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Nadolol is a hydrophilic β-adrenoceptor blocker with a relatively long half-life and negligible metabolism. It is a substrate of P-glycoprotein and organic anion transporting polypeptide 1A2, and may serve as an in vivo probe drug for the assessment of drug-drug and food-drug interactions mediated by these transporters. In the present study, we aimed to develop limited sampling strategy (LSS) models for predicting the area under the plasma concentration-time curve (AUC 0-∞ ) of nadolol. Plasma concentration data (C t ) in healthy volunteers reported in four previous studies were randomly divided into a training dataset for model development (n = 15) and a test dataset for model validation (n = 16). By multiple linear regression analysis, we confirmed that four out of the eight models using two time points and all models using three time points met the acceptable criteria. In particular, the three time point models using (C 3 , C 6 , and C 24 ) and (C 4 , C 8 , and C 24 ) showed better predictive performances with r 2 values of 0.983 and 0.980, respectively. In drug interaction studies of nadolol with itraconazole, rifampicin, grapefruit juice, and green tea extract, both LSS models accurately predicted the AUC 0-∞ with percent mean absolute error ≤11% and percent root mean square error ≤12%. In addition, using digitized pharmacokinetic data of nadolol, both LSS models were further validated by predicting the AUC 0-∞ in different doses. The results suggest that the LSS models using three time points allow a reliable prediction of AUC 0-∞ of nadolol in healthy individuals., (© 2024, The American College of Clinical Pharmacology.)

The effects of pharmaceutical excipients on intestinal drug absorption have been highlighted and careful excipient selection is required to develop biologically equivalent formulations. This study aimed to evaluate the effects of excipients on drug permeability and compare the characteristics of in vitro screening methods. Three in vitro models, the commercial precoated parallel artificial membrane permeability assay (PAMPA), PermeaPad TM , and Caco-2 monolayer, were used to evaluate the effects of 14 excipients on the permeability of several drugs with different biopharmaceutical classification system classes. Concentration-dependent effects were analyzed to distinguish non-specific effects. The permeability of low-permeability drugs was increased by excipients such as hydroxypropyl cellulose and povidone K30 in the precoated PAMPA model, whereas PermeaPad TM maintained membrane integrity at higher concentrations. Conversely, croscarmellose sodium and sodium lauryl sulfate (SLS) decreased the permeability of highly permeable drugs in both precoated PAMPA and PermeaPad TM assays in a concentration-dependent manner. In Caco-2 monolayer assays, most excipients showed minimal effects on drug permeability. However, SLS significantly reduces the permeability of highly permeable drugs at concentrations above the critical micelle concentration, thereby compromising the integrity of the cell monolayer. Our results suggested that most of excipients, except SLS, did not affect the membrane permeation of drugs at clinically used concentrations. The pre-coated PAMPA model demonstrated high sensitivity to excipient effects, making it suitable for conservative evaluation. The PermeaPad TM and Caco-2 models allowed assessment at higher excipient concentrations, with PermeaPad TM being particularly useful for excipients that cause toxicity in Caco-2 cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Drug molecules exist as complexed with serum proteins such as human serum albumin (HSA) and/or unbound free form in the blood circulation. Drugs can be effective only when they are free. Thus, it is important to understand aspects that are important for interaction between drugs and interacting proteins. In this study, interactions among 2990 FDA approved drugs and HSA were computational analyzed to unravel principles that are critical for drug-HSA interactions. Docking results showed that drugs have higher affinity toward cavity-1 (C1) than cavity-2 (C2). A total of 1131 drug molecules have docking score greater than 60 while 768 molecules have docking score greater than 60 when they are docked in C2. In addition, three solvent channels have potential to direct solvent to C1 cavity while C2 does not have any effective channel. The post MD analyses demonstrated that drugs are making polar interactions with basic amino acids in the binding cavities. Verbscoside and ceftazidime both have stable low RMSD values throughout MD simulation with 2 Å on average in C1 cavity. The ligand RMSD shows less stability for verbscoside, which is around 4 Å when it is in complex with HSA in C1. The individual contribution of the residues K192, K196, R215, and R254 to ceftazidime are -1.92 ± 0.18, -3.09 ± 0.09, -2.17 ± 0.17, and - 2.32 ± 0.098, respectively. These residues contribute the binding energy of the verbscoside by -6.06 ± 0.08, -2.10 ± 0.06, and - 1.57 ± 0.03 kcal/mol individually in C1 cavity. C2 is making polar interactions with drug via R469, K472, and K488 residues and their contribution to the two drugs are -3.13 ± 0.21 kcal/mol for R469, -1.94 ± 0.18 kcal/mol for K472, and -1.96 ± 0.11 kcal/mol for K488 to total binding energy of ceftazidime. The binding energy of verbscoside is 57.17 ± 7.00 kcal/mol and Arg-407 has the highest contribution this bind energy individually with -4.29 ± 0.12 kcal/mol. Drugs with hydrogen bond donor/acceptor chemical adducts such as verbscoside involve higher hydrogen bond formation in C1 pocket. Ceftazidime makes interaction with HSA toward hydrophobic residues, L384, L404, L487, and L488 in the C2 cavity., (© 2024 The Author(s). Journal of Molecular Recognition published by John Wiley & Sons Ltd.)

Sunitinib, a novel anti-tumor small molecule targeting VEGFR, is prescribed for advanced RCC and GISTs. Sunitinib is primarily metabolized by the CYP3A enzyme. It is well-known that dexamethasone serves as a potent inducer of this enzyme system. Nonetheless, the effect of dexamethasone on sunitinib metabolism remains unclear. This study examined the effect of dexamethasone on the pharmacokinetics of sunitinib and its metabolite N-desethyl sunitinib in rats. The plasma levels of both compounds were measured using UHPLC-MS/MS. Pharmacokinetic parameters and metabolite ratio values were calculated. Compare to control group, the low-dose dexamethasone group and high-dose dexamethasone group decreased the AUC (0-t) values of sunitinib by 47 % and 45 %, respectively. Meanwhile, the AUC (0-t) values of N-desethyl sunitinib were increased by 2.2-fold and 2.4-fold in low-dose dexamethasone group and high-dose dexamethasone group, respectively. The CL values for sunitinib were both approximately 45 % higher in the two dexamethasone groups. Remarkably, metabolite ratio values increased over 5-fold in both low-dose dexamethasone group and high-dose dexamethasone group, indicating a significant enhancement of sunitinib metabolism by dexamethasone. Moreover, the total levels of sunitinib and its metabolite are also significantly increased. The impact of interactions on sunitinib metabolism, as observed with CYP3A inducers such as dexamethasone, is a crucial consideration for clinical practice. To optimize the dosage and prevent adverse drug events, therapeutic drug monitoring can be employed to avoid the toxicity from such interactions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study intended to evaluate the interactions between zamicastat and epoprostenol in healthy human subjects. This was a single-center, open-label, two-period study. In period 1, epoprostenol 8 ng/kg/min was administered alone. In period 2, epoprostenol 8 ng/kg/min was administered following an 8-day treatment with zamicastat. Since the initial dose of epoprostenol showed to be insufficiently tolerated, it was decreased to 6 ng/kg/min. Blood samples were collected to determine the metabolites of epoprostenol and concentrations of zamicastat and its metabolites. A total of 54 subjects were enrolled and data from 28 subjects were available for pharmacokinetic analysis. The epoprostenol plus zamicastat-to-epoprostenol geometric means ratio (GMR) and corresponding 90% confidence interval (CI) for C av,ss and area under the plasma concentration-time curve from time 0 up to 16 h at steady state (AUC 0-16,ss ) of the metabolites of epoprostenol were within the acceptance bioequivalence range (80.00%-125.00%). The intrasubject coefficient of variation (ISCV) was below 10% for both parameters, on both metabolites. For zamicastat AUC 0-τ,ss , the zamicastat plus epoprostenol-to-zamicastat GMR and corresponding 90% CI were within the bioequivalence acceptance range, while for zamicastat C max,ss , the lower limit of the 90% CI was slightly below the acceptance range. For zamicastat metabolites, C max,ss and AUC 0-τ,ss and the zamicastat plus epoprostenol-to-zamicastat GMR were below the acceptance bioequivalence range. ISCV was between 30% and 41% for C max,ss and between 21% and 41% for AUC 0-τ,ss , for zamicastat and both metabolites. This study showed that the administration of zamicastat did not significantly modify the cardiovascular effects of epoprostenol and that the interactions between zamicastat and epoprostenol are not expected to be clinically relevant., (© 2024, The American College of Clinical Pharmacology.)

Schizophrenia is a complex psychotic disorder characterized by positive symptoms, such as hallucinations and delusions, and negative symptoms, including emotional withdrawal and apathy. Its profound impact on an individual's functioning requires meticulous and sustained management, typically through the use of antipsychotic medications. While these treatments aim to alleviate symptoms and improve quality of life, long-term therapy often necessitates careful balancing to mitigate potential side effects. As a result, ongoing monitoring and personalized care are essential for effective management. This case report discusses a 44-year-old male with chronic schizophrenia who experienced worsening psychotic symptoms following an interaction between aripiprazole, a partial dopamine agonist, and haloperidol, a first-generation antipsychotic (FGA). Due to aripiprazole's unique mechanism of action, his medication regimen was adjusted, discontinuing aripiprazole and transitioning him to risperidone 4 mg twice daily, valproic acid 500 mg twice daily (BID), haloperidol 10 mg twice daily, and quetiapine 200 mg once daily (OD). Following these adjustments, the patient showed significant improvement over the subsequent weeks and was discharged from inpatient care. This case underscores the unexpected consequences of combining two medications and highlights the challenges posed by aripiprazole's mechanism of action. It emphasizes the importance of vigilant monitoring and careful drug selection when managing schizophrenia, particularly in cases involving complex pharmacological profiles., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Farooq et al.)

Everolimus is an oral mammalian target of rapamycin (mTOR) inhibitor used in cancer chemotherapy and transplantation. Due to its therapeutic properties, everolimus has been used long-term in clinical practice. Drug interactions with everolimus during gastrointestinal absorption can alter the oral bioavailability of everolimus and/or concomitant drugs. However, the effects of everolimus on gastrointestinal absorption remain unknown. The present study assessed the impact of continuous exposure to everolimus on expression and function of the ATP-binding cassette (ABC) transporter ABCB1 and ABCG2 using a Caco-2 intestinal cell model. Caco-2 subline, Caco/EV, was established by continuously exposing Caco-2 cells to 1 µM everolimus. Cell viability was evaluated using WST-1 assay. mRNA levels were measured by reverse transcription-quantitative PCR. Transport activity of ABCB1 was evaluated through the cellular accumulation of Rhodamin 123, a substrate for ABCB1. The half-maximal inhibitory concentration (IC 50 ) values for everolimus in Caco-2 and Caco/EV cells were 0.31 and 4.33 µM, respectively, indicating 14-fold resistance in Caco/EV cells. Sensitivity to paclitaxel and 7-ethyl-10-hydroxycamptothecin, which are substrates for ABCB1 and ABCG2, respectively, was enhanced in Caco/EV, but not in Caco-2 cells. The IC 50 values of cisplatin were comparable in both cell lines. Furthermore, mRNA expression levels of ABCB1 and ABCG2 were lower in Caco/EV cells than in Caco-2 cells, and the cellular accumulation of Rhodamine 123 was significantly higher in Caco/EV cells. These findings demonstrated that continuous exposure to everolimus suppressed the expression and function of ABCB1 and ABCG2, suggesting potential drug-drug interactions via the suppression of ABCB1 and ABCG2 in the intestinal tract., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Nakayama et al.)

Aims: Dersimelagon is a novel, investigational, orally administered, selective agonist of the melanocortin-1 receptor that has demonstrated efficacy at increasing symptom-free light exposure and an acceptable safety profile in patients with protoporphyria. A phase 1 drug-drug interaction (DDI) study demonstrated that dersimelagon 300 mg has the potential for clinically relevant DDIs with drugs that are substrates for breast cancer resistance protein, such as atorvastatin and rosuvastatin. This study uses physiologically based pharmacokinetic (PBPK) modelling to further investigate the DDI effects at lower doses of dersimelagon with substrate drugs., Methods: The data from in silico, in vitro and in vivo studies were used to construct a PBPK model for dersimelagon to assess the DDI potential between dersimelagon and substrate drugs for cytochrome P450 3A, P-glycoprotein, organic anion transporting polypeptide 1B1/1B3, organic anion transporter 3 and breast cancer resistance protein, including atorvastatin and rosuvastatin., Results: The systemic exposure of atorvastatin based on the maximum plasma concentration and area under the plasma concentration-time curve was predicted to increase 1.21-fold and 1.25-fold, respectively, if coadministered with dersimelagon 100 mg, and 1.42-fold and 1.45-fold with dersimelagon 200 mg. The systemic exposure of rosuvastatin followed trends similar to atorvastatin (1.67-fold and 1.34-fold increase in maximum plasma concentration and area under the plasma concentration-time curve, respectively, with dersimelagon 100 mg, and 2.40-fold and 1.69-fold with dersimelagon 200 mg)., Conclusion: Overall, PBPK modelling results indicate that the simulated changes in plasma exposure of atorvastatin and rosuvastatin following coadministration with dersimelagon 100 or 200 mg are not clinically significant, but caution and appropriate clinical monitoring should be recommended., (© 2024 Mitsubishi Tanabe Pharma Corporation. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Hospital pharmacy plays an important role in ensuring medical care quality and safety, especially in the area of drug information retrieval, therapy guidance, and drug-drug interaction management. ChatGPT is a powerful artificial intelligence language model that can generate natural-language texts. Here, we explored the applications and reflections of ChatGPT in hospital pharmacy, where it may enhance the quality and efficiency of pharmaceutical care. We also explored ChatGPT's prospects in hospital pharmacy and discussed its working principle, diverse applications, and practical cases in daily operations and scientific research. Meanwhile, the challenges and limitations of ChatGPT, such as data privacy, ethical issues, bias and discrimination, and human oversight, are discussed. ChatGPT is a promising tool for hospital pharmacy, but it requires careful evaluation and validation before it can be integrated into clinical practice. Some suggestions for future research and development of ChatGPT in hospital pharmacy are provided., (©Xingang Li, Heng Guo, Dandan Li, Yingming Zheng. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 04.10.2024.)

Objective: To evaluate age, adjunctive antiseizure medication (ASM), and specific ASMs on lacosamide (LCM) weight normalized dose-to-concentration ratio (DCR) and US Food and Drug Administration (FDA) dosing guidelines in pediatric patients., Methods: Patients 1 mo to ≤18 years with a LCM serum concentration between October 2009 and June 2017 were considered. Demographics, LCM DCR, and adjunctive ASM were recorded. LCM DCR/hr was used as a surrogate for clearance. Data were stratified by age (1 mo-< 2 yr; ≥ 2-6 yr; ≥ 6-12 yr; and ≥12-≤18 yr), FDA dosing weights, and ASM potential to interaction with LCM., Results: There were 646 sera (380 patients) with median dose 8.36 mg/kg/day (IQR, 5.92-11.16). 50.2% of doses were within FDA-weight guidelines; however, 40.4% exceeded recommendations. Most (81.3%) LCM concentrations were between 2 and 12 mg/L. A difference existed in DCR between ages, with those <2 years having the highest DCR (p < 0.001). Moving across age groups, the DCR decreases by 30.7%, 50.5%, and 63.4%. There was a weak (r 2 = 0.073) but significant (p < 0.001) negative correlation between DCR and age. 84.8% received adjunctive ASM consisting of at least one of 31 different ASMs. DCR was higher with adjunctive ASMs compared with monotherapy [0.061 (0.039-0.095) vs 0.043 (0.030-0.062)], respectively (p < 0.001) and was greatest with inducers. Phenobarbital increased DCR by 2.6-fold, topiramate by 72.1%, and clobazam by 32.6%. Inhibitors had no effect., Conclusions: The correlation between age and DCR was weak, accounting for 6% of variability. Strong inducers significantly increased DCR. Synergy may exist when multiple inducers are given. Weak inhibitors did not affect DCR. Those ≥6 to 11 kg, ≥30 to 50 kg, and those given strong inducers may require larger -initial LCM doses. Serum concentrations should be used to individualize dosing, especially in those receiving strong inducers., Competing Interests: Disclosures Drs Woods, Phelps, Christensen, and Meibohm declare no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. Dr Wheless has received grant support from Lundbeck, Eisai, GlaxoSmithKline, King Pharmaceuticals, Supernus, The Shainberg Foundation, and the National Institutes of Health. He has served as a consultant to Lundbeck, Cyberonics, Pfizer, Eisai, and Sunovion and has received speaking fees from Lundbeck, Questcor, Cyberonics, and Eisai. Dr Woods, Phelps, and Christensen had full access to all the data and take responsibility for the integrity of the data and accuracy of the data analysis., (Copyright. Pediatric Pharmacy Association. All rights reserved. For permissions, email: membership@pediatricpharmacy.org.)

Background: Inhaled corticosteroids (ICS) are effective in managing asthma and chronic obstructive pulmonary disease (COPD) but increase the risk of pneumonia. Benzodiazepines (BZD), commonly prescribed for comorbid psychiatric disorders in asthma or COPD patients, are also associated with pneumonia. This study investigates the risk of pneumonia associated with the concomitant use of ICS and BZD., Methods: Data from the FDA Adverse Event Reporting System from Q4 2013 to Q3 2023 were extracted. Reports involving asthma or COPD patients were included. Disproportionality analysis and logistic regression analysis were performed to assess the risk of pneumonia associated with the combined use of ICS and BZD. Additive and multiplicative models were used to further confirm the results. Additionally, subgroup analyses were conducted based on gender, age, and disease type., Results: A total of 238,411 reports were included. The combined use of ICS and BZD was associated with a higher reporting of pneumonia (ROR: 2.41, 95% CI 2.25-2.58). Using additive and multiplicative methods, the results remained significant. The strongest risk signals were observed in specific drug combinations, such as mometasone with clonazepam, budesonide with temazepam, and mometasone with zopiclone. Subgroup analyses showed higher pneumonia risks in females, patients over 60 years old, and those with asthma., Conclusion: Our findings identified a significantly elevated pneumonia risk with the combined use of ICS and BZD. These results highlighted the necessity for cautious co-prescription of ICS and BZD and suggested the need for more comprehensive clinical studies to assess this interaction., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Enfortumab vedotin is an antibody-drug conjugate (ADC) comprised of a Nectin-4-directed antibody and monomethyl auristatin E (MMAE), which is primarily eliminated through P-glycoprotein (P-gp)-mediated excretion and cytochrome P450 3A4 (CYP3A4)-mediated metabolism. A physiologically based pharmacokinetic (PBPK) model was developed to predict effects of combined P-gp with CYP3A4 inhibitor/inducer (ketoconazole/rifampin) on MMAE exposure when coadministered with enfortumab vedotin and study enfortumab vedotin with CYP3A4 (midazolam) and P-gp (digoxin) substrate exposure. A PBPK model was built for enfortumab vedotin and unconjugated MMAE using the PBPK simulator ADC module. A similar model was developed with brentuximab vedotin, an ADC with the same valine-citrulline-MMAE linker as enfortumab vedotin, for MMAE drug-drug interaction (DDI) verification using clinical data. The DDI simulation predicted a less-than-2-fold increase in MMAE exposure with enfortumab vedotin plus ketoconazole (MMAE geometric mean ratio [GMR] for maximum concentration [C max ], 1.15; GMR for area under the time-concentration curve from time 0 to last quantifiable concentration [AUC last ], 1.38). Decreased MMAE exposure above 50% but below 80% was observed with enfortumab vedotin plus rifampin (MMAE GMR C max , 0.72; GMR AUC last , 0.47). No effect of enfortumab vedotin on midazolam or digoxin systemic exposure was predicted. Results suggest that combination enfortumab vedotin, P-gp, and a CYP3A4 inhibitor may result in increased MMAE exposure and patients should be monitored for potential adverse effects. Combination P-gp and a CYP3A4 inducer may result in decreased MMAE exposure. No exposure change is expected for CYP3A4 or P-gp substrates when combined with enfortumab vedotin.ClinicalTrials.gov identifier Not applicable., Competing Interests: Declarations Competing interests Mary P. Choules is an employee of Astellas Pharma, Inc. Peiying Zuo was an employee of Astellas at the time of the analysis; any meeting attendance to support this analysis was paid for by Astellas. They report an unpaid role as Secretary and steering committee member of Mathematical and Computational Sciences (MCS) special interest group in International Society of Pharmacometrics (ISoP). Yukio Otsuka is an employee of Astellas Pharma, Inc. and reports stock or stock options with Astellas Pharma, Inc. Amit Garg is an employee of Seagen, Inc. Mei Tang is an employee of Astellas Pharma, Inc. Peter Bonate is an employee of Astellas Pharma, Inc. Research involving human participants and/or animals This PBPK DDI study utilized data from clinical trials conducted in accordance with the Declaration of Helsinki and International Council for Harmonisation guidelines for good clinical practice. Informed consent This PBPK DDI study utilized data from clinical trials in which written/signed informed consent was obtained from patients before screening., (© 2023. The Author(s).)

Background/objectives: Index substrates are used to understand the processes involved in pharmacokinetic (PK) drug-drug interactions (DDIs). The aim of this analysis is to review metabolite measurement in clinical DDI studies, focusing on index substrates for cytochrome P450 (CYP) enzymes, including CYP1A2 (caffeine), CYP2B6 (bupropion), CYP2C8 (repaglinide), CYP2C9 ((S)-warfarin, flurbiprofen), CYP2C19 (omeprazole), CYP2D6 (desipramine, dextromethorphan, nebivolol), and CYP3A (midazolam, triazolam)., Methods: All data used in this evaluation were obtained from the Certara Drug Interaction Database. Clinical index substrate DDI studies with PK data for at least one metabolite, available from literature and recent new drug application reviews, were reviewed. Further, for positive DDI studies, a correlation analysis was performed between changes in plasma exposure of index substrates and their marker metabolites., Results: A total of 3261 individual index DDI studies were available, with 45% measuring at least one metabolite. The occurrence of metabolite measurement in clinical DDI studies varied widely between index substrates and enzymes., Discussion and Conclusions: For substrates such as caffeine, bupropion, omeprazole, and dextromethorphan, the use of the metabolite/parent area under the curve ratio can provide greater sensitivity to DDI or reduce intrasubject variability. In some cases (e.g., omeprazole, repaglinide), the inclusion of metabolite measurement can provide mechanistic insights to understand complex interactions.

Diarrhea is a common illness for travelers. Traveler's diarrhea is typically defined as experiencing at least three unformed stools per day during a stay abroad or within 10 days of returning from the destination. In this review, we consulted five databases, namely, Medicine Complete, Medscape, Drugs.com, Epocrates, and DDInter, to conduct a comprehensive drug interaction analysis. We selected commonly prescribed medications used for the treatment of traveler's diarrhea, including ciprofloxacin, levofloxacin, norfloxacin, ofloxacin, azithromycin, rifaximin, bismuth salicylate, and loperamide. The antidiabetic medications chosen included metformin, glipizide, glimepiride, sitagliptin, linagliptin, dapagliflozin, empagliflozin, and acarbose. The chosen antihypertensive drugs were telmisartan, olmesartan, amlodipine, nifedipine, enalapril, ramipril, metoprolol, and propranolol. Aspirin, clopidogrel, ticagrelor, rivaroxaban, warfarin, atorvastatin, and rosuvastatin were also chosen as they play an essential role in cardiovascular treatment. We performed comprehensive interaction checks across all five databases for each combination of a traveler's diarrhea medication and medication from one of the three comorbid conditions (antidiabetic, antihypertensive, or cardioprotective). We categorized the severity of interactions as mild, moderate, or severe. Similarly, we used colors to highlight the number of databases reporting drug interactions, providing insights into the reliability of these interactions across sources. Interactions with antidiabetic drugs revealed that fluoroquinolones and sulfonylureas produce severe interaction effects. Comparatively, rifaximin can be safer as it exhibited mild interaction only with metformin, whereas the other antidiabetic drugs showed no interaction effect. Levofloxacin was found to be the safest drug among hypertensive individuals as it exerted no interaction effects with any of the antihypertensive medications. Levofloxacin and rifaximin were considered to be safe as these drugs interacted with only two cardioprotective drugs. This review features the importance of a precise approach in prescribing medications for traveler's diarrhea, especially for patients with chronic comorbidities. These findings play a pivotal role in improving awareness and providing tailored treatment for the interaction to ensure patient well-being., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, B et al.)

The present study evaluated the rational prescription of linezolid, the prevalence of thrombocytopenia, and major drug interactions in patients with cardiovascular diseases. We conducted a retrospective cross-sectional study on linezolid-treated patients at Shahid Chamran Heart Hospital in Isfahan from March 21, 2021, to March 20, 2022. Our research involved 132 patients who received linezolid. We reported 43.18% of linezolid prescriptions as irrational. Linezolid-induced thrombocytopenia is more common than previous studies, with a prevalence of 47.9%. We found a significant relationship between thrombocytopenia and the concomitant use of aspirin. The duration of treatment was identified as predicting factor for linezolid-induced thrombocytopenia. Moreover, the prevalence of interactions in the X and D categories was determined. Serotonergic and catecholamine medications were associated with 56.1% and 47.7% medication interactions, respectively. Our study found a high prevalence of linezolid-induced thrombocytopenia among patients with cardiovascular diseases. Based on this study, physicians should focus more closely on prescribing linezolid to patients with cardiovascular diseases. In addition to following rational antibiotic use, this susceptible group is also at an elevated risk of side effects (thrombocytopenia) and medication interactions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Dianatkhah, Salami, Soltani and Hosseini.)

Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is a refractory chronic respiratory infectious disease and its prevalence is increasing globally. The standard treatment regimen for NTM-PD involves long-term multidrug therapy including macrolides. The incidence of adverse events is high given the advanced age of many NTM-PD patients. In addition, drug-drug interactions under coexisting conditions add additional complexity. Despite guidelines advocating multidrug therapy for NTM-PD, low adherence rates probably owing to the relatively frequent adverse events and drug interactions. An appropriate treatment regimen can improve the bacteriological response rates, reduce the development of macrolide resistance, and mitigate adverse events. Of particular concern are the interactions arising from new complications that develop with NTM-PD. Notably, chronic pulmonary aspergillosis occasionally co-infects NTM-PD, which can lead to poor prognosis. The primary therapeutic modality for chronic pulmonary aspergillosis is the azoles. However, the interaction with rifamycin is problematic, making it challenging to continue standard treatment for NTM-PD and requiring drug adjustments. The implications of rifamycin extend beyond chronic pulmonary aspergillosis, impacting various other diseases such as those requiring immunosuppressive agents and AIDS patients requiring antiretroviral therapy. Hence, a comprehensive consideration of drug interactions is imperative for the initiation of NTM-PD treatment. This mini-review focuses on drug-drug interactions in a multidrug regimen for NTM-PD and discusses the essential points to be considered in the treatment of NTM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Takeda, Takazono and Mukae.)

In the process of the drug development, studies on the cytochrome P450 (CYP) profiles after its administration provided fundamental information regarding drug interactions with concomitantly administered drugs. Here, we evaluated the influence of the administration of H12-(ADP)-liposomes, a platelet substitute, on the mRNA and protein expression, and metabolic activity of CYPs, with focus on the CYP1A2, CYP2C11 and CYP3A2, in rat liver.At 24 h after administering saline or H12-(ADP)-liposomes (10 mg of lipids/kg), a quantitative RT-PCR and western blot analysis revealed that the mRNA and proteins expression of all of the target hepatic CYP isoforms were not different between the saline and H12-(ADP)-liposome groups. Furthermore, an ex vivo CYP metabolic activity assay showed that hepatic CYP metabolic activities in the H12-(ADP)-liposome group were comparable to the corresponding saline group. On the other hand, the area under the blood concentration-time curve for substitutes for CYP1A2 and CYP2C11 was higher in H12-(ADP)-liposome group than in saline group, but the degree of elevations was negligible levels.At a minimum, based on these results, we conclude that H12-(ADP)-liposomes have no quantitative and qualitative effect on the hepatic CYP isoforms, indicating that the drug interactions of H12-(ADP)-liposomes with CYP-metabolizing drugs would be negligible.

Introduction: Lithium is a key medication for treating various neuropsychiatric disorders, with a narrow therapeutic index and significant drug interactions. Monitoring lithium blood levels is crucial. This study aims to investigate the relationship between lithium blood levels and demographic characteristics such as age and gender, as well as possible drug interactions, in patients with a history of lithium use who applied to various services and outpatient clinics., Materials & Methods: The files of 438 patients who were admitted to various services and outpatient clinics of Kırklareli Training and Research Hospital between January 1 and December 31, 2023, were retrospectively reviewed. Patients' blood lithium levels, gender, age, service/outpatient clinic they admitted to, other medications used, urea, creatinine, and eGFR values were recorded., Results: When the demographic characteristics of 438 patients were examined, 62% were female (270), 38% were male (168), and the average age was 46.3 ± 14.8 years, showing a normal distribution. It was found that 192 patients (71 males, 121 females) had therapeutic lithium blood levels, while 244 patients (97 males, 147 females) had levels below 0.6 mmol/L. Two female patients had blood levels above the therapeutic range (1.23 and 1.43 mmol/L). Among the clinics and services, the four most frequented were the psychiatry clinic (314 patients), internal medicine clinic (36 patients), emergency service (27 patients), and medical oncology clinic (17 patients). Of the 314 patients admitted to the psychiatry clinic, 168 had therapeutic drug levels; only 7 of the 36 admitted to internal medicine had therapeutic levels; 12 of the 27 patients in the emergency service had therapeutic levels; and all 17 patients in medical oncology had levels below therapeutic limits., Discussion: The data emphasize the importance of regular blood level monitoring to ensure lithium treatment's efficacy and patient safety. It is noteworthy that most patients in the psychiatry clinic had therapeutic drug levels, while those in other clinics had lower levels., Conclusion: In conclusion, this study highlights the importance of regular blood level monitoring to ensure the efficacy and safety of lithium treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Uskur, Güven and Tat.)

Objective: Pacritinib is a novel kinase inhibitor approved for the treatment of adults with intermediate or high-risk primary or secondary myelofibrosis. Strong and moderate CYP3A4 inhibitors, such as some azole antifungals, are contraindicated or recommended to be avoided in combination with pacritinib, respectively. We aim to report our experience in patients who received pacritinib with concurrent azole antifungal therapy., Data Sources: We queried for patients with hematologic malignancies in the electronic medical record who received concurrent pacritinib and azole antifungal therapy., Data Summary: There were five cases of concurrent pacritinib and azole antifungal therapy in which none of the patients experienced grade 3 or higher non-hematologic toxicities. Some patients required dose modifications and/or interruptions in pacritinib therapy., Conclusion: This is the first clinical experience describing concurrent pacritinib and azole antifungals. Our experience shows that in the setting where this interaction cannot be avoided, concurrent administration is feasible with close monitoring and possible empiric dose reductions in select patients., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ticagrelor is contraindicated in combination with cytochrome P450 3A4 and 3A5 enzyme (CYP3A4/5) inducers due to increased clearance, causing diminished antiplatelet effects. The emergent nature of acute coronary syndromes (ACS) may preclude scrutinization of home medications before P2Y 12 inhibitor administration. The purpose of this case series is to establish the temporal impact of CYP3A4/5 enzyme induction on ticagrelor's pharmacodynamic effect by utilizing VerifyNow platelet aggregation studies. This was a retrospective case series of three patients who were taking a CYP3A4/5-inducing medication and loaded with ticagrelor for ACS. The duration of ticagrelor's antiplatelet effect was dramatically shortened in the presence of background CYP3A4/5 induction. The offset of antiplatelet effect, defined by platelet reactivity units (PRU), was 10-24 hours in the presence of CYP3A4/5 enzyme induction compared to the anticipated 36-48 hours. This was consistent across CYP3A4/5-inducing medications including carbamazepine, phenobarbital, and phenytoin. This study demonstrates rapid return of platelet function after a ticagrelor loading dose in the presence of CYP3A4/5-inducing medications. Monitoring of PRU every 6-12 hours with subsequent loading with clopidogrel or prasugrel should be considered. Larger scale studies are warranted to confirm these results., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The growing co-consumption of botanical natural products with conventional medications has intensified the need to understand potential effects on drug safety and efficacy. This review delves into the intricacies of intestinal pharmacokinetic interactions between botanical natural products and drugs, such as alterations in drug solubility, permeability, transporter activity, and enzyme-mediated metabolism. It emphasizes the importance of understanding how drug solubility, dissolution, and osmolality interplay with botanical constituents in the gastrointestinal tract, potentially altering drug absorption and systemic exposure. Unlike reviews that focus primarily on enzyme and transporter mechanisms, this article highlights the lesser known but equally important mechanisms of interaction. Applying the Biopharmaceutics Drug Disposition Classification System (BDDCS) can serve as a framework for predicting and understanding these interactions. Through a comprehensive examination of specific botanical natural products such as byakkokaninjinto, green tea catechins, goldenseal, spinach extract, and quercetin, we illustrate the diversity of these interactions and their dependence on the physicochemical properties of the drug and the botanical constituents involved. This understanding is vital for healthcare professionals to effectively anticipate and manage potential natural product-drug interactions, ensuring optimal patient therapeutic outcomes. By exploring these emerging mechanisms, we aim to broaden the scope of natural product-drug interaction research and encourage comprehensive studies to better elucidate complex mechanisms.

Background: This study evaluated the pharmacokinetic interactions of orally administered chloroquine and metoclopramide., Methods: The study employed a randomized and two-phase cross-over design with 4-week washout plan. Twelve healthy male volunteers were shortlisted according to the set criteria and were administered with metoclopramide 10 mg PO and chloroquine (a total of 1500 mg) at different intervals which were (500 mg at 0, 6, and 24 h). The concentration of chloroquine and metoclopramide in the blood samples was estimated using a validated HPLC-UV technique to affirm the maximum concentration (C max ), time to reach C max (T max ), and area under the curve (AUC)., Results: C max , T 1/2 , and AUC of metoclopramide were increased up to 20, 10, and 47.8%, respectively, by the concomitantly administering Chloroquine. Chloroquine-treated phase showed increased values of Cmax (ng/ml), AUC (ng.h/ml), and T ½ (h), i.e. 41.35 ± 1.61, 504.12 ± 66.25, and 5.72 ± 2.63, as compared to that reference phase i.e. 34.52 ± 4.92, 341.14 ± 112.8, and 5.19 ± 1.14, respectively., Conclusions: Chloroquine was found to attenuate CYP2D6 activity in healthy Pakistani male volunteers. Hence, patients that are prescribed with metoclopramide or other CYP2D6-substrate drugs require a dose adjustment when administered with chloroquine.

Background: Levonorgestrel implant is a highly effective hormonal contraceptive, but its efficacy may be compromised when used with cytochrome enzyme inducers such as efavirenz. The primary aim of this study was to evaluate methods of mitigating the drug interaction. Methods: Using a physiologically-based pharmacokinetic (PBPK) model for levonorgestrel that we developed within the Simcyp ® program, we evaluated a higher dose of levonorgestrel implant, a lower dose of efavirenz, and the combination of both, as possible methods to mitigate the interaction. In addition, we investigated the impact on levonorgestrel total and unbound concentrations of other events likely to be associated with efavirenz coadministration: changes in plasma protein binding of levonorgestrel (as with displacement) and high variability of efavirenz exposure (as with genetic polymorphism of its metabolism). The range of fraction unbound tested was 0.6% to 2.6%, and the range of efavirenz exposure ranged from the equivalent of 200 mg to 4800 mg doses. Results: Levonorgestrel plasma concentrations at any given time with a standard 150 mg implant dose are predicted to be approximately 68% of those of control when given with efavirenz 600 mg and 72% of control with efavirenz 400 mg. With double-dose levonorgestrel, the predictions are 136% and 145% of control, respectively. A decrease in levonorgestrel plasma protein binding is predicted to primarily decrease total levonorgestrel plasma concentrations, whereas higher efavirenz exposure is predicted to decrease total and unbound concentrations. Conclusions: Simulations suggest that doubling the dose of levonorgestrel, particularly in combination with 400 mg daily efavirenz, may mitigate the drug interaction. Changes in levonorgestrel plasma protein binding and efavirenz genetic polymorphism may help explain differences between model predictions and clinical data but need to be studied further.

Background: Despite evidence demonstrating the effectiveness of aprepitant for chemotherapy-induced nausea and vomiting (CINV), its use in stem cell transplant settings across Canada is not standard. While pharmacokinetic data exists, the clinical significance of cytochrome P450 3A4 (CYP 3A4) inhibition of cyclophosphamide by aprepitant is unclear. Reduced activation of cyclophosphamide may reduce the effectiveness of dose-intensive cyclophosphamide, etoposide, and cisplatin (DICEP)., Objectives: To compare response rates to DICEP in patients with Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma (DLBCL) in the presence and absence of aprepitant., Methods: A retrospective review of patients who received full-dose DICEP for relapsed/refractory HL or DLBCL between June 1995 and September 2018 at the Foothills Medical Centre (FMC) in Calgary, Alberta, Canada was conducted. Descriptive statistics were used to assess response rate, as defined by the 2007 International Working Group response criteria., Results: Of the 218 patients included in this study, 87.6% of patients in the control group and 88.5% of patients in the aprepitant group responded to DICEP (difference 0.025 [95% CI, -0.066 to 0.114], p = 0.827). Univariate analyses for age, sex, type of cancer, stage of cancer, number of prior relapses, and relapse status were not significant. No significant differences were observed for secondary outcomes., Conclusion: Response rates to DICEP in relapsed/refractory HL and DLBCL patients were similar regardless of aprepitant use. Considering these results and the effectiveness of aprepitant in CINV, its addition to standard antiemetic therapy in patients receiving DICEP should be given strong consideration in the transplant setting., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: This study aimed to examine the prognostic impact of concomitant pH-regulating drug use in patients with epidermal growth factor receptor (EGFR)-mutation-positive non-small-cell lung cancer (NSCLC) receiving EGFR-tyrosine kinase inhibitors (TKIs)., Methods: We conducted a nationwide retrospective cohort study and reviewed clinical data of consecutive patients with NSCLC treated with the first-line EGFR-TKIs in 46 hospitals between April 2010 and March 2020. Cox regression analyses were conducted to examine the differences in overall survival (OS) between patients treated with and without concomitant pH-regulating drugs, including potassium-competitive acid blockers (P-CABs), proton pump inhibitors (PPIs), and H 2 -receptor antagonists (H 2 RAs)., Results: A total of 758 patients were included in the final dataset, of which 307 (40%) were administered concomitant pH-regulating drugs while receiving frontline EGFR-TKIs. After adjusting for basic patient characteristics, patients administered gefitinib, erlotinib, afatinib, and osimertinib with concomitant pH-regulating drugs had lower OS than those without concomitant pH-regulating drugs, with hazard ratios of 1.74 (with a 95% confidence interval of 1.34-2.27), 1.33 (0.80-2.22), 1.73 (0.89-3.36), and 5.04 (1.38-18.44), respectively. The 2-year OS rates of patients receiving gefitinib with or without concomitant pH-regulating drugs were 65.4 and 77.5%, those for erlotinib were 55.8 and 66.6%, and those for afatinib were 63.2 and 76.9%, respectively. The 1-year OS rates of patients receiving osimertinib with or without concomitant pH-regulating drugs were 88.1% and 96.9%, respectively., Conclusion: In addition to the first-generation EGFR-TKIs, the second- and third-generation EGFR-TKIs also resulted in OS deterioration in patients with EGFR mutation-positive NSCLC when used concurrently with pH-regulating drugs., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Aspirin and anti-P2Y12 are widely prescribed in cardiovascular patients, often in combination with proton pump inhibitors (PPIs) to limit the risk of upper gastrointestinal bleedings. The potential interaction between PPIs and antiplatelet agents has been widely discussed, but doubts remain as to whether PPIs may reduce the cardiovascular protection provided by aspirin, prasugrel, ticagrelor, and clopidogrel., Areas Covered: Many pharmacokinetic (PK) and pharmacodynamic (PD) studies have confirmed the interaction, especially between PPIs and clopidogrel, but with uncertain consequences on clinical outcomes. Therefore, we aimed to summarize the evidence for the widespread combined use of oral antiplatelet drugs and PPIs, to outline the current evidence supporting or opposing drug-drug interaction, and to discuss the clinical implications of such interactions., Expert Opinion: A large body of evidence describes the PK/PD interaction of antiplatelet drugs with PPIs and its potential role in increasing clinical cardiovascular adverse events, but no solid clinical data have confirmed these effects. In the light of the published studies, there seems to be no restriction on the choice of PPI with aspirin, prasugrel, and/or ticagrelor. The choice of a PPI with no (or minimal) interference with the hepatic cytochrome P450 2C19 is preferred in patients receiving clopidogrel.

Cytochrome P450 3A4 (CYP3A4) is a crucial enzyme in the metabolism of xenobiotics, particularly in drug metabolism interactions (DDIs), making it a significant factor in clinical drug use. However, current assay techniques are both laborious and costly, making it difficult to construct a high-throughput monitoring method that can be used in conjunction with the clinic. This poses certain safety hazards for drug combination. Therefore, it is crucial to develop a synchronized monitoring method for the inhibition and induction of CYP3A4. In this study, we utilized 3D culture technology to develop a HepaRG cells spheroid model. The CYP450 and transporter expression, the albumin secretion, and urea synthesis capacity characteristics were analyzed. The NEN probe was utilized as a tracer molecule for CYP3A4. The fluorescence intensity of metabolites was characterized by laser confocal technique to determine the inhibition and expression of CYP3A4 in the HepaRG cell spheroid model by the antibiotics for sepsis. The results indicate that the HepaRG sphere model successfully possessed the physiological phenotype of the liver, which could be used for drug interaction monitoring. Through positive drug testing, NEN probe was able to achieve bidirectional characterization of CYP3A4 induction and inhibition. The monitoring method described in this paper was successfully applied to drug interaction monitoring of commonly used antibiotics in sepsis patients, which is a convenient and rapid monitoring method. The proposed method offers a new strategy for monitoring CYP3A4-mediated drug-drug interactions with a high-throughput assay, which will help to improve the safety of clinical drug combination., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Purpose: Clozapine is the effective therapy for treatment-refractory schizophrenia. However, the use of clozapine is limited by its adverse effects. As propranolol is frequently used for the prevention and treatment of clozapine-induced tachycardia, we performed a meta-analysis to evaluate the effects of propranolol on steady state pharmacokinetics of clozapine in schizophrenic patients., Methods: We included 16 retrospective studies on the effects of propranolol on steady state pharmacokinetics of clozapine in schizophrenic patients, with data from both generic and brand name treatment phases in eight clozapine bioequivalence studies conducted in a single center in China from 2018 to 2022. Review Manager 5.4 was used for meta-analysis of the included studies., Results: The SMDs with 95% CIs of AUC 0-12 , C max,ss , C, and C were calculated to be 0.44 (0.23, 0.64), 0.40 (0.20, 0.61), 0.43 (0.22, 0.63), and 0.44 (0.23, 0.64), respectively. These findings proved that combination with propranolol would increase the systemic exposure of clozapine. T 1/2 of clozapine was significantly longer in the presence of propranolol than in the absence of propranolol (SMD = 0.32, 95% CI [0.12, 0.52], p = 0.002). There was no statistically significant difference for T of clozapine in the presence or absence of propranolol (SMD =  - 0.05, 95% CI [- 0.25, 0.15], p = 0.63)., Conclusion: The combination with propranolol could significantly increase systemic exposure and extended T 1/2 of clozapine, and thus need to be considered in prescribing decisions., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

To elucidate the impact of CYP3A4 activity inhibition and genetic polymorphism on the metabolism of crizotinib. Enzymatic incubation systems for crizotinib were established, and Sprague-Dawley rats were utilized for in vivo experiments. Analytes were quantified using LC-MS/MS. Upon screening 122 drugs and natural compounds, proanthocyanidins emerged as inhibitor of crizotinib metabolism, exhibiting a relative inhibition rate of 93.7%. The IC 50 values were 24.53 ± 0.32 μM in rat liver microsomes and 18.24 ± 0.12 μM in human liver microsomes. In vivo studies revealed that proanthocyanidins markedly affected the pharmacokinetic parameters of crizotinib. Co-administration led to a significant reduction in the AUC (0-t) , C max of PF-06260182 (the primary metabolite of crizotinib), and the urinary metabolic ratio. This interaction is attributed to the mixed-type inhibition of liver microsome activity by proanthocyanidins. CYP3A4, being the principal metabolic enzyme for crizotinib, has its genetic polymorphisms significantly influencing crizotinib's pharmacokinetics. Kinetic data showed that the relative metabolic rates of crizotinib across 26 CYP3A4 variants ranged from 13.14% (CYP3A4.12, 13) to 188.57% (CYP3A4.33) when compared to the wild-type CYP3A4.1. Additionally, the inhibitory effects of proanthocyanidins varied between CYP3A4.12 and CYP3A4.33, when compared to the wild type. Our findings indicate that proanthocyanidins coadministration and CYP3A4 genetic polymorphism can significantly influence crizotinib metabolism., Competing Interests: Declaration of competing interest The authors declare that no conflict of interest need to be stated., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The clinical management of malignant tumours is challenging, often leading to severe adverse effects and death. Drug resistance (DR) antagonises the effectiveness of treatments, and increasing drug dosage can worsen the therapeutic index (TI). Current efforts to overcome DR predominantly involve the use of drug combinations, including applying multiple anti-cancerous drugs, employing drug sensitisers, which are chemical agents that enhance pharmacokinetics (PK), including the targeting of cellular pathways and regulating pertinent membrane transporters. While combining multiple compounds may lead to drug-drug interactions (DDI) or polypharmacy effect, the use of drug sensitisers permits rapid attainment of effective treatment dosages at the disease site to prevent early DR and minimise side effects and will reduce the chance of DDI as lower drug doses are required. This review highlights the essential use of TI in evaluating drug dosage for cancer treatment and discusses the lack of a unified standard for TI within the field. Commonly used benefit-risk assessment criteria are summarised, and the critical exploration of the current use of TI in the pharmaceutical industrial sector is included. Specifically, this review leads to the discussion of drug sensitisers to facilitate improved ratios of effective dose to toxic dose directly in humans. The combination of drug and sensitiser molecules might see additional benefits to rekindle those drugs that failed late-stage clinical trials by the removal of detrimental off-target activities through the use of lower drug doses. Drug combinations and employing drug sensitisers are potential means to combat DR. The evolution of drug combinations and polypharmacy on TI are reviewed. Notably, the novel binary weapon approach is introduced as a new opportunity to improve TI. This review emphasises the urgent need for a criterion to systematically evaluate drug safety and efficiency for practical implementation in the field.

Background: Statins are widely used in cardiovascular disease (CVD) as a common lipid-lowering drug, while quinolones are widely used for the treatment of infectious diseases. It is common to see CVD in combination with infectious diseases, therefore it is often the case that statins and quinolones are used in combination. Data suggest combinations of statin and quinolone may be associated with potentially life-threatening myopathy, rhabdomyolysis and acute hepatitis. This systematic review aims to characterize data regarding patients affected by the statin-quinolone interaction., Methods: The purpose of this systematic review was to collect and evaluate the evidence surrounding statin-quinolone drug interactions and to discuss related risk mitigation strategies. The following databases were searched: PubMed (Medline), Embase, Scopus, and Cochrane Library. The systematic electronic literature search was conducted with the following search terms. In this study, three types of search terms were used: statins-related terms, quinolones-related terms, and drug interactions-related terms., Results: There were 16 case reports that met the criteria for qualitative analysis. Patients were involved in the following adverse reactions: rhabdomyolysis (n = 12), acute hepatitis (n = 1), muscle weakness (n = 1), hip tendinopathy (n = 1), or myopathy (n = 1). In the included literature, patients vary in the dose and type of statins they take, including simvastatin (n = 10) at a dose range of 20-80 mg/d and atorvastatin (n = 4) at a dose of 80 mg/d. There were 2 patients with unspecified statin doses, separately using simvastatin and atorvastatin. The quinolones in combination were ciprofloxacin (n = 9) at a dose range of 800-1500 mg/d, levofloxacin (n = 6) at a dose range of 250-1000 mg/d, and norfloxacin (n = 1) in an unspecified dose range. 81% of the case patients were over 60 years of age, and about 1/3 had kidney-related diseases such as diabetic nephropathy, post-transplantation, and severe glomerulonephritis. Nearly two-third of the patients were on concomitant cytochrome P450 3A4 (CYP3A4) inhibitors, P-glycoprotein (P-gp) inhibitors, or organic anion transporting polypeptide 1B1 (OATP1B1) inhibitors., Conclusion: Patients treated with statin-quinolone combination should be monitored more closely for changes in aspartate aminotransferase or creatine kinase (CK) levels, and muscle symptoms, especially in patients with ciprofloxacin or levofloxacin, with simvastatin and high-dose atorvastatin, over 60 years of age, with kidney-related diseases, and on concomitant CYP3A4 inhibitors., (© 2024. The Author(s).)

Sotorasib is a small molecule that irreversibly inhibits the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein with a G12C amino acid substitution mutant protein. The impact of cytochrome P450 (CYP) 3A4 inhibition and induction on sotorasib pharmacokinetics (PKs) was evaluated in 2 separate studies in healthy volunteers (N = 14/study). The impact of CYP3A4 inhibition was interrogated utilizing repeat doses of 200 mg of itraconazole, a strong CYP3A4 inhibitor, on 360 mg of sotorasib PKs. The impact of CYP3A4 induction was interrogated utilizing multiple doses of 600 mg of rifampin, a strong CYP3A4 inducer. Additionally, the impact of organic anion transporting polypeptide (OATP) 1B1/3 inhibition on 960 mg of sotorasib PKs was interrogated after a single dose of 600 mg of rifampin. CYP3A4 inhibition did not significantly impact sotorasib C max but did lead to a 26% increase in sotorasib AUC inf . CYP3A4 induction decreased sotorasib C max by 35% and AUC inf by 51%. OATP1B1/3 inhibition decreased sotorasib C max and AUC inf by 16% and 23%, respectively. These results support that sotorasib can be given together with strong CYP3A4 and OATP1B1/3 inhibitors but the co-administration of sotorasib and strong CYP3A4 inducers should be avoided., (© 2024, The American College of Clinical Pharmacology.)

Drug-drug interaction (DDI) trials are an important part of drug development as they provide evidence on the benefits and risks when two or more drugs are taken concomitantly. Sample size calculation is typically recommended to be based on the existence of clinically justified no-effect boundaries but these are challenging to define in practice, while the default no-effect boundaries of 0.8-1.25 are known to be overly conservative requiring a large sample size. In addition, no-effect boundaries are of little use when there is prior pharmacological evidence that a mild or moderate interaction between two drugs may be present, in which case effect boundaries would be more useful. We introduce precision-based sample size calculation that accounts for both the stochastic nature of the pharmacokinetic parameters and the anticipated width of (no-)effect boundaries, should these exist. The methodology is straightforward, requires considerably less sample size and has favorable operating characteristics. A case study on statins is presented to illustrate the ideas., (© 2024 John Wiley & Sons Ltd.)

Background: Factors affecting serum concentrations of levetiracetam in dogs are unknown and could affect the efficacy of levetiracetam in controlling seizures in dogs with epilepsy., Hypothesis/objectives: Higher PO doses of levetiracetam will be needed in dogs to achieve serum concentrations shown to be effective in humans. Determine factors that could influence serum levetiracetam concentrations and justify dose adjustment in some epileptic dogs., Animals: Sixty-nine client-owned dogs with epilepsy treated with levetiracetam alone or in combination, based on 127 trough serum concentration measurements of levetiracetam., Methods: Retrospective cohort study. Linear mixed models were used to assess the effect of patient signalment and concurrent drug administration on serum concentrations of levetiracetam and the effect of serum concentration of levetiracetam on seizure frequency reduction., Results: The PO dose of levetiracetam significantly explained changes in serum levetiracetam concentration, and this causal link was stronger with monotherapy (R 2  = 0.59, P < .001). Phenobarbital significantly decreased serum levetiracetam concentration in a dose dependent manner (R 2  = 0.30, P = .003). Based on our model, a levetiracetam dosage of 99-216 mg/kg/day is necessary to obtain a serum levetiracetam concentration of 20 μg/mL when used alone or concurrently with 7 mg/kg/day of phenobarbital. No other factors were found to influence serum levetiracetam concentrations. No therapeutic range could be identified., Conclusion and Clinical Importance: Our data suggest that a dosage of 99-216 mg/kg/day of levetiracetam is needed to achieve a serum concentration known to be therapeutically effective in humans, especially when administered concomitantly with phenobarbital., (© 2024 The Author(s). Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

This study aimed to provide an understanding of the influence of eugenol on CYP1A2, 2C9, 2D6, and 3A4 in human liver microsomes (HLM). Specific substrate for CYP1A2, 2C9, 2D6, and 3A4 were incubated in HLM with or without eugenol. The formation of their respective metabolites was assessed with HPLC analytical methods. Eugenol at 1, 10 and 100 µM levels inhibited the activity of CYP1A2 and CYP2C9 by 23.38 %, 23.57 %, 39.80 % and 62.82 %, 63.27 %, 67.70 % respectively. While, CYP2D6 and CYP3A4 activity was decreased by 40.70 %, 45.88 %, 62.68 % and 37.41 %, 42.58 % and 67.86 % at 1, 10 and 100 µM eugenol level respectively. The IC 50 value of eugenol for CYP2D6 and CYP3A4 was calculated as 11.09 ± 3.49 µM and 13.48 ± 3.86 µM respectively. Potential herb-drug interactions was noted when eugenol is administered simultaneously with medications metabolized by these enzymes, most notably CYP2C9, CYP2D6 and CYP3A4., Competing Interests: “The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper”., (© 2024 The Authors.)

Background and Purpose: Cotrimoxazole, a commonly prescribed antibiotic, has substantial resistance, especially in Indonesia, with its uropathogenic resistance reaching 67% in 2017. Although cotrimoxazole has been suggested to be co-administered with lactoferrin to enhance its antibacterial effectiveness and this practice has been widely adopted since the Covid-19 pandemic, the impact of lactoferrin on the pharmacokinetics of cotrimoxazole remains relatively unknown. This study aims to conduct a preliminary clinical investigation into the impact of lactoferrin supplementation on the pharmacokinetics of cotrimoxazole, focusing on the elimination rate and excretion of unchanged drug in urine., Experimental Approach: This study employed a blinded, cross-over, single-dose pharmacokinetics investigation, which included five healthy volunteers as participants. In the initial period, the first group received cotrimoxazole (80 mg trimethoprim and 400 mg sulfamethoxazole) along with a lactoferrin-containing supplement, while the second group only received cotrimoxazole. Subsequently, after a washout period, the conditions were reversed. Urine sampling was conducted at intervals from 0 to 24 hours post-medication, and drug levels in the urine were determined using high-performance liquid chromatography., Key Results: The population-based pharmacokinetic analysis revealed that the optimal model was the one-compartment model with first-order elimination and proportional residual error., Conclusion: The findings show that the administration of lactoferrin-containing supplements did not significantly influence the covariate model and, therefore, did not alter the pharmacokinetics parameter of cotrimoxazole in urine with a single administration, implying that lactoferrin did not cause drug interaction problems when given simultaneously., Competing Interests: Conflict of interest: All authors declare that there are no conflicts of interest in the writing of this article., (Copyright © 2024 by the authors.)

Background: Voriconazole is primarily metabolized by CYP2C19 and CYP3A4. Drug interactions that affect this pathway can alter its plasma exposures, resulting in untargeted voriconazole concentrations., Case Summary: In this case report, we describe the case of a 64-year-old man who was treated for non-Hodgkin's lymphoma with continuous glucocorticoids co-administrated with voriconazole against invasive pulmonary aspergillosis. A decrease in trough concentration (C min ) of voriconazole was observed and related with co-administration of dexamethasone in the patient carrying the CYP2C19 *1*2 genotype: voriconazole C min /dose ratios of 0.018 (0.1 mg L -1 /5.7 mg kg -1  day -1 ), 0.18 (1 mg L -1 /5.7 mg kg -1  day -1 ), and 0.23 (2 mg L -1 /8.6 mg kg -1  day -1 ) at dexamethasone doses of 20, 12.5, and 2.5 mg, respectively. Sub-therapeutic voriconazole C min was associated with high- and moderate-dose dexamethasone (20 and 12.5 mg), leading to failure of antifungal treatment., Conclusion: The extent of voriconazole-dexamethasone interaction was determined by the dose of dexamethasone and associated with the CYP2C19 *1*2 genotype. Therapeutic drug monitoring of voriconazole is necessary to avoid clinically relevant interactions for optimal antifungal therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Huang, Chen, Zhong and Tan.)

Purpose: Nirmatrelvir/ritonavir is one of few options for outpatient treatment of COVID-19, but its use has been limited in transplant recipients due to significant drug interactions with immunosuppressants. Tacrolimus toxicity is possible when the drug is coadministered with nirmatrelvir/ritonavir and may require urgent reduction of tacrolimus levels. This case series describes the use of phenytoin for enzyme induction in 5 adult solid organ transplant recipients with supratherapeutic tacrolimus levels resulting from coadministration with nirmatrelvir/ritonavir., Summary: Solid organ transplant recipients are at high risk for complications related to COVID-19. Outpatient treatment options are limited, and therapeutic drug monitoring is complex in patients requiring quarantine. The 5 solid organ transplant recipients described herein were initiated on nirmatrelvir/ritonavir in the outpatient setting and subsequently presented with supratherapeutic tacrolimus concentrations greater than 59 ng/mL and developed signs and symptoms of tacrolimus toxicity. In all patients, nirmatrelvir/ritonavir and tacrolimus were discontinued, and oral phenytoin (200-400 mg/day) was given for 2 to 4 days. Tacrolimus was resumed once tacrolimus levels decreased to appropriate levels., Conclusion: These observations demonstrate that metabolism induction using phenytoin may be a useful strategy in the setting of supratherapeutic tacrolimus levels resulting from concomitant administration with nirmatrelvir/ritonavir., (© American Society of Health-System Pharmacists 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Although nirmatrelvir/ritonavir (NMV/r) reportedly increases blood levels of tacrolimus (TAC) due to CYP3A4 inhibition and other factors, reports on the use of NMV/r in combination with tacrolimus hydrate extended-release capsules (TAC-ER) in lung transplant patients are limited. Herein, we present a case with post-lung transplantation of elevated blood trough levels of TAC after concomitant use of NMV/r. A woman in her 60s had undergone lung transplantation. She had coronavirus disease 2019 (COVID-19) and was co-administered NMV/r and TAC-ER, with the trough level controlled at approximately 4 μg/mL. Upon the co-administration of NMV/r and TAC-ER, the patient developed diarrhea and vomiting and was hospitalized. TAC-ER was discontinued on day 6, and TAC level was measured on day 8 and had risen above 100 ng/mL. This level gradually decreased to 17.8 ng/mL on day 11 and 2.4 ng/mL on day 15; therefore, TAC-ER was resumed at 2.5 mg/day. On day 18, the TAC level was 5.2 ng/mL, which was within the target range, and the patient was discharged on day 19. This is the first report of a post-lung transplant patient co-administered TAC-ER with NMV/r, who showed abnormally high blood TAC levels above the detection limit. In patients using TAC-ER after lung transplantation, it may be useful to confirm that the TAC blood level is below the effective therapeutic range before resuming TAC-ER safely., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Yoshida et al.)

The article has been withdrawn at the request of the author and the editor of the journal Current Drug Metabolism., Bentham Science apologizes to the readers of the journal for any inconvenience this may have caused., The Bentham editorial policy on article withdrawal can be found at https://benthamscience.com/editorial-policiesmain.php, Bentham Science Disclaimer: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication, the authors agree that the publishers have the legal right to take appropriate action against the authors if plagiarism or fabricated information is discovered. By submitting a manuscript, the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Dose selection for investigations of intrinsic and extrinsic factors of pharmacokinetic variability as well as safety is a challenging question in the early clinical stage of drug development. The dose of an investigational product is chosen considering the compound information available to date, feasibility of the assessments, regulatory requirements, and the intent to maximize information for later regulatory submission. This review selected 37 programs as case examples of recently approved drugs to explore the doses selected with focus on studies of drug interaction, renal and hepatic impairment, food effect and concentration-QTc assessment.The review found that regulatory agencies may consider alternative approaches if justified and safe as illustrated in these examples. It is thus recommendable to use the first in human trial as an opportunity to assess QT-prolongation and drug interactions using probes or endogenous markers while maximizing the DDI potential, increasing sensitivity and ensuring safety. Early understanding of dose proportionality assists dose finding and simple and fast to conduct DDI study designs are advantageous. Single dose impairment studies despite non-proportional/time-dependent PK are often acceptability.Overall, the early understanding of the drug's safety profile is essential to ensure the safety of doses selected while preventing clinical trials with unnecessary exposure when using high doses or multiple doses. The information collected in this retrospective survey is a good reminder to tailor the early clinical program to the profile and needs of the molecule and consider regulatory opportunities to streamline the development path., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Purpose: Oral anticoagulants (OACs) and aspirin can trigger bleeding events when used alone or in combination. The purpose of this study was to compare the risk of any type of bleeding in individuals exposed to a combination of OAC and aspirin with the risk in those taking an OAC or aspirin alone., Methods: MEDLINE and Web of Science were queried in January 2021 for eligible articles. Studies were included if they were either randomized controlled trials (RCTs) or observational studies and evaluated the number of any bleeding events in two groups, one with exposure to both OAC and aspirin and one with exposure to OAC alone or aspirin alone. Pooled odds ratios were calculated using a random-effects model., Results: Forty-two studies were included. In an analysis of 15 RCTs and 19 observational studies evaluating OAC plus aspirin versus OAC alone, a significant difference in the risk of bleeding was observed in the combination groups, with an odds ratio [OR] of, 1.36 (95% CI, 1.15-1.59) for RCTs and an OR of 1.42 (95% CI-, 1.09-1.87) for observational studies. When OAC plus aspirin was compared to aspirin alone, a higher rate of bleeding was found in the combination group (OR, 2.36; 95%CI, 1.91-2.92) in the analysis of 15 RCTs, but no significant difference was found among 10 observational studies (OR, 1.93; 95% Cl, 0.99-3.75)., Conclusion: The risk of any type of bleeding was significantly increased among patients taking aspirin plus OAC compared to those taking OAC alone in both RCTs and observational studies. Evaluation of RCTs comparing OAC plus aspirin to aspirin alone suggests increased bleeding risk as well., (© American Society of Health-System Pharmacists 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Polypharmacy is common in older adults with psychiatric disorders, but no consensus has reached about the reliable indicators evaluating the benefits and risks of drug-drug interactions (DDIs) in polypharmacy. We aimed to identify indicators suitable for evaluating the clinical significance of DDIs in polypharmacy in older adults with psychiatric disorders., Methods: The online tools were used to distribute and collect the questionnaires. The Delphi method was applied to analyze experts' opinions. The degree of authority and coordination of experts were analyzed using the coefficient of variation, coefficient of coordination, expert's judgment factor, familiarity with the study content factor, and Kendall coordination coefficient. Statistical analysis was conducted using the IBM SPSS® Statistics Package version 26.0., Results: After three rounds of expert consultation, five primary and eleven secondary indicators were identified. The primary "pharmacodynamic indicator" included "severity of adverse drug reactions", "duration of adverse drug reaction", "symptom relief", "time to onset of symptomatic relief", "number of days in hospital", and "duration of medication". The secondary "pharmacokinetic indicator" contained "dosage administered" and "dosing intervals". The primary "patient tolerance indicator" contained one secondary indicator of "patient tolerability". The primary indicator "patient adherence" contained one secondary indicator of "patient adherence to medication". The primary indicator "cost of drug combination" contained one secondary indicator of "readmission". These indicators were used to determine the clinical significance of DDIs during polypharmacy., Conclusions: The clinical significance of drug combinations should be taken into account when polypharmacy is used in the elderly. The five primary indicators and eleven secondary indicators might be preferred to evaluate their risks and benefits. Medication management in this population requires a multidisciplinary team, in which nurses play a key role. Future research should focus on how to establish efficient multidisciplinary team workflows and use functional factors to assess DDIs in polypharmacy for psychiatric disorders., (© 2024. The Author(s).)

The permeation of small molecules across biological membranes is a crucial process that lies at the heart of life. Permeation is involved not only in the maintenance of homeostasis at the cell level but also in the absorption and biodistribution of pharmacologically active substances throughout the human body. Membranes are formed by phospholipid bilayers that represent an energy barrier for permeating molecules. Crossing this energy barrier is assumed to be a singular event, and permeation has traditionally been described as a first-order kinetic process, proportional only to the concentration gradient of the permeating substance. For a given membrane composition, permeability was believed to be a unique property dependent only on the permeating molecule itself. We provide experimental evidence that this long-held view might not be entirely correct. Liposomes were used in copermeation experiments with a fluorescent probe, where simultaneous permeation of two substances occurred over a single phospholipid bilayer. Using an assay of six commonly prescribed drugs, we have found that the presence of a copermeant can either enhance or suppress the permeation rate of the probe molecule, often more than 2-fold in each direction. This can have significant consequences for the pharmacokinetics and bioavailability of commonly prescribed drugs when used in combination and provide new insight into so-far unexplained drug-drug interactions as well as changing the perspective on how new drug candidates are evaluated and tested.

Background: Up to 1/2 of outpatients prescribed clozapine may be partially/fully non-adherent, based on therapeutic drug monitoring (TDM). Three indices for measuring partial/full non-adherence are proposed a: 1) clozapine concentration/dose (C/D) ratio which drops to half or more of what is expected in the patient; 2) clozapine/norclozapine ratio that becomes inverted; and 3) clozapine concentration that becomes non-detectable., Methods: These 3 proposed indices are based on a literature review and 17 cases of possible non-adherence from 3 samples: 1) an inpatient study in a Chinese hospital, 2) an inpatient randomized clinical trial in a United States hospital, and 3) and a Uruguayan outpatient study., Results: The first index of non-adherence is a clozapine C/D ratio which is less than half the ratio corresponding to the patient's specific ancestry group and sex-smoking subgroup. Knowing the minimum therapeutic dose of the patient based on repeated TDM makes it much easier to establish non-adherence. The second index is inverted clozapine/norclozapine ratios in the absence of alternative explanations. The third index is undetectable concentrations. By using half-lives, the chronology of the 3 indices of non-adherence was modeled in two patients: 1) the clozapine C/D ratio dropped to ≥1/2 of what is expected from the patient (around day 2); 2) the clozapine/norclozapine ratio became inverted (around day 3); and 3) the clozapine concentration became undetectable by the laboratory (around days 9-11)., Conclusion: Prospective studies should further explore these proposed clozapine indices in average patients, poor metabolizers (3 presented) and ultrarapid metabolizers (2 presented)., Competing Interests: Declaration of competing interest GS has received speaker/consultation fees from HLS Therapeutics and Thermo Fisher. AEAY has received speaker/advisory board fees from Janssen, Abdi İbrahim Otsuka and Nobel, and has received investigator fees from Janssen. CBE received honoraria for conferences from Forum pour la formation médicale, Janssen-Cilag, Lundbeck, Otsuka, Sandoz, Servier, Sunovion, Sysmex Suisse AG, Takeda, Vifor-Pharma, and Zeller in the past 3 years. SRC received speaker/consultation fees from: Janssen-Cilag, Lundbeck, Otsuka and Servier and research funding from Janssen-Cilag, Lundbeck, Otsuka and Gilead. SHK has received research grants from Janssen and Dongwha. JGL has consulted/spoken on behalf of Saladax Biomedical. RMP has received speaker/consultation fees from Eisai, HLS Therapeutics, Jansen, Lundbeck, and Otsuka. HT has received grants from Daiichi Sankyo and Novartis Pharma; speaker's fees from EA. Pharma, Eisai, Kyowa, Janssen, Lundbeck, Meiji Seika Pharma, MSD, Otsuka, Sumitomo Pharma, Takeda, and Yoshitomiyakuhin; and consulting fees from Janssen, Mitsubishi Tanabe Pharma, Ono, and Sumitomo Pharma. CUC has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Denovo, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, LB Pharma and Quantic. In the last 3 years, the remaining authors report no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Adverse events related to drug therapy are a major cause of iatrogenicity. They are responsible of increased morbidity, leading to hospitalization, sometimes in emergency, and mortality, not only in ambulatory care but also during hospitalization itself. Causes are multiple : among them, confusion leading to an erroneous drug administration, mistakes regarding dosage, risks associated to self-medication, drug-drug interactions or even food-drug interactions. Elderly population is exposed to an increased incidence of drug iatrogenicity because older patients cumulate numerous risk factors, especially polypharmacy and cognitive disorders. Prevention of drug iatrogenicity is a key objective from a public health point of view. Preventive measures should target the prescriber (physician), the dispenser (pharmacist), the user (patient) and the supplier (pharmaceutical industry).

Clozapine was first manufactured in China in 1976. Clozapine is currently used not only for treatment-refractory schizophrenia (TRS), but also continues to be used in the treatment of patients with non-TRS and other mental disorders; moreover, low-dose clozapine is also used in sedative-hypnotic therapy and in combination with other drugs. There is need for studies in China using various titrations and assessing their risk for myocarditis and aspiration pneumonia. The Chinese clozapine package insert will also greatly benefit from these changes., Competing Interests: Declaration of competing interest In the last 3 years, the authors report no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

The purpose of this study is to clarify the drug interaction profile of aumolertinib, and the influence of CYP3A4 genetic polymorphism on aumolertinib metabolic characteristics. Through microsomal enzyme reactions, we screened 153 drugs and identified 15 that significantly inhibited the metabolism of aumolertinib. Among them, telmisartan and carvedilol exhibited potent inhibitory activities in rat liver microsomes (RLM) and human liver microsomes (HLM). In vivo , the pharmacokinetic parameters of aumolertinib, including AUC and C max , were significantly altered when co-administered with carvedilol, with a notable decrease in the clearance rate CL z/F . Interestingly, the pharmacokinetic parameters of the metabolite HAS-719 exhibited a similar trend as aumolertinib when co-administered. Mechanistically, both telmisartan and carvedilol exhibited a mixed-type inhibition on the metabolism of aumolertinib. Additionally, we used a baculovirus-insect cell expression system to prepare 24 recombinant CYP3A4 microsomes and obtained enzymatic kinetic parameters using aumolertinib as a substrate. Enzyme kinetic studies obtained the kinetic parameters of various CYP3A4 variant-mediated metabolism of aumolertinib. Based on the relative clearance rates, CYP3A4.4, 5, 7, 8, 9, 12, 13, 14, 17, 18, 19, 23, 24, 33, and 34 showed significantly lower clearance rates compared to the wild-type. Among the different CYP3A4 variants, the inhibitory potency of telmisartan and carvedilol on the metabolism of aumolertinib also varied. The IC 50 values of telmisartan and carvedilol in CYP3A4.1 were 6.68 ± 1.76 μM and 0.60 ± 0.25 μM, respectively, whereas in CYP3A4.12, the IC 50 exceeded 100 μM. Finally, we utilized adeno-associated virus to achieve liver-specific high expression of CYP3A4*1 and CYP3A4*12. In the group with high expression of the less active CYP3A4*12, the magnitude of the drug-drug interaction was significantly attenuated. In conclusion, CYP3A4 genetic polymorphism not only influences the pharmacokinetic characteristics of aumolertinib, but also the inhibitory potency of telmisartan and carvedilol on it., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ye, Ni, Li, Wang, Luo, Wang, Xu, Zhong, Qian and Xiao.)

Objective: Guanyu Zhixie Granule (GYZXG) is a traditional Chinese medicine compound with definite efficacy in intervening in gastric ulcers (GUs). However, the effect mechanisms on GU are still unclear. This study aimed to explore its mechanism against GU based on amalgamated strategies., Methods: The comprehensive chemical characterization of the active compounds of GYZXG was conducted using UHPLC-Q/TOF-MS. Based on these results, key targets and action mechanisms were predicted through network pharmacology. GU was then induced in rats using anhydrous ethanol (1 mL/200 g). The intervention effects of GYZXG on GU were evaluated by measuring the inhibition rate of GU, conducting HE staining, and assessing the levels of IL-6 , TNF-α , IL-10 , IL-4 , Pepsin ( PP ), and epidermal growth factor ( EGF ). Real-time quantitative PCR (RT-qPCR) was used to verify the mRNA levels of key targets and pathways. Metabolomics, combined with 16S rRNA sequencing, was used to investigate and confirm the action mechanism of GYZXG on GU. The correlation analysis between differential gut microbiota and differential metabolites was conducted using the spearman method., Results: For the first time, the results showed that nine active ingredients and sixteen targets were confirmed to intervene in GU when using GYZXG. Compared with the model group, GYZXG was found to increase the ulcer inhibition rate in the GYZXG-M group ( p  < 0.05), reduce the levels of IL-6 , TNF-α , PP in gastric tissue, and increase the levels of IL-10 , IL-4 , and EGF . GYZXG could intervene in GU by regulating serum metabolites such as Glycocholic acid, Epinephrine, Ascorbic acid, and Linoleic acid, and by influencing bile secretion, the HIF-1 signaling pathway, and adipocyte catabolism. Additionally, GYZXG could intervene in GU by altering the gut microbiota diversity and modulating the relative abundance of Bacteroidetes , Bacteroides , Verrucomicrobia , Akkermansia , and Ruminococcus . The differential gut microbiota was strongly associated with serum differential metabolites. KEGG enrichment analysis indicated a significant role of the HIF-1 signaling pathway in GYZXG's intervention on GU. The changes in metabolites within metabolic pathways and the alterations in RELA , HIF1A , and EGF mRNA levels in RT-qPCR experiments provide further confirmation of this result., Conclusion: GYZXG can intervene in GU induced by anhydrous ethanol in rats by regulating gut microbiota and metabolic disorders, providing a theoretical basis for its use in GU intervention., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Ma, Ji, Wu, Li, Dong, Yang, Wei and Hua.)