimensions at first-episode psychosis: evidence for an affective pathway to psychosis

Childhood adversity is associated with various clinical dimensions in psychosis; however, how genetic vulnerability shapes the adversity-associated psychopathological signature is yet to be studied. We studied data of 583 First Episode Psychosis (FEP) cases from the EU-GEI FEP case-control study, including Polygenic risk scores for major depressive disorder (MDD-PRS), bipolar disorder (BD-PRS) and schizophrenia (SZ-PRS); childhood adversity measured with the total score of the Childhood Trauma Questionnaire (CTQ); and positive, negative, depressive and manic psychopathological domains from a factor model of transdiagnostic dimensions. Genes and environment interactions were explored as a departure from a multiplicative effect of PRSs and total CTQ on each dimension. Analyses were adjusted for age, sex, 10 PCA, site of recruitment and for medication. A childhood adversity and PRS multiplicative interaction was observed between A) the CTQ and MDD-PRS on the predominance of positive (β = 0.42, 95% CI = [0.155, 0.682], p = 0.004); and depressive (β = 0.33, 95% CI = [0.071, 0.591], p = 0.013) dimensions; B) between the CTQ and BD-PRS on the positive dimension (β = 0.45, 95% CI = [0.106, 0.798], p = 0.010), and C) with the CTQ and SZ-PRS on the positive dimension (β = −0.34, 95% CI = [−0.660, −0.015], p = 0.040). Bonferroni corrected p-value of significance was set at 0.0125. In conclusion, despite being underpowered, this study suggests that genetic liability for MDD and BD may have a moderating effect on the sensibility of childhood adversity on depressive and positive psychotic dimensions. This supports the hypothesis of an affective pathway to psychosis in those exposed to childhood adversity.

Influence of inpatient withdrawal treatment on drug safety in alcohol use disorder — a quasi-experimental pre-post study

ObjectiveMost patients with alcohol use disorder (AUD) regularly take medication. Alcohol interacts negatively with many commonly prescribed medications. Little is known about whether the risk of potential alcohol-medication and drug-drug interactions increases or decreases in patients with AUD during inpatient withdrawal treatment. The aim of our study was to determine the prevalence and characteristics of potential alcohol-medication and drug-drug interactions in patients with AUD before and after withdrawal treatment in an addiction unit.DesignProspective monocentric quasi-experimental pre-post study.MethodsMedication records before and after withdrawal treatment were analyzed and screened for potential alcohol-medication (pAMI) and drug-drug interactions (pDDI) using the drugs.com classification and the AiDKlinik® electronic interaction program, respectively.ResultsWe enrolled 153 patients with AUD who were treated in an addiction unit of a university hospital in Germany. Of these, 67.3% experienced at least one pAMI before and 91.5% after withdrawal treatment. In total, there were 278 pAMIs classified as “mild,” “moderate,” or “severe” before and 370 pAMIs after withdrawal treatment. Additionally, there were 76 pDDIs classified as “moderate,” “severe,” or “contraindicated combinations” both before and after withdrawal treatment.ConclusionThe risk of exposure to pAMIs and pDDIs increases during inpatient withdrawal treatment in patients with AUD. Improvements in the quality of prescribing should particularly focus on the use of antihypertensives and opioids.

Silexan in anxiety, depression, and related disorders: pharmacological background and clinical data.

We present a narrative review of clinical trials investigating the anxiolytic and antidepressant effects of silexan, an active substance derived from lavender oil and summarize nonclinical findings from pharmacological studies supporting its therapeutic use. Six studies investigated the efficacy of the lavender oil in patients with subthreshold and generalized anxiety disorders as well as in mixed anxiety and depressive disorder (MADD). Furthermore, we present data indicating that silexan may influence sleep quality as well as anxiety or depressive disorders in individuals with post-COVID-19. Silexan taken orally at a daily dose of 80mg for 10 weeks was significantly superior to placebo in reducing psychic and somatic symptoms of anxiety and was as effective as 0.5mg/d lorazepam and 20mg/d paroxetine. In patients with mild or moderate major depression, silexan was superior to placebo and comparably effective to 50mg/d sertraline. Significant antidepressant effects were also observed in MADD and depression co-morbid with anxiety. The herbal product had a beneficial effect on activities of daily living and health-related quality of life. Adverse events associated with silexan in clinical trials were limited to eructation and mild, transient gastrointestinal complaints. The herbal product was not associated with drug interactions, sedation, sleep disturbance, dependence and abuse potential, sexual dysfunction, weight gain or withdrawal symptoms. Silexan was therefore safe and effective in subthreshold and syndromal anxiety disorders and in major depression.

Modulation of Multispecific Transporters by Uncaria tomentosa Extract and Its Major Phytoconstituents

Background/Objectives: One of the major risks associated with the concomitant use of herbal products and therapeutic drugs is herb–drug interactions (HDIs). The most common mechanism leading to HDIs is the inhibition and/or induction of transport proteins and drug-metabolizing enzymes by herbal ingredients, causing changes in the pharmacokinetic disposition of the victim drug. The present study aimed to determine the potential interactions of Uncaria tomentosa (UT) (cat’s claw), a popular herb due to its supposed health benefits. Methods: The effect of UT extract and its major oxindole alkaloids was investigated on multispecific solute carrier (SLC) and ATP-binding cassette (ABC) drug transporters, using SLC transporter-overexpressing cell lines and vesicles prepared from ABC transporter-overexpressing cells. Results: UT extract significantly inhibited all ABC transporters and the majority of the SLC transporters tested. Of the investigated oxindole alkaloids, isopteropodine significantly inhibited OATP, OCT1 and OCT2, OAT3, ENT4, MDR1, and BCRP transporters. OCTs, OCTN1-, ENT1-, and MDR1-mediated substrate accumulation was below 50% in the presence of mitraphylline. Conclusions: Based on the calculated intestinal concentration of UT extract, interactions with intestinal transporters, especially OATP2B1, ENTs, MRP1, MRP2, MDR1, and BCRP could be relevant in vivo. Our data can help to predict the clinical consequences of UT co-administration with drugs, such as increased toxicity or altered efficacy. In conclusion, the use of these in vitro models is applicable for the analysis of transporter-mediated HDIs similar to drug–drug interaction (DDI) prediction.

Computer-Aided Identification and Design of Ligands for Multi-Targeting Inhibition of a Molecular Acute Myeloid Leukemia Network

Background/Objectives: Acute myeloid leukemia (AML) is characterized by therapeutic failure and long-term risk for disease relapses. As several therapeutic targets participate in networks, they can rewire to eventually evade single-target drugs. Hence, multi-targeting approaches are considered on the expectation that interference with many different components could synergistically hinder activation of alternative pathways and demolish the network one-off, leading to complete disease remission. Methods: Herein, we established a network-based, computer-aided approach for the rational design of drug combinations and de novo agents that interact with many AML network components simultaneously. Results: A reconstructed AML network guided the selection of suitable protein hubs and corresponding multi-targeting strategies. For proteins responsive to existing drugs, a greedy algorithm identified the minimum amount of compounds targeting the maximum number of hubs. We predicted permissible combinations of amiodarone, artenimol, fostamatinib, ponatinib, procaine, and vismodegib that interfere with 3–8 hubs, and we elucidated the pharmacological mode of action of procaine on DNMT3A. For proteins that do not respond to any approved drugs, namely cyclins A1, D2, and E1, we used structure-based de novo drug design to generate a novel triple-targeting compound of the chemical formula C15H15NO5, with favorable pharmacological and drug-like properties. Conclusions: Overall, by integrating network and structural pharmacology with molecular modeling, we determined two complementary strategies with the potential to annihilate the AML network, one in the form of repurposable drug combinations and the other as a de novo synthesized triple-targeting agent. These target–drug interactions could be prioritized for preclinical and clinical testing toward precision medicine for AML.

Real-world analysis of levetiracetam-associated rhabdomyolysis: insights from the FDA adverse event reporting system

ABSTRACT Background Levetiracetam, a widely prescribed antiseizure medication, is recognized for its broad-spectrum efficacy, good tolerability, and minimal drug interactions. This study examines the association between levetiracetam and rhabdomyolysis, utilizing real-world data from the FDA Adverse Event Reporting System (FAERS) database to further elucidate its safety profile. Methods This study extracted adverse events related to levetiracetam from the FAERS database (Q1 2013 to Q1 2024). Four types of disproportionality analysis identified rhabdomyolysis as a significant adverse even. Logistic regression assessed risk factors, including gender, age, and severity. A Gaussian Mixture Model analyzed the time-to-onset distribution of rhabdomyolysis, while the impact of concomitant medications on its risk was evaluated using Reporting Odds Ratio (ROR). Results Levetiracetam significantly increased rhabdomyolysis risk (ROR = 13.5). Males showed a higher incidence (OR = 2.60). Most adverse events occurred within the first 30 days, with a bimodal onset distribution. Co-administration of antibiotics, antipsychotics, and PPIs elevated the risk while other antiseizure medications did not. Conclusion This study found a significant association between levetiracetam and the risk of rhabdomyolysis, highlighting the need for increased clinical vigilance in this patient population. Future research should focus on elucidating the underlying mechanisms and optimizing clinical guidelines.

Family planning knowledge, use, and associated factors among women with mental illness and epilepsy in Rwanda: a cross-sectional study

IntroductionFamily planning knowledge and access to quality family planning services occupy a central position in the lives of all women of reproductive age. However, women with mental illness and epilepsy who are at a high risk of sexual violence, unwanted pregnancies, poor obstetric outcomes, and drug interaction consequences, need it the most. Understanding their family planning knowledge and utilization remains crucial for meeting their needs. The present study aims to assess knowledge, use of family planning, and associated factors among women living with mental illness and epilepsy who attend the Ndera Neuropsychiatric Hospital and affiliated branches.MethodologyA cross-sectional study was conducted between October 2022 and February 2023. The study involved a purposive sample of 289 women who attended the Ndera Neuropsychiatric Hospital and its two affiliated branches during the data collection period. Psychiatric nurses administered a structured questionnaire. Data were analyzed using descriptive statistics, and multiple logistic regression analysis was performed to assess the factors associated with the use of family planning methods.ResultsOut of 289 who participated in the study, the majority (96.9%) were aware of family planning methods, most (67.8%) had used one method once in their life course, a half (51.9%) were using a family planning method at the time of data collection, and a slight number (26%) expressed intentions of using a family planning method in the future. The most known and used methods were respectively the injectable (17.5%) and oral contraceptive pill (17.5%). Regarding the natural family planning methods, breastfeeding and withdrawal were less used. Being single (AOR = 66.4, 95% CI: 9.8, 44) or married (AOR = 51.4, 95% CI: 11.9–22), having a primary level of education (AOR = 5.6, 95% CI: 2.0, 15.9), knowing a contraceptive method (AOR = 5.8, 95% CI: 0.6, 49) and suffering from brief psychotic disorders (AOR = 2.7, 95% CI: 1.1, 6.6) predicted a higher utilization of family planning.ConclusionMost of the women with mental illness in this study were aware of family planning methods and had used one of the family planning methods in life. The national average is below when it comes to family planning awareness. It is important to improve family planning education and counseling for women who attend psychiatric outpatient clinics.

Clinical pharmacist interventions in nutrition-and drug-related problems in critically ill patients with renal dysfunction: a non-randomized controlled study

BackgroundCritically ill intensive care unit (ICU) patients often face life-threatening drug-related problems (DRPs) and malnutrition. Clinical pharmacists (CPs) play a crucial role in mitigating these issues and improving outcomes.AimThis study was designed to detect, prevent, reduce or resolve nutrition-related problems (NRPs) and DRPs in intensive care patients with renal dysfunction through clinical pharmacy services.MethodThis 9-month, prospective, non-randomized, controlled study was conducted in the ICU. During the intervention period (IP), CP recommendations addressing NRPs and DRPs were provided to the healthcare team. NRPs were evaluated using an expert-developed enteral nutrition consensus protocol, while DRPs were classified according to the Pharmaceutical Care Network Europe (PCNE) Classification for Drug-Related Problems Version 9.1.ResultsThe study included 60 patients with a median age of 73 years (IQR: 60.5–80). A total of 504 DRPs (8.4 per patient) were identified across all patients. DRPs were decreased by 50% during the IP compared to the observation period (OP) (p &amp;lt; 0.001). The most common causes of DRPs were ‘too low a drug dose’ (22.2%), ‘drug–drug interactions’ (17%), and ‘too high a drug dose’ (16.4%). Of the recommendations made to the prescribing physician, 140 (97.9%) were accepted. In the IP, targeted calorie and protein supplementation was fully achieved in more patients (p &amp;lt; 0.05). The most common recommendations included ‘changes in the rate of nutrition’ (66.7%), ‘vitamin supplementation’ (16.7%), and ‘changes in enteral nutrition products’ (7.7%).ConclusionThis study highlights the high incidence of DRPs and malnutrition risk in ICU patients with renal dysfunction, emphasizing the vital role of clinical pharmacists. Their collaboration with healthcare professionals significantly reduced both DRPs and NRPs.

Harnessing AlphaFold to reveal hERG channel conformational state secrets.

To design safe, selective, and effective new therapies, there must be a deep understanding of the structure and function of the drug target. One of the most difficult problems to solve has been resolution of discrete conformational states of transmembrane ion channel proteins. An example is K v 11.1 (hERG), comprising the primary cardiac repolarizing current, I kr . hERG is a notorious drug anti-target against which all promising drugs are screened to determine potential for arrhythmia. Drug interactions with the hERG inactivated state are linked to elevated arrhythmia risk, and drugs may become trapped during channel closure. However, the structural details of multiple conformational states have remained elusive. Here, we guided AlphaFold2 to predict plausible hERG inactivated and closed conformations, obtaining results consistent with multiple available experimental data. Drug docking simulations demonstrated hERG state-specific drug interactions in good agreement with experimental results, revealing that most drugs bind more effectively in the inactivated state and are trapped in the closed state. Molecular dynamics simulations demonstrated ion conduction for an open but not AlphaFold2 predicted inactivated state that aligned with earlier studies. Finally, we identified key molecular determinants of state transitions by analyzing interaction networks across closed, open, and inactivated states in agreement with earlier mutagenesis studies. Here, we demonstrate a readily generalizable application of AlphaFold2 as an effective and robust method to predict discrete protein conformations, reconcile seemingly disparate data and identify novel linkages from structure to function.

Evaluation of drug use in stroke patients at the inpatient unit of Brebes Hospital, Central Java

Background: Effective stroke treatment is complicated by factors such as polypharmacy, drug interactions, and side effects, leading to drug-related problems (DRPs) that hinder therapeutic outcomes. Evaluating drug use in stroke patients is crucial to ensure rational, safe, effective, and efficient treatment, ultimately improving therapeutic outcomes. Objective: This study aimed to evaluate the drug use patterns in inpatient stroke patients at Brebes Hospital, focusing on the appropriateness of drug selection, dosage, administration, and the impact of patient characteristics on DRPs. Method: A retrospective, descriptive evaluative design was employed, with data collected from medical records of stroke patients hospitalized at Brebes Hospital between May and July 2022. A total of 135 patients (110 ischemic, 25 hemorrhagic stroke) were included through consecutive sampling. Univariate analysis was used to describe patient characteristics and treatment patterns, while bivariate analysis with the chi-square test assessed the relationship between patient characteristics and DRPs. Results: The most common medications included citicoline (88.15%), clopidogrel (68.85%), and amlodipine (40.48%). DRPs were identified, including non-compliance with guidelines (1 case), contraindicated drugs (5 cases), and inappropriate drug selection (1 case). Notably, five cases of contraindicated use of omeprazole with clopidogrel and one case of phenytoin without indication were observed. Patient characteristics such as age and comorbidities did not significantly influence the incidence of DRPs (p &gt; 0.05). Conclusion: The study found irrational drug use in stroke patients, with DRPs posing challenges for treatment optimization. Addressing DRPs through improved prescribing practices and pharmacist intervention is crucial to enhancing therapeutic outcomes in stroke management.

The Role of ABCB1, ABCG2, and SLC Transporters in Pharmacokinetic Parameters of Selected Drugs and Their Involvement in Drug–Drug Interactions

The Role of ABCB1, ABCG2, and SLC Transporters in Pharmacokinetic Parameters of Selected Drugs and Their Involvement in Drug–Drug Interactions

Establishing a physiologically based pharmacokinetic framework for aldehyde oxidase and dual aldehyde oxidase-CYP substrates.

Aldehyde oxidase (AO) contributes to the clearance of many approved and investigational small molecule drugs, which are often dual substrates of AO and drug-metabolizing enzymes such as cytochrome P450s (CYPs). As such, the lack of established framework for quantitative translation of the clinical pharmacologic correlates of AO-mediated clearance represents an unmet need. This study aimed to evaluate the utility of physiologically based pharmacokinetic (PBPK) modeling in the development of AO and dual AO-CYP substrates. PBPK models were developed for capmatinib, idelalisib, lenvatinib, zaleplon, ziprasidone, and zoniporide, incorporating invitro functional data from human liver subcellular fractions and human hepatocytes. Prediction of metabolic elimination with/without the additional empirical scaling factors (ESFs) was assessed. Clinical pharmacokinetics, human mass balance, and drug-drug interaction (DDI) studies with CYP3A4 modulators, where available, were used to refine/verify the models. Due to the lack of clinically significant AO-DDIs with known AO inhibitors, the fraction metabolized by AO (fmAO) was verified indirectly. Clearance predictions were improved by using ESFs (GMFE ≤1.4-fold versus up to fivefold with physiologically-based scaling only). Observed fmi from mass balance studies were crucial for model verification/refinement, as illustrated by capmatinib, where the fmAO (40%) was otherwise underpredicted up to fourfold. Subsequently, independent DDI studies with ketoconazole, itraconazole, rifampicin, and carbamazepine verified the fmCYP3A4, with predicted ratios of the area under the concentration-time curve (AUCR) within 1.5-fold of the observations. In conclusion, this study provides a novel PBPK-based framework for predicting AO-mediated pharmacokinetics and quantitative assessment of clinical DDI risks for dual AO-CYP substrates within a totality-of-evidence approach.

Identification of human pregnane X receptor antagonists utilizing a high-throughput screening platform.

Pregnane X receptor (PXR) is a xenobiotic-sensing nuclear receptor with a well-established role in regulating drug metabolism and clearance. Recent studies have shown that PXR is involved in cell proliferation, apoptosis, immune response, and energy homeostasis. It is important to identify compounds that may modulate PXR activity to prevent drug-drug interactions, distinguish chemicals which could potentially generate toxicity, and identify compounds for further development towards therapeutic usage. In this study, we have screened the National Center for Advancing Translational Sciences (NCATS) Pharmacologically Active Chemical Toolbox (NPACT) library, which consists of 5,099 unique pharmacologically active synthetic and naturally derived small molecules to identify PXR antagonists. Ninety-four compounds were identified as potential PXR antagonists through a primary screen and 66 were confirmed in a confirmation study. Of these compounds, twenty potential PXR antagonists, including gamma-secretase modulator 2 (GSM2) and fusidic acid, were selected for further study based on their efficacy, potency, and novelty. Their PXR inhibition abilities were assessed by examining their effects on cytrochrome P450 (CYP) 3A4 mRNA expression using metabolically competent HepaRG cells. Additionally, a pharmacological inhibition assay using various concentrations of rifampicin as a stimulator was performed in HepG2-CYP3A4-hPXR cells to confirm the activity of the 20 selected compounds against PXR. Finally, HepaRG cells were used to confirm PXR antagonism by verification of a concentration-dependent decrease of CYP3A4 when co-treated with the known PXR agonist, rifampicin. Additionally, the potent actives were further investigated using molecular docking to find the potential interactions of the novel ligands with the active sites of hPXR. To our knowledge from the current study, GSM2 and fusidic acid have been identified as novel PXR antagonists, which provides useful information for further investigation regarding possible drug-drug interactions, as well as the detection of potential therapeutic effects or other toxic consequences.

Clinical Development of the GluN2B-selective NMDA Receptor Inhibitor NP10679 for the Treatment of Neurologic Deficit after Subarachnoid Hemorrhage.

Aneurysmal subarachnoid hemorrhage (aSAH) may be associated with cerebral vasospasm, which can lead to delayed cerebral ischemia, infarction, and worsened functional outcomes. The delayed nature of cerebral ischemia secondary to SAH-related vasculopathy presents a window of opportunity for the evaluation of well-tolerated neuroprotective agents administered soon after ictus. Secondary ischemic injury in SAH is associated with increased extracellular glutamate, which can overactivate NMDA receptors (NMDARs), thereby triggering NMDAR-mediated cellular damage. In this study, we have evaluated the effect of the pH-sensitive GluN2B-selective NMDAR inhibitor, NP10679, on neurologic impairment after SAH. This compound demonstrates a selective increase in potency at the acidic extracellular pH levels that occur in the setting of ischemia. We found that NP10679 produced durable improvement of behavioral deficits in a well-characterized murine model of SAH, and these effects were greater than those produced by nimodipine alone, the current standard of care. In addition, we observed an unexpected reduction in SAH-induced luminal narrowing of the middle cerebral artery. Neither nimodipine nor NP10679 alter each other's pharmacokinetic profile, suggesting no obvious drug-drug interactions. Based on allometric scaling of both toxicological and efficacy data, the therapeutic margin in man should be at least 2. These results further demonstrate the utility of pH-dependent neuroprotective agents and GluN2B-selective NMDAR inhibitors as potential therapeutic strategies for the treatment of aSAH. Significance Statement This report describes the properties and utility of the GluN2B-selective pH-sensitive NMDA receptor inhibitor, NP10679, in a well-characterized rodent model of subarachnoid hemorrhage. We show that the administration of NP10679 improves long-term neurological function following subarachnoid hemorrhage, and that in rats there are no drug-drug interactions between NP10679 and nimodipine, the standard of care for this indication.

DESAFIOS DO MANEJO DO LÍTIO NO PACIENTE PSIQUIÁTRICO: ESTRATÉGIAS PARA GARANTIR A SEGURANÇA E EFICÁCIA DO TRATAMENTO

Although lithium has been used for decades, its management remains a clinical challenge, since it is a drug with narrow therapeutic indices and with possible adverse effects. Therefore, this study aims to present evidence and clinical challenges of lithium management in psychiatry, in order to contribute to a better understanding of the use of this drug and the conscious management of patients who use this medication. This is a retrospective, documental Integrative Literature Review about the challenges of lithium management in psychiatric patients. For the development of this work, the following steps were followed: 1) Construction of the theme and the guiding question; 2) Establishment of inclusion and exclusion criteria; 3) Collection of studies in the scientific bases; 4) Evaluation of the selected abstracts; 5) Evaluation and categorization of studies in full; 6) Analysis and interpretation of the results. Lithium, as a mood stabilizer, was a great historical discovery and its importance lies in its effectiveness in controlling the symptoms of bipolarity, being considered a first-line mood stabilizer for the treatment of bipolar disorder and other psychopathologies. It is concluded, therefore, that the management of lithium in the treatment of psychiatric disorders requires a careful and individualized approach, taking into account the efficacy of the drug, patient safety and possible drug interactions and clinical conditions. Knowledge of the common and rare side effects of lithium is essential to ensure successful and safe treatment.