Expert opinion on drug metabolism & toxicology最新文献_第10页

Population pharmacokinetics of olanzapine in pediatric patients with psychiatric disorders. 奥氮平在儿科精神病患者中的群体药代动力学。

Expert opinion on drug metabolism & toxicology Pub Date : 2024-08-01 Epub Date: 2024-07-23 DOI: 10.1080/17425255.2024.2380472

Yan-Nan Zang, Zhou Wan, Fei Jia, Qi Yang, Chen-Geng Liu, Qian Wang, Shan-Shan Liu, Fang Dong, An-Ning Li, Jose de Leon, Gang Wang, Can-Jun Ruan

{"title":"Population pharmacokinetics of olanzapine in pediatric patients with psychiatric disorders.","authors":"Yan-Nan Zang, Zhou Wan, Fei Jia, Qi Yang, Chen-Geng Liu, Qian Wang, Shan-Shan Liu, Fang Dong, An-Ning Li, Jose de Leon, Gang Wang, Can-Jun Ruan","doi":"10.1080/17425255.2024.2380472","DOIUrl":"10.1080/17425255.2024.2380472","url":null,"abstract":"Objective: To develop and validate a population pharmacokinetic (PPK) model of oral olanzapine in pediatric Chinese patients in order to individualize therapy in this population.Methods: A total of 897 serum concentrations from 269 pediatric patients taking oral olanzapine (ages 8-17 years) were collected. Demographic parameters, biological characteristics and concomitant medications were investigated as covariates. The data were analyzed using a nonlinear mixed-effects modeling approach. Bootstrapping (1000 runs), normalized prediction distribution error (NPDE), and external validation of 62 patients were employed. Simulations were performed to explore the individualized dosing regimens in various situations.Results: The one-compartment model with first-order absorption and elimination had an apparent clearance (CL/F) of 10.38 L/h, a distribution volume (V/F) of 9.41 L/kg and an absorption rate constant (Ka) fixed at 0.3 h-1. The equation was CL∕F (L∕h) = 10.38 × (body weight∕60)0.25 ×1.33 (if male) × 0.71 (if co-occurrence of infection) × 0.51 (if co-therapy with fluvoxamine) × 1.27 (if co-therapy with sertraline) × 1.43 (if co-therapy with valproate). The final model had satisfactory stability, robustness, and predictive ability. The results from a simulation suggested the oral olanzapine doses required for male and female pediatric patients weighing between 40 and 60 kg without co-medication were 10-15 mg/day and 7.5-10 mg/day, respectively, and dosage adjustments should be based on sex and body weight; and co-administrated with valproate, sertraline, or fluvoxamine.Conclusion: This model may help individualize optimum dosing of oral olanzapine for pediatric patients.","PeriodicalId":94005,"journal":{"name":"Expert opinion on drug metabolism & toxicology","volume":" ","pages":"827-840"},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141621968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pharmacokinetic evaluation of ibrexafungerp for the treatment of vulvovaginal candidiasis and beyond. 用于治疗外阴阴道念珠菌病及其他疾病的伊曲沙芬格普药代动力学评估。

Expert opinion on drug metabolism & toxicology Pub Date : 2024-08-01 Epub Date: 2024-07-03 DOI: 10.1080/17425255.2024.2373095

Gage M Dixon, James S Lewis, George R Thompson

{"title":"Pharmacokinetic evaluation of ibrexafungerp for the treatment of vulvovaginal candidiasis and beyond.","authors":"Gage M Dixon, James S Lewis, George R Thompson","doi":"10.1080/17425255.2024.2373095","DOIUrl":"10.1080/17425255.2024.2373095","url":null,"abstract":"Introduction: Ibrexafungerp is a new triterpenoid antifungal agent with activity against a variety of fungal species, including Aspergillus spp. and echinocandin-resistant Candida spp.Areas covered: This evaluation will summarize currently available clinical evidence on the use of ibrexafungerp in the treatment/prevention of vulvovaginal candidiasis (VVC) and detail the mechanism of action, pharmacokinetic/pharmacodynamic parameters, and ongoing/latest research involving ibrexafungerp.Expert opinion: The evidence involving the utilization of ibrexafungerp for the treatment of VVC shows that it is superior when compared to placebo and has comparable clinical cure rates when compared with fluconazole. Ibrexafungerp demonstrates reliable coverage against several Candida spp. including echinocandin-resistant strains, Candida auris, and Aspergillus spp. For VVC, a dose of 300 mg (two 150 mg tablets) twice daily is recommended and does not require dose adjustments based on renal or hepatic function. The use of ibrexafungerp outside of VVC is currently under study with several ongoing trials showing promising interim data.","PeriodicalId":94005,"journal":{"name":"Expert opinion on drug metabolism & toxicology","volume":" ","pages":"713-718"},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141494583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pharmacokinetic review of janus kinase inhibitors and its clinical implications for the management of rheumatoid arthritis. anus 激酶抑制剂的药代动力学回顾及其对类风湿关节炎治疗的临床意义。

Expert opinion on drug metabolism & toxicology Pub Date : 2024-08-01 Epub Date: 2024-06-26 DOI: 10.1080/17425255.2024.2373092

S Chandrashekara

{"title":"Pharmacokinetic review of janus kinase inhibitors and its clinical implications for the management of rheumatoid arthritis.","authors":"S Chandrashekara","doi":"10.1080/17425255.2024.2373092","DOIUrl":"10.1080/17425255.2024.2373092","url":null,"abstract":"Introduction: In the realm of autoimmune rheumatic diseases, understanding JAK inhibitors (JAKi) nuances is vital. Baricitinib, tofacitinib, upaacitinib, filgotinib, and peficitinib exhibit subtle yet impactful pharmacokinetic (PK) and pharmacodynamic (PD) variations.Areas covered: This narrative review critically assesses PK and PD distinctions among globally approved JAKi for rheumatoid arthritis, which primarily guide clinical decisions in autoimmune diseases, particularly rheumatoid arthritis. It explores the intricate JAK-STAT signaling pathway, offering insights into JAKs' roles in inflammation, hematopoiesis, and immune homeostasis. Emphasis on PK parameters, including absorption, distribution, metabolism, and excretion, along with CYP3A4 drug interactions, is highlighted. The review underscores integrating PK and PD properties, considering patient-specific factors like hepatic and renal clearance, for judicious JAKi selection in RA and related autoimmune conditions. The literature has been collected from all available databases based on the review question.Expert opinion: Integrating PK and PD properties with patient-specific factors is pivotal for judicious JAKi selection. Recognizing disparities in PK and PD across diseases, ethnicities, and environmental factors is crucial for personalized JAKi choices. This expert opinion underscores the significance of a second compartment analysis, elucidating the interplay between PK and PD and its impact on JAKi efficacy.","PeriodicalId":94005,"journal":{"name":"Expert opinion on drug metabolism & toxicology","volume":" ","pages":"741-748"},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141447871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dose optimization of β-lactam antibiotics in children: from population pharmacokinetics to individualized therapy. 儿童使用β-内酰胺类抗生素的剂量优化：从群体药代动力学到个体化治疗。

Expert opinion on drug metabolism & toxicology Pub Date : 2024-08-01 DOI: 10.1080/17425255.2024.2385403

Perrin Ngougni Pokem, Dorian Vanneste, Stef Schouwenburg, Alan Abdulla, Matthias Gijsen, Evelyn Dhont, Dimitri Van der Linden, Isabel Spriet, Pieter De Cock, Birgit Koch, Françoise Van Bambeke, Gert-Jan Wijnant

{"title":"Dose optimization of β-lactam antibiotics in children: from population pharmacokinetics to individualized therapy.","authors":"Perrin Ngougni Pokem, Dorian Vanneste, Stef Schouwenburg, Alan Abdulla, Matthias Gijsen, Evelyn Dhont, Dimitri Van der Linden, Isabel Spriet, Pieter De Cock, Birgit Koch, Françoise Van Bambeke, Gert-Jan Wijnant","doi":"10.1080/17425255.2024.2385403","DOIUrl":"10.1080/17425255.2024.2385403","url":null,"abstract":"Introduction: β-Lactams are the most widely used antibiotics in children. Their optimal dosing is essential to maximize their efficacy, while minimizing the risk for toxicity and the further emergence of antimicrobial resistance. However, most β-lactams were developed and licensed long before regulatory changes mandated pharmacokinetic studies in children. As a result, pediatric dosing practices are poorly harmonized and off-label use remains common today.Areas covered: β-Lactam pharmacokinetics and dose optimization strategies in pediatrics, including fixed dose regimens, therapeutic drug monitoring, and model-informed precision dosing are reviewed.Expert opinion/commentary: Standard pediatric doses can result in subtherapeutic exposure and non-target attainment for specific patient subpopulations (neonates, critically ill children, e.g.). Such patients could benefit greatly from more individualized approaches to dose optimization, beyond a relatively simple dose adaptation based on weight, age, or renal function. In this context, Therapeutic Drug Monitoring (TDM) and Model-Informed Precision Dosing (MIPD) emerge as particularly promising avenues. Obstacles to their implementation include the lack of strong evidence of clinical benefit due to the paucity of randomized clinical trials, of standardized assays for monitoring concentrations, or of adequate markers for renal function. The development of precision medicine tools is urgently needed to individualize therapy in vulnerable pediatric subpopulations.","PeriodicalId":94005,"journal":{"name":"Expert opinion on drug metabolism & toxicology","volume":" ","pages":"787-804"},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141794286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

How can we better address the pharmacokinetics of antipsychotics in children and adolescents? 如何更好地处理儿童和青少年抗精神病药物的药代动力学问题？

Expert opinion on drug metabolism & toxicology Pub Date : 2024-08-01 Epub Date: 2024-07-12 DOI: 10.1080/17425255.2024.2378887

Georgios Schoretsanitis, Jose de Leon, Christoph U Correll

{"title":"How can we better address the pharmacokinetics of antipsychotics in children and adolescents?","authors":"Georgios Schoretsanitis, Jose de Leon, Christoph U Correll","doi":"10.1080/17425255.2024.2378887","DOIUrl":"10.1080/17425255.2024.2378887","url":null,"abstract":"Introduction: Despite a steady increase of antipsychotic prescriptions in children and adolescents, knowledge about pharmacokinetics and dosing of antipsychotics in children and adolescents remains limited.Areas covered: We discuss seven issues with major impact on the pharmacokinetics of antipsychotics in youth: estrogens, ii) obesity, iii) ethnicity, iv) smoking, v) inflammation, vi) drug-drug interactions (DDIs), and vii) pharmacogenetics. Despite their major impact, these issues have not been adequately considered in the context of dosing algorithms for antipsychotics in youth. A simple tool to quantify the impact of these pharmacokinetics issues on antipsychotics is therapeutic drug monitoring (TDM), which refers to the quantification of the prescribed medication in the blood of the patients, as a surrogate for the peripheral antipsychotic exposure. We also provide summary tables extrapolated from the adult literature on metabolism, therapeutic reference ranges (TRRs) and DDIs.Expert opinion: Despite considerable experience with TDM for antipsychotics in the management of other patient subgroups, TDM use for antipsychotics in children and adolescents may be limited with TRRs invariably being extrapolated from adult patients. Advancing TDM knowledge is expected to help clinicians address the special properties of pharmacokinetics of antipsychotics and ultimately enable antipsychotic dose individualization in youth.","PeriodicalId":94005,"journal":{"name":"Expert opinion on drug metabolism & toxicology","volume":" ","pages":"719-726"},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141565406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Recent progress in adverse events of carboxylic acid non-steroidal anti-inflammatory drugs (CBA-NSAIDs) and their association with the metabolism: the consequences on mitochondrial dysfunction and oxidative stress, and prevention with natural plant extracts. 羧酸类非甾体抗炎药（CBA-NSAIDs）不良反应及其与新陈代谢关系的最新进展：对线粒体功能障碍和氧化应激的影响，以及天然植物提取物的预防作用。

Expert opinion on drug metabolism & toxicology Pub Date : 2024-08-01 Epub Date: 2024-07-12 DOI: 10.1080/17425255.2024.2378885

Yanan Liu, Chao Yang, Jieying Zhang, Awais Ihsan, Irma Ares, Marta Martínez, Bernardo Lopez-Torres, María-Rosa Martínez-Larrañaga, Xu Wang, Arturo Anadón, María-Aránzazu Martínez

{"title":"Recent progress in adverse events of carboxylic acid non-steroidal anti-inflammatory drugs (CBA-NSAIDs) and their association with the metabolism: the consequences on mitochondrial dysfunction and oxidative stress, and prevention with natural plant extracts.","authors":"Yanan Liu, Chao Yang, Jieying Zhang, Awais Ihsan, Irma Ares, Marta Martínez, Bernardo Lopez-Torres, María-Rosa Martínez-Larrañaga, Xu Wang, Arturo Anadón, María-Aránzazu Martínez","doi":"10.1080/17425255.2024.2378885","DOIUrl":"10.1080/17425255.2024.2378885","url":null,"abstract":"Introduction: Carboxylic acid non-steroidal anti-inflammatory drugs (CBA-NSAIDs) are extensively used worldwide due to their antipyretic, analgesic, and anti-inflammatory effects. CBA-NSAIDs have reasonable margin of safety at therapeutic doses, and in the current climate, do not possess addiction potential like opioid drugs. Studies have revealed that various adverse events of CBA-NSAIDs are related mitochondrial dysfunction and oxidative stress.Areas covered: This review article summarizes adverse events induced by CBA-NSAIDs, mechanisms of mitochondrial damage, oxidative stress, and metabolic interactions. Meanwhile, this review discusses the treatment and prevention of CBA-NSAIDs damage by natural plant extracts based on antioxidant effects.Expert opinion: CBA-NSAIDs can induce reactive oxygen species (ROS) production, mediate DNA, protein and lipid damage, lead to imbalance of cell antioxidant status, change of mitochondrial membrane potential, activate oxidative stress signal pathway, thus leading to oxidative stress and cell damage. Adverse events caused by CBA-NSAIDs often exhibit dose and time dependence. In order to avoid adverse events caused by CBA-NSAIDs, it is necessary to provide detailed patient consultation and eliminate influencing factors. Moreover, constructive research studies on the organ-specific toxicity and mechanism of natural plant extracts in preventing and treating metabolic abnormalities of CBA-NSAIDs, will provide important value for warning and guidance for use of CBA-NSAIDs.","PeriodicalId":94005,"journal":{"name":"Expert opinion on drug metabolism & toxicology","volume":" ","pages":"765-785"},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141565407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Physiologically based pharmacokinetic modeling in obesity: applications and challenges. 基于生理学的肥胖症药物动力学模型：应用与挑战。

Expert opinion on drug metabolism & toxicology Pub Date : 2024-08-01 Epub Date: 2024-08-12 DOI: 10.1080/17425255.2024.2388690

Ruwei Yang, Qin Ding, Junjie Ding, Liyong Zhu, Qi Pei

{"title":"Physiologically based pharmacokinetic modeling in obesity: applications and challenges.","authors":"Ruwei Yang, Qin Ding, Junjie Ding, Liyong Zhu, Qi Pei","doi":"10.1080/17425255.2024.2388690","DOIUrl":"10.1080/17425255.2024.2388690","url":null,"abstract":"Introduction: Rising global obesity rates pose a threat to people's health. Obesity causes a series of pathophysiologic changes, making the response of patients with obesity to drugs different from that of nonobese, thus affecting the treatment efficacy and even leading to adverse events. Therefore, understanding obesity's effects on pharmacokinetics is essential for the rational use of drugs in patients with obesity.Areas covered: Articles related to physiologically based pharmacokinetic (PBPK) modeling in patients with obesity from inception to October 2023 were searched in PubMed, Embase, Web of Science and the Cochrane Library. This review outlines PBPK modeling applications in exploring factors influencing obesity's effects on pharmacokinetics, guiding clinical drug development and evaluating and optimizing clinical use of drugs in patients with obesity.Expert opinion: Obesity-induced pathophysiologic alterations impact drug pharmacokinetics and drug-drug interactions (DDIs), altering drug exposure. However, there is a lack of universal body size indices or quantitative pharmacology models to predict the optimal for the patients with obesity. Therefore, dosage regimens for patients with obesity must consider individual physiological and biochemical information, and clinically individualize therapeutic drug monitoring for highly variable drugs to ensure effective drug dosing and avoid adverse effects.","PeriodicalId":94005,"journal":{"name":"Expert opinion on drug metabolism & toxicology","volume":" ","pages":"805-816"},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141891357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

An update on oral antiplatelet drug interactions with proton pump inhibitors: what are the risks? 口服抗血小板药物与质子泵抑制剂相互作用的最新进展：有哪些风险？

Expert opinion on drug metabolism & toxicology Pub Date : 2024-08-01 Epub Date: 2024-07-15 DOI: 10.1080/17425255.2024.2378888

Georges Jourdi, Jean-Sébastien Hulot, Pascale Gaussem

{"title":"An update on oral antiplatelet drug interactions with proton pump inhibitors: what are the risks?","authors":"Georges Jourdi, Jean-Sébastien Hulot, Pascale Gaussem","doi":"10.1080/17425255.2024.2378888","DOIUrl":"10.1080/17425255.2024.2378888","url":null,"abstract":"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.","PeriodicalId":94005,"journal":{"name":"Expert opinion on drug metabolism & toxicology","volume":" ","pages":"749-764"},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141565405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pharmacokinetics of aspirin: evaluating shortcomings in the literature. 阿司匹林的药代动力学：评估文献中的不足之处。

Expert opinion on drug metabolism & toxicology Pub Date : 2024-08-01 Epub Date: 2024-08-02 DOI: 10.1080/17425255.2024.2386368

Jacobus Lukas Visagie, Gabriel Sanjo Aruwajoye, Rencia van der Sluis

{"title":"Pharmacokinetics of aspirin: evaluating shortcomings in the literature.","authors":"Jacobus Lukas Visagie, Gabriel Sanjo Aruwajoye, Rencia van der Sluis","doi":"10.1080/17425255.2024.2386368","DOIUrl":"10.1080/17425255.2024.2386368","url":null,"abstract":"Introduction: Aspirin is known for its therapeutic benefits in preventing strokes and relieving pain. However, it is toxic to some individuals, and the biological mechanisms causing toxicity are unknown. Limited literature is available on the role of glycine conjugation as the principal pathway in aspirin detoxification. Previous studies have quantified this two-step enzyme reaction as a singular enzymatic process. Consequently, the individual contributions of these enzymes to the kinetics remain unclear.Areas covered: This review summarized the available information on the pharmacokinetics and detoxification of aspirin by the glycine conjugation pathway. Literature searches were conducted using Google Scholar and the academic journal databases accessible through the North-West University Library. Furthermore, the factors affecting interindividual variation in aspirin metabolism and what is known regarding aspirin toxicity were discussed.Expert opinion: The greatest drawback in understanding the pharmacokinetics of aspirin is the limited information available on the substrate preference of the xenobiotic ligase (ACSM) responsible for activating salicylate to salicyl-CoA. Furthermore, previous pharmacokinetic studies did not consider the contribution of other substrates from the diet or genetic variants, to the detoxification rate of glycine conjugation. Impaired glycine conjugation might contribute to adverse health effects seen in Reye's syndrome and cancer.","PeriodicalId":94005,"journal":{"name":"Expert opinion on drug metabolism & toxicology","volume":" ","pages":"727-740"},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141876984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Overview of preclinical and clinical studies investigating pharmacokinetics and drug-drug interactions of padsevonil. 调查帕塞呋尼尔药代动力学和药物间相互作用的临床前和临床研究概述。

Expert opinion on drug metabolism & toxicology Pub Date : 2024-08-01 Epub Date: 2024-07-09 DOI: 10.1080/17425255.2024.2373108

Hugues Chanteux, Merran MacPherson, Hester Kramer, Christian Otoul, Takuya Okagaki, Chiara Rospo, Steven De Bruyn, Mark Watling, Massimo Bani, David Sciberras

{"title":"Overview of preclinical and clinical studies investigating pharmacokinetics and drug-drug interactions of padsevonil.","authors":"Hugues Chanteux, Merran MacPherson, Hester Kramer, Christian Otoul, Takuya Okagaki, Chiara Rospo, Steven De Bruyn, Mark Watling, Massimo Bani, David Sciberras","doi":"10.1080/17425255.2024.2373108","DOIUrl":"10.1080/17425255.2024.2373108","url":null,"abstract":"Background: Padsevonil is an antiseizure medication candidate intended to benefit patients with drug-resistant epilepsy. Our investigations aimed at characterizing pharmacokinetics and drug-drug interaction (DDI) profile of padsevonil.Research design and methods: An overview of preclinical and clinical pharmacology studies conducted during padsevonil development is provided.Results: In preclinical studies, cytochrome (CYP) 3A4 was identified as the main P450 isoform involved in padsevonil metabolism, with potential minor contribution from CYP2C19. Padsevonil was shown to be a time-dependent CYP2C19-inhibitor, weak CYP3A4-inducer, weak inhibitor of P-gp/OCT1/MATE2-K, and potent OCT2-inhibitor. Initial clinical pharmacology studies in healthy participants showed that padsevonil had (i) good absorption, (ii) clearance mediated mainly by metabolism, and (iii) time-dependent kinetics. A study in genotyped participants confirmed the role of CYP2C19 in clearance and time-dependent kinetics; the major contribution of CYP3A4 was confirmed in DDI studies with CYP3A4-inducers (carbamazepine, oxcarbazepine) and -inhibitor (erythromycin). Padsevonil did not affect pharmacokinetics of valproate/lamotrigine/levetiracetam/oxcarbazepine or oral contraceptives. In a cocktail clinical study, padsevonil showed moderate CYP2C19 inhibition (omeprazole) and weak CYP3A4 induction (oral midazolam). No specific effects on CYP1A2 (caffeine), CYP2C9 (S-warfarin), and CYP2D6 (dextromethorphan) were observed.Conclusions: The studies presented helped in understanding padsevonil disposition and risks of DDIs, which would inform dosing and prescribing.Clinical trial registration: https://www.clinicaltrials.gov identifiers are NCT04131517, NCT03480243, NCT03695094, NCT04075409.","PeriodicalId":94005,"journal":{"name":"Expert opinion on drug metabolism & toxicology","volume":" ","pages":"841-855"},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141461353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0