Background and objective: Therapeutic drug monitoring (TDM) is an effective tool for the management of patients who are administered linezolid. The use of saliva for TDM has potential advantages over the use of plasma; however, only a few reports have compared drug concentrations in the saliva and plasma. Moreover, there are no reports on the salivary concentration of tedizolid, an oxazolidinone antibiotic similar to linezolid. In the present study, the concentrations of tedizolid and linezolid in rat submandibular saliva were compared with those measured in the plasma.
Methods: Tedizolid (10 mg/kg, n = 6) and linezolid (12 mg/kg, n = 5) were administered via the rat tail vein. Submandibular saliva and plasma samples were collected for up to 8 h after the initiation of drug administration, and assayed for the concentrations of tedizolid and linezolid.
Results: A strong correlation was found between the saliva and plasma concentrations of tedizolid (r = 0.964, p < 0.001) and linezolid (r = 0.936, p < 0.001). The value of tedizolid maximum concentration of drug (Cmax) was 0.99 ± 0.08 µg/mL in the saliva and 14.46 ± 1.71 µg/mL in the plasma. Meanwhile, the Cmax of linezolid was 8.01 ± 1.42 µg/mL in the saliva and 13.00 ± 1.90 µg/mL in the plasma. According to these results, the saliva/plasma concentration ratios of tedizolid and linezolid in rats were 0.0513 ± 0.0080 and 0.6341 ± 0.0339, respectively.
Conclusions: Considering the correlation between saliva and plasma concentrations of tedizolid and linezolid, as well as the characteristics of saliva, the results of this study suggest that saliva is a useful matrix for TDM.
背景与目的:治疗性药物监测(TDM)是管理使用利奈唑胺患者的有效工具。使用唾液治疗TDM比使用血浆有潜在的优势;然而,只有少数报告比较了唾液和血浆中的药物浓度。此外,尚未见类似利奈唑胺的恶唑烷类抗生素tedizolid唾液浓度的报道。本研究比较了大鼠下颌骨唾液中泰地唑胺和利奈唑胺的浓度与血浆中的浓度。方法:大鼠尾静脉给药Tedizolid (10 mg/kg, n = 6)和linezolid (12 mg/kg, n = 5)。在给药后8小时内采集下颌下唾液和血浆样本,检测泰地唑胺和利奈唑胺的浓度。结果:唾液和血浆中tedizolid浓度(r = 0.964, p max)分别为0.99±0.08µg/mL和14.46±1.71µg/mL。利奈唑胺在唾液中的Cmax为8.01±1.42µg/mL,在血浆中的Cmax为13.00±1.90µg/mL。结果显示,大鼠唾液浓度比为0.0513±0.0080,利奈唑胺浓度比为0.6341±0.0339。结论:考虑唾液与血浆中泰地唑胺和利奈唑胺浓度的相关性,以及唾液的特点,本研究结果提示唾液是TDM的有用基质。
{"title":"Monitoring Salivary Concentrations of Tedizolid and Linezolid Using Rats.","authors":"Yuki Inoue, Yuki Sato, Hitoshi Kashiwagi, Shunsuke Nashimoto, Mitsuru Sugawara, Yoh Takekuma","doi":"10.1007/s13318-023-00836-6","DOIUrl":"https://doi.org/10.1007/s13318-023-00836-6","url":null,"abstract":"<p><strong>Background and objective: </strong>Therapeutic drug monitoring (TDM) is an effective tool for the management of patients who are administered linezolid. The use of saliva for TDM has potential advantages over the use of plasma; however, only a few reports have compared drug concentrations in the saliva and plasma. Moreover, there are no reports on the salivary concentration of tedizolid, an oxazolidinone antibiotic similar to linezolid. In the present study, the concentrations of tedizolid and linezolid in rat submandibular saliva were compared with those measured in the plasma.</p><p><strong>Methods: </strong>Tedizolid (10 mg/kg, n = 6) and linezolid (12 mg/kg, n = 5) were administered via the rat tail vein. Submandibular saliva and plasma samples were collected for up to 8 h after the initiation of drug administration, and assayed for the concentrations of tedizolid and linezolid.</p><p><strong>Results: </strong>A strong correlation was found between the saliva and plasma concentrations of tedizolid (r = 0.964, p < 0.001) and linezolid (r = 0.936, p < 0.001). The value of tedizolid maximum concentration of drug (C<sub>max</sub>) was 0.99 ± 0.08 µg/mL in the saliva and 14.46 ± 1.71 µg/mL in the plasma. Meanwhile, the C<sub>max</sub> of linezolid was 8.01 ± 1.42 µg/mL in the saliva and 13.00 ± 1.90 µg/mL in the plasma. According to these results, the saliva/plasma concentration ratios of tedizolid and linezolid in rats were 0.0513 ± 0.0080 and 0.6341 ± 0.0339, respectively.</p><p><strong>Conclusions: </strong>Considering the correlation between saliva and plasma concentrations of tedizolid and linezolid, as well as the characteristics of saliva, the results of this study suggest that saliva is a useful matrix for TDM.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10158433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-01DOI: 10.1007/s13318-023-00831-x
Athanasios A Tsekouras, Panos Macheras
Background and objectives: Naloxone for opioid overdose treatment can be administered by intravenous injection, intramuscular injection, or intranasal administration. Published data indicate differences in naloxone pharmacokinetics depending on the route of administration. The aim of this study was to analyze pharmacokinetic data in the same way that we recently successfully applied the concept of the finite absorption time in orally administered drug formulations.
Methods: Using the model equations already derived, we performed least squares analysis on 24 sets of naloxone concentration in the blood as a function of time.
Results: We found that intramuscular and intranasal administration can be described more accurately when considering zero-order absorption kinetics for finite time compared with classical first order absorption kinetics for infinite time.
Conclusions: One-compartment models work well for most cases. Two-compartment models provide better details, but have higher parameter uncertainties. The absorption duration can be determined directly from the model parameters and thus allow an easy comparison between the ways of administration. Furthermore, the precise site of injection for intramuscular delivery appears to make a difference in terms of the duration of the drug absorption.
{"title":"Re-examining Naloxone Pharmacokinetics After Intranasal and Intramuscular Administration Using the Finite Absorption Time Concept.","authors":"Athanasios A Tsekouras, Panos Macheras","doi":"10.1007/s13318-023-00831-x","DOIUrl":"https://doi.org/10.1007/s13318-023-00831-x","url":null,"abstract":"<p><strong>Background and objectives: </strong>Naloxone for opioid overdose treatment can be administered by intravenous injection, intramuscular injection, or intranasal administration. Published data indicate differences in naloxone pharmacokinetics depending on the route of administration. The aim of this study was to analyze pharmacokinetic data in the same way that we recently successfully applied the concept of the finite absorption time in orally administered drug formulations.</p><p><strong>Methods: </strong>Using the model equations already derived, we performed least squares analysis on 24 sets of naloxone concentration in the blood as a function of time.</p><p><strong>Results: </strong>We found that intramuscular and intranasal administration can be described more accurately when considering zero-order absorption kinetics for finite time compared with classical first order absorption kinetics for infinite time.</p><p><strong>Conclusions: </strong>One-compartment models work well for most cases. Two-compartment models provide better details, but have higher parameter uncertainties. The absorption duration can be determined directly from the model parameters and thus allow an easy comparison between the ways of administration. Furthermore, the precise site of injection for intramuscular delivery appears to make a difference in terms of the duration of the drug absorption.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10171505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-01DOI: 10.1007/s13318-023-00835-7
Paul A G de Klaver, Ron J Keizer, Rob Ter Heine, Lisa Smits, Paul J Boekema, Inge Kuntzel, Tiny Schaap, Annick de Vries, Karien Bloem, Theo Rispens, Frank Hoentjen, Luc J J Derijks
Background and objective: Underdosing of adalimumab can result in non-response and poor disease control in patients with rheumatic disease or inflammatory bowel disease. In this pilot study we aimed to predict adalimumab concentrations with population pharmacokinetic model-based Bayesian forecasting early in therapy.
Methods: Adalimumab pharmacokinetic models were identified with a literature search. A fit-for-purpose evaluation of the model was performed for rheumatologic and inflammatory bowel disease (IBD) patients with adalimumab peak (first dose) and trough samples (first and seventh dose) obtained by a volumetric absorptive microsampling technique. Steady state adalimumab concentrations were predicted after the first adalimumab administration. Predictive performance was calculated with mean prediction error (MPE) and normalised root mean square error (RMSE).
Results: Thirty-six patients (22 rheumatologic and 14 IBD) were analysed in our study. After stratification for absence of anti-adalimumab antibodies, the calculated MPE was -2.6% and normalised RMSE 24.0%. Concordance between predicted and measured adalimumab serum concentrations falling within or outside the therapeutic window was 75%. Three patients (8.3%) developed detectable concentrations of anti-adalimumab antibodies.
Conclusion: This prospective study demonstrates that adalimumab concentrations at steady state can be predicted from early samples during the induction phase.
Clinical trial registration: The trial was registered in the Netherlands Trial Register with trial registry number NTR 7692 ( www.trialregister.nl ).
{"title":"Early At-Home Measurement of Adalimumab Concentrations to Guide Anti-TNF Precision Dosing: A Pilot Study.","authors":"Paul A G de Klaver, Ron J Keizer, Rob Ter Heine, Lisa Smits, Paul J Boekema, Inge Kuntzel, Tiny Schaap, Annick de Vries, Karien Bloem, Theo Rispens, Frank Hoentjen, Luc J J Derijks","doi":"10.1007/s13318-023-00835-7","DOIUrl":"https://doi.org/10.1007/s13318-023-00835-7","url":null,"abstract":"<p><strong>Background and objective: </strong>Underdosing of adalimumab can result in non-response and poor disease control in patients with rheumatic disease or inflammatory bowel disease. In this pilot study we aimed to predict adalimumab concentrations with population pharmacokinetic model-based Bayesian forecasting early in therapy.</p><p><strong>Methods: </strong>Adalimumab pharmacokinetic models were identified with a literature search. A fit-for-purpose evaluation of the model was performed for rheumatologic and inflammatory bowel disease (IBD) patients with adalimumab peak (first dose) and trough samples (first and seventh dose) obtained by a volumetric absorptive microsampling technique. Steady state adalimumab concentrations were predicted after the first adalimumab administration. Predictive performance was calculated with mean prediction error (MPE) and normalised root mean square error (RMSE).</p><p><strong>Results: </strong>Thirty-six patients (22 rheumatologic and 14 IBD) were analysed in our study. After stratification for absence of anti-adalimumab antibodies, the calculated MPE was -2.6% and normalised RMSE 24.0%. Concordance between predicted and measured adalimumab serum concentrations falling within or outside the therapeutic window was 75%. Three patients (8.3%) developed detectable concentrations of anti-adalimumab antibodies.</p><p><strong>Conclusion: </strong>This prospective study demonstrates that adalimumab concentrations at steady state can be predicted from early samples during the induction phase.</p><p><strong>Clinical trial registration: </strong>The trial was registered in the Netherlands Trial Register with trial registry number NTR 7692 ( www.trialregister.nl ).</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10174378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background and objectives: The oral bioavailability of withangulatin A (WA) is low and may undergo first-pass metabolism because of the presence of two esters bonds. This study aimed to identify the hydrolysis behavior and mechanism of WA, thus enriching its structure-pharmacokinetic relationship.
Methods: The in vivo pharmacokinetic studies of WA in rats were first investigated, followed by in vitro assays including metabolic stability, phenotyping identification and metabolic kinetics assays. After screening out the responsible enzymes with higher catalytic capacity, molecular docking study was performed to demonstrate the interaction mode between WA and metabolic enzymes. Then, metabolites in human serum albumin (HSA) were identified by LC-TOF-MS/MS.
Results: In rats, the oral bioavailability of WA was only 2.83%. In vitro, WA was hydrolyzed in both rat and human plasma and could not be inhibited by selective esterase inhibitors. Physiologic concentration of HSA not recombinant human carboxylesterases (rhCES) could significantly hydrolyze WA, and it had a similar hydrolytic capacity with human plasma to WA. Furthermore, WA could stably bind to HSA by forming hydrogen bonds with Lys199 and Arg410, accompanied by the metabolic reaction of the lactone ring opening.
Conclusion: The study showed that WA underwent obvious hydrolysis in rat and human plasma, which implied a strong first-pass effect. Serum albumin rather than common esterases primarily contributed to the hydrolytic metabolism of WA in plasma.
背景和目的:withangulatin A (WA)的口服生物利用度较低,由于存在两个酯键,可能经历首次代谢。本研究旨在确定WA的水解行为和水解机制,从而丰富其结构-药动学关系。方法:首先进行大鼠体内药代动力学研究,然后进行体外代谢稳定性、表型鉴定和代谢动力学分析。筛选出催化能力较高的相关酶后,进行分子对接研究,验证WA与代谢酶的相互作用模式。采用LC-TOF-MS/MS对人血清白蛋白(HSA)代谢产物进行鉴定。结果:WA在大鼠体内的口服生物利用度仅为2.83%。在体外,WA在大鼠和人血浆中均可水解,且不受选择性酯酶抑制剂的抑制。非重组人羧酸酯酶(rhCES)生理浓度的HSA能显著水解WA,且与人血浆水解WA的能力相似。此外,WA可以与Lys199和Arg410形成氢键与HSA稳定结合,并伴有内酯环打开的代谢反应。结论:研究表明,WA在大鼠和人血浆中均发生了明显的水解,具有较强的首过效应。血清白蛋白而非普通酯酶主要参与血浆中WA的水解代谢。
{"title":"Hydrolytic Metabolism of Withangulatin A Mediated by Serum Albumin Instead of Common Esterases in Plasma.","authors":"Yu Zhuang, Yuxiao Wang, Ning Li, Haitao Meng, Zhiyu Li, Jianguang Luo, Zhixia Qiu","doi":"10.1007/s13318-023-00834-8","DOIUrl":"https://doi.org/10.1007/s13318-023-00834-8","url":null,"abstract":"<p><strong>Background and objectives: </strong>The oral bioavailability of withangulatin A (WA) is low and may undergo first-pass metabolism because of the presence of two esters bonds. This study aimed to identify the hydrolysis behavior and mechanism of WA, thus enriching its structure-pharmacokinetic relationship.</p><p><strong>Methods: </strong>The in vivo pharmacokinetic studies of WA in rats were first investigated, followed by in vitro assays including metabolic stability, phenotyping identification and metabolic kinetics assays. After screening out the responsible enzymes with higher catalytic capacity, molecular docking study was performed to demonstrate the interaction mode between WA and metabolic enzymes. Then, metabolites in human serum albumin (HSA) were identified by LC-TOF-MS/MS.</p><p><strong>Results: </strong>In rats, the oral bioavailability of WA was only 2.83%. In vitro, WA was hydrolyzed in both rat and human plasma and could not be inhibited by selective esterase inhibitors. Physiologic concentration of HSA not recombinant human carboxylesterases (rhCES) could significantly hydrolyze WA, and it had a similar hydrolytic capacity with human plasma to WA. Furthermore, WA could stably bind to HSA by forming hydrogen bonds with Lys199 and Arg410, accompanied by the metabolic reaction of the lactone ring opening.</p><p><strong>Conclusion: </strong>The study showed that WA underwent obvious hydrolysis in rat and human plasma, which implied a strong first-pass effect. Serum albumin rather than common esterases primarily contributed to the hydrolytic metabolism of WA in plasma.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10175495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-01DOI: 10.1007/s13318-023-00833-9
Sara Bettonte, Mattia Berton, Felix Stader, Manuel Battegay, Catia Marzolini
Background: People living with HIV may present co-morbidities requiring the initiation and subsequently the discontinuation of medications with inducing properties. The time to reach maximal enzyme induction and to return to baseline enzyme levels has not been thoroughly characterized.
Objective: The aim of this study was to evaluate the onset and disappearance of dolutegravir [uridine diphosphate glucuronosyltransferase (UGT) 1A1 and cytochrome P450 (CYP) 3A4 substrate] and raltegravir (UGT1A1 substrate) induction with strong and moderate inducers using physiologically based pharmacokinetic (PBPK) modeling.
Methods: The predictive performance of the PBPK model to simulate dolutegravir and raltegravir pharmacokinetics and to reproduce the strength of induction was verified using clinical drug-drug interaction studies (steady-state induction) and switch studies (residual induction). The model was considered verified when the predictions were within 2-fold of the observed data. One hundred virtual individuals (50% female) were generated to simulate the unstudied scenarios. The results were used to calculate the fold-change in CYP3A4 and UGT1A1 enzyme levels upon initiation and discontinuation of strong (rifampicin) or moderate (efavirenz or rifabutin) inducers.
Results: The time for reaching maximal induction and subsequent disappearance of CYP3A4 induction was 14 days for rifampicin and efavirenz but 7 days for rifabutin. The distinct timelines for the moderate inducers relate to their different half-lives and plasma concentrations. The induction and de-induction processes were more rapid for UGT1A1.
Conclusions: Our simulations support the common practice of maintaining the adjusted dosage of a drug for another 2 weeks after stopping an inducer. Furthermore, our simulations suggest that an inducer should be administered for at least 14 days before conducting interaction studies to reach maximal induction.
{"title":"Management of Drug Interactions with Inducers: Onset and Disappearance of Induction on Cytochrome P450 3A4 and Uridine Diphosphate Glucuronosyltransferase 1A1 Substrates.","authors":"Sara Bettonte, Mattia Berton, Felix Stader, Manuel Battegay, Catia Marzolini","doi":"10.1007/s13318-023-00833-9","DOIUrl":"https://doi.org/10.1007/s13318-023-00833-9","url":null,"abstract":"<p><strong>Background: </strong>People living with HIV may present co-morbidities requiring the initiation and subsequently the discontinuation of medications with inducing properties. The time to reach maximal enzyme induction and to return to baseline enzyme levels has not been thoroughly characterized.</p><p><strong>Objective: </strong>The aim of this study was to evaluate the onset and disappearance of dolutegravir [uridine diphosphate glucuronosyltransferase (UGT) 1A1 and cytochrome P450 (CYP) 3A4 substrate] and raltegravir (UGT1A1 substrate) induction with strong and moderate inducers using physiologically based pharmacokinetic (PBPK) modeling.</p><p><strong>Methods: </strong>The predictive performance of the PBPK model to simulate dolutegravir and raltegravir pharmacokinetics and to reproduce the strength of induction was verified using clinical drug-drug interaction studies (steady-state induction) and switch studies (residual induction). The model was considered verified when the predictions were within 2-fold of the observed data. One hundred virtual individuals (50% female) were generated to simulate the unstudied scenarios. The results were used to calculate the fold-change in CYP3A4 and UGT1A1 enzyme levels upon initiation and discontinuation of strong (rifampicin) or moderate (efavirenz or rifabutin) inducers.</p><p><strong>Results: </strong>The time for reaching maximal induction and subsequent disappearance of CYP3A4 induction was 14 days for rifampicin and efavirenz but 7 days for rifabutin. The distinct timelines for the moderate inducers relate to their different half-lives and plasma concentrations. The induction and de-induction processes were more rapid for UGT1A1.</p><p><strong>Conclusions: </strong>Our simulations support the common practice of maintaining the adjusted dosage of a drug for another 2 weeks after stopping an inducer. Furthermore, our simulations suggest that an inducer should be administered for at least 14 days before conducting interaction studies to reach maximal induction.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/6c/b0/13318_2023_Article_833.PMC10322778.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9798742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-01Epub Date: 2023-06-23DOI: 10.1007/s13318-023-00840-w
Angela V Berry, Allison Conelius, Jason A Gluck, David P Nicolau, Joseph L Kuti
Background and objective: Extracorporeal membrane oxygenation (ECMO) is used in critically ill patients that require respiratory and/or cardiac support. Cefiderocol is a novel siderophore antibiotic that may require use in infected critically ill patients supported by ECMO. The objective of this study was to determine the loss of cefiderocol through an ex vivo adult ECMO circuit using a Quadrox-iD oxygenator.
Methods: A 3/8-inch, simulated, ex vivo closed-loop ECMO circuit was prepared with a Quadrox-iD adult oxygenator and primed with fresh whole blood. Cefiderocol was administered into the circuit to achieve a starting concentration of approximately 90 mg/L. Post-oxygenator blood samples were collected at 0, 0.25, 0.5, 1, 2, 4, 6, 12, and 24 h after the addition of the drug to determine the loss in the circuit. A glass control jar was prepared with the same blood matrix and maintained at the same temperature to determine drug degradation. The experiment was conducted in triplicate. The rate of cefiderocol loss in the ECMO circuit was compared with that in the control by one-way analysis of variance.
Results: At 0 h, the difference between the pre- and post-oxygenator concentrations was - 4 ± 4% (range 0 to - 7%). After 24 h, the cefiderocol percent reduction was similar between the ECMO circuit and control (50% ± 13 vs. 50% ± 9, p = 1.0).
Conclusions: The degradation rate of cefiderocol did not differ significantly within the ECMO circuit and control, suggesting no loss due to sequestration or adsorption. Pharmacokinetic studies in patients supported by ECMO are warranted to determine final dosing recommendations.
{"title":"Cefiderocol is Not Sequestered in an Ex Vivo Extracorporeal Membrane Oxygenation (ECMO) Circuit.","authors":"Angela V Berry, Allison Conelius, Jason A Gluck, David P Nicolau, Joseph L Kuti","doi":"10.1007/s13318-023-00840-w","DOIUrl":"10.1007/s13318-023-00840-w","url":null,"abstract":"<p><strong>Background and objective: </strong>Extracorporeal membrane oxygenation (ECMO) is used in critically ill patients that require respiratory and/or cardiac support. Cefiderocol is a novel siderophore antibiotic that may require use in infected critically ill patients supported by ECMO. The objective of this study was to determine the loss of cefiderocol through an ex vivo adult ECMO circuit using a Quadrox-iD oxygenator.</p><p><strong>Methods: </strong>A 3/8-inch, simulated, ex vivo closed-loop ECMO circuit was prepared with a Quadrox-iD adult oxygenator and primed with fresh whole blood. Cefiderocol was administered into the circuit to achieve a starting concentration of approximately 90 mg/L. Post-oxygenator blood samples were collected at 0, 0.25, 0.5, 1, 2, 4, 6, 12, and 24 h after the addition of the drug to determine the loss in the circuit. A glass control jar was prepared with the same blood matrix and maintained at the same temperature to determine drug degradation. The experiment was conducted in triplicate. The rate of cefiderocol loss in the ECMO circuit was compared with that in the control by one-way analysis of variance.</p><p><strong>Results: </strong>At 0 h, the difference between the pre- and post-oxygenator concentrations was - 4 ± 4% (range 0 to - 7%). After 24 h, the cefiderocol percent reduction was similar between the ECMO circuit and control (50% ± 13 vs. 50% ± 9, p = 1.0).</p><p><strong>Conclusions: </strong>The degradation rate of cefiderocol did not differ significantly within the ECMO circuit and control, suggesting no loss due to sequestration or adsorption. Pharmacokinetic studies in patients supported by ECMO are warranted to determine final dosing recommendations.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9799771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-01DOI: 10.1007/s13318-023-00837-5
Ping Wang, Jinrong Liu, Xiaojuan Tan, Fred Yang, James McCabe, Jay Zhang
Background and objectives: Ocedurenone (KBP-5074) is a novel nonsteroidal mineralocorticoid receptor antagonist that has demonstrated safety and efficacy in clinical trials in patients with uncontrolled hypertension and stage 3b/4 chronic kidney disease. This study evaluated the involvement of cytochrome P450 (CYP) isozymes and drug transporters in the biotransformation of ocedurenone, and whether ocedurenone inhibited or induced CYP enzymes and transporters. Clinical pharmacokinetic drug-drug interaction (DDI) of ocedurenone with CYP3A inhibitor and inducer were investigated in healthy volunteers.
Methods: In vitro tests were conducted to determine which CYP enzymes were involved in ocedurenone's metabolism and whether ocedurenone inhibited or induced these CYP enzymes; ocedurenone substrate characteristics for efflux and uptake transporters and its inhibitory potential on major drug transporters were also assessed. A clinical DDI study was conducted in healthy volunteers to evaluate the effects of a strong CYP3A inhibitor (itraconazole) and inducer (rifampin) on ocedurenone's pharmacokinetics.
Results: The in vitro study showed that ocedurenone was primarily metabolized by CYP3A4 and that it did not inhibit CYP enzymes. Ocedurenone appeared to be a substrate of BCRP and P-gp efflux transporters and inhibited BCRP, BSEP, MDR1, MATE1 and 2-K, OATP1B1/3, and OCT1. The clinical DDI study showed that itraconazole reduced ocedurenone's oral clearance by 51% and increased area under the plasma concentration-time curve extrapolated to infinity (AUC0-inf) by 104%, while rifampin increased its oral clearance by 6.4-fold and decreased plasma AUC0-inf by 84%.
Conclusion: Ocedurenone was shown to be a CYP3A substrate, with no inhibition potential on major drug metabolizing CYP enzymes and transporters at clinical efficacious doses. Ocedurenone did not induce CYP1A2 and 3A4 activity in cultured human primary hepatocytes. Clinical DDI study indicated ocedurenone was well tolerated when administered as a single 0.5-mg dose both alone and with itraconazole or rifampin, and while itraconazole had a weak effect on ocedurenone's pharmacokinetics, rifampin had a significant effect reducing systemic exposures.
{"title":"Pharmacokinetics and Drug-Drug Interaction of Ocedurenone (KBP-5074) in vitro and in vivo.","authors":"Ping Wang, Jinrong Liu, Xiaojuan Tan, Fred Yang, James McCabe, Jay Zhang","doi":"10.1007/s13318-023-00837-5","DOIUrl":"https://doi.org/10.1007/s13318-023-00837-5","url":null,"abstract":"<p><strong>Background and objectives: </strong>Ocedurenone (KBP-5074) is a novel nonsteroidal mineralocorticoid receptor antagonist that has demonstrated safety and efficacy in clinical trials in patients with uncontrolled hypertension and stage 3b/4 chronic kidney disease. This study evaluated the involvement of cytochrome P450 (CYP) isozymes and drug transporters in the biotransformation of ocedurenone, and whether ocedurenone inhibited or induced CYP enzymes and transporters. Clinical pharmacokinetic drug-drug interaction (DDI) of ocedurenone with CYP3A inhibitor and inducer were investigated in healthy volunteers.</p><p><strong>Methods: </strong>In vitro tests were conducted to determine which CYP enzymes were involved in ocedurenone's metabolism and whether ocedurenone inhibited or induced these CYP enzymes; ocedurenone substrate characteristics for efflux and uptake transporters and its inhibitory potential on major drug transporters were also assessed. A clinical DDI study was conducted in healthy volunteers to evaluate the effects of a strong CYP3A inhibitor (itraconazole) and inducer (rifampin) on ocedurenone's pharmacokinetics.</p><p><strong>Results: </strong>The in vitro study showed that ocedurenone was primarily metabolized by CYP3A4 and that it did not inhibit CYP enzymes. Ocedurenone appeared to be a substrate of BCRP and P-gp efflux transporters and inhibited BCRP, BSEP, MDR1, MATE1 and 2-K, OATP1B1/3, and OCT1. The clinical DDI study showed that itraconazole reduced ocedurenone's oral clearance by 51% and increased area under the plasma concentration-time curve extrapolated to infinity (AUC<sub>0-inf</sub>) by 104%, while rifampin increased its oral clearance by 6.4-fold and decreased plasma AUC<sub>0-inf</sub> by 84%.</p><p><strong>Conclusion: </strong>Ocedurenone was shown to be a CYP3A substrate, with no inhibition potential on major drug metabolizing CYP enzymes and transporters at clinical efficacious doses. Ocedurenone did not induce CYP1A2 and 3A4 activity in cultured human primary hepatocytes. Clinical DDI study indicated ocedurenone was well tolerated when administered as a single 0.5-mg dose both alone and with itraconazole or rifampin, and while itraconazole had a weak effect on ocedurenone's pharmacokinetics, rifampin had a significant effect reducing systemic exposures.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/7a/3f/13318_2023_Article_837.PMC10322960.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10176052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-01DOI: 10.1007/s13318-023-00838-4
Isabel Piel, Anna Engelen, Dieter Lang, Simone I Schulz, Michael Gerisch, Christine Brase, Wiebke Janssen, Lukas Fiebig, Stefan Heitmeier, Friederike Kanefendt
Background and objectives: Current anticoagulants pose an increased risk of bleeding. The development of drugs targeting factor XIa, like asundexian, may provide a safer treatment option. A human mass‑balance study was conducted to gain a deeper understanding of the absorption, distribution, metabolism, excretion, and potential for drug-drug interaction of asundexian. Additionally, an overview of the biotransformation and clearance pathways for asundexian in humans and bile-duct cannulated (BDC) rats in vivo, as well as in vitro in hepatocytes of both species, is reported.
Methods: The mass balance, biotransformation, and excretion pathways of asundexian were investigated in six healthy volunteers (single oral dose of 25 mg [14C]asundexian) and in BDC rats (intravenous [14C]asundexian 1 mg/kg).
Results: Overall recovery of radioactivity was 101% for humans (samples collected up to 14 days after dosing), and 97.9% for BDC rats (samples collected in the 24 h after dosing). Radioactivity was mainly excreted into feces in humans (80.3%) and into bile/feces in BDC rats (> 94%). The predominant clearance pathways in humans were amide hydrolysis to metabolite M1 (47%) and non-labeled M9 with subsequent N-acetylation to M10; oxidative biotransformation was a minor pathway (13%). In rats, hydrolysis of the terminal amide to M2 was the predominant pathway. In human plasma, asundexian accounted for 61.0% of total drug-related area under the plasma concentration-time curve (AUC); M10 was the major metabolite (16.4% of the total drug-related AUC). Excretion of unmetabolized drug was a significant clearance pathway in both species (human, ~ 37%; BDC rat, ~ 24%). The near-complete bioavailability of asundexian suggests negligible limitations on absorption and first-pass metabolism. Comparison with radiochromatograms from incubations with human or rat hepatocytes indicated consistency across species and a good overall in vitro/in vivo correlation.
Conclusions: Similar to preclinical experiments, total asundexian-derived radioactivity is cleared quantitatively predominantly via feces. Excretion occurs mainly via amide hydrolysis and as the unchanged drug.
{"title":"Metabolism and Disposition of the Novel Oral Factor XIa Inhibitor Asundexian in Rats and in Humans.","authors":"Isabel Piel, Anna Engelen, Dieter Lang, Simone I Schulz, Michael Gerisch, Christine Brase, Wiebke Janssen, Lukas Fiebig, Stefan Heitmeier, Friederike Kanefendt","doi":"10.1007/s13318-023-00838-4","DOIUrl":"https://doi.org/10.1007/s13318-023-00838-4","url":null,"abstract":"<p><strong>Background and objectives: </strong>Current anticoagulants pose an increased risk of bleeding. The development of drugs targeting factor XIa, like asundexian, may provide a safer treatment option. A human mass‑balance study was conducted to gain a deeper understanding of the absorption, distribution, metabolism, excretion, and potential for drug-drug interaction of asundexian. Additionally, an overview of the biotransformation and clearance pathways for asundexian in humans and bile-duct cannulated (BDC) rats in vivo, as well as in vitro in hepatocytes of both species, is reported.</p><p><strong>Methods: </strong>The mass balance, biotransformation, and excretion pathways of asundexian were investigated in six healthy volunteers (single oral dose of 25 mg [<sup>14</sup>C]asundexian) and in BDC rats (intravenous [<sup>14</sup>C]asundexian 1 mg/kg).</p><p><strong>Results: </strong>Overall recovery of radioactivity was 101% for humans (samples collected up to 14 days after dosing), and 97.9% for BDC rats (samples collected in the 24 h after dosing). Radioactivity was mainly excreted into feces in humans (80.3%) and into bile/feces in BDC rats (> 94%). The predominant clearance pathways in humans were amide hydrolysis to metabolite M1 (47%) and non-labeled M9 with subsequent N-acetylation to M10; oxidative biotransformation was a minor pathway (13%). In rats, hydrolysis of the terminal amide to M2 was the predominant pathway. In human plasma, asundexian accounted for 61.0% of total drug-related area under the plasma concentration-time curve (AUC); M10 was the major metabolite (16.4% of the total drug-related AUC). Excretion of unmetabolized drug was a significant clearance pathway in both species (human, ~ 37%; BDC rat, ~ 24%). The near-complete bioavailability of asundexian suggests negligible limitations on absorption and first-pass metabolism. Comparison with radiochromatograms from incubations with human or rat hepatocytes indicated consistency across species and a good overall in vitro/in vivo correlation.</p><p><strong>Conclusions: </strong>Similar to preclinical experiments, total asundexian-derived radioactivity is cleared quantitatively predominantly via feces. Excretion occurs mainly via amide hydrolysis and as the unchanged drug.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/2b/eb/13318_2023_Article_838.PMC10322790.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10176553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-01DOI: 10.1007/s13318-023-00830-y
Tsubasa Watanabe, Tomohiro Yoshikawa, Hiroki Tanaka, Yuko Kinashi, Genro Kashino, Shin-Ichiro Masunaga, Toshimitsu Hayashi, Koki Uehara, Koji Ono, Minoru Suzuki
Background and objective: Boron neutron capture therapy (BNCT) is a binary cancer treatment that combines boron administration and neutron irradiation. The tumor cells take up the boron compound and the subsequent neutron irradiation results in a nuclear fission reaction caused by the neutron capture reaction of the boron nuclei. This produces highly cytocidal heavy particles, leading to the destruction of tumor cells. p-boronophenylalanine (BPA) is widely used in BNCT but is insoluble in water and requires reducing sugar or sugar alcohol as a dissolvent to create an aqueous solution for administration. The purpose of this study was to investigate the pharmacokinetics of 14C-radiolabeled BPA using sorbitol as a dissolvent, which has not been reported before, and confirm whether neutron irradiation with a sorbitol solution of BPA can produce an antitumor effect of BNCT.
Materials and methods: In this study, we evaluated the sugar alcohol, sorbitol, as a novel dissolution aid and examined the consequent stability of the BPA for long-term storage. U-87 MG and SAS tumor cell lines were used for in vitro and in vivo experiments. We examined the pharmacokinetics of 14C-radiolabeled BPA in sorbitol solution, administered either intravenously or subcutaneously to a mouse tumor model. Neutron irradiation was performed in conjunction with the administration of BPA in sorbitol solution using the same tumor cell lines both in vitro and in vivo.
Results: We found that BPA in sorbitol solution maintains stability for longer than in fructose solution, and can therefore be stored for a longer period. Pharmacokinetic studies with 14C-radiolabeled BPA confirmed that the sorbitol solution of BPA distributed through tumors in much the same way as BPA in fructose. Neutron irradiation was found to produce dose-dependent antitumor effects, both in vitro and in vivo, after the administration of BPA in sorbitol solution.
Conclusion: In this report, we demonstrate the efficacy of BPA in sorbitol solution as the boron source in BNCT.
{"title":"Pharmacokinetic Study of <sup>14</sup>C-Radiolabeled p-Boronophenylalanine (BPA) in Sorbitol Solution and the Treatment Outcome of BPA-Based Boron Neutron Capture Therapy on a Tumor-Bearing Mouse Model.","authors":"Tsubasa Watanabe, Tomohiro Yoshikawa, Hiroki Tanaka, Yuko Kinashi, Genro Kashino, Shin-Ichiro Masunaga, Toshimitsu Hayashi, Koki Uehara, Koji Ono, Minoru Suzuki","doi":"10.1007/s13318-023-00830-y","DOIUrl":"https://doi.org/10.1007/s13318-023-00830-y","url":null,"abstract":"<p><strong>Background and objective: </strong>Boron neutron capture therapy (BNCT) is a binary cancer treatment that combines boron administration and neutron irradiation. The tumor cells take up the boron compound and the subsequent neutron irradiation results in a nuclear fission reaction caused by the neutron capture reaction of the boron nuclei. This produces highly cytocidal heavy particles, leading to the destruction of tumor cells. p-boronophenylalanine (BPA) is widely used in BNCT but is insoluble in water and requires reducing sugar or sugar alcohol as a dissolvent to create an aqueous solution for administration. The purpose of this study was to investigate the pharmacokinetics of <sup>14</sup>C-radiolabeled BPA using sorbitol as a dissolvent, which has not been reported before, and confirm whether neutron irradiation with a sorbitol solution of BPA can produce an antitumor effect of BNCT.</p><p><strong>Materials and methods: </strong>In this study, we evaluated the sugar alcohol, sorbitol, as a novel dissolution aid and examined the consequent stability of the BPA for long-term storage. U-87 MG and SAS tumor cell lines were used for in vitro and in vivo experiments. We examined the pharmacokinetics of <sup>14</sup>C-radiolabeled BPA in sorbitol solution, administered either intravenously or subcutaneously to a mouse tumor model. Neutron irradiation was performed in conjunction with the administration of BPA in sorbitol solution using the same tumor cell lines both in vitro and in vivo.</p><p><strong>Results: </strong>We found that BPA in sorbitol solution maintains stability for longer than in fructose solution, and can therefore be stored for a longer period. Pharmacokinetic studies with <sup>14</sup>C-radiolabeled BPA confirmed that the sorbitol solution of BPA distributed through tumors in much the same way as BPA in fructose. Neutron irradiation was found to produce dose-dependent antitumor effects, both in vitro and in vivo, after the administration of BPA in sorbitol solution.</p><p><strong>Conclusion: </strong>In this report, we demonstrate the efficacy of BPA in sorbitol solution as the boron source in BNCT.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9790727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: The demand for physiologically based pharmacokinetic (PBPK) model is increasing currently. New drug application (NDA) of many compounds is submitted with PBPK models for efficient drug development. Tissue-to-plasma partition coefficient (Kp) is a key parameter for the PBPK model to describe differential equations. However, it is difficult to obtain the Kp value experimentally because the measurement of drug concentration in the tissue is much harder than that in plasma.
Objective: Instead of experiments, many researchers have sought in silico methods. Today, most of the models for Kp prediction are using in vitro and in vivo parameters as explanatory variables. We thought of physicochemical descriptors that could improve the predictability. Therefore, we aimed to develop the two-dimensional quantitative structure-activity relationship (2D-QSAR) model for Kp using physicochemical descriptors instead of in vivo experimental data as explanatory variables.
Methods: We compared our model with the conventional models using 20-fold cross-validation according to the published method (Yun et al. J Pharmacokinet Pharmacodyn 41:1-14, 2014). We used random forest algorithm, which is known to be one of the best predictors for the 2D-QSAR model. Finally, we combined minimum in vitro experimental values and physiochemical descriptors. Thus, the prediction method for Kp value using a few in vitro parameters and physicochemical descriptors was developed; this is a multimodal model.
Results: Its accuracy was found to be superior to that of the conventional models. Results of this research suggest that multimodality is useful for the 2D-QSAR model [RMSE and % of two-fold error: 0.66 and 42.2% (Berezohkovsky), 0.52 and 52.2% (Rodgers), 0.65 and 34.6% (Schmitt), 0.44 and 61.1% (published model), 0.41 and 62.1% (traditional model), 0.39 and 64.5% (multimodal model)].
Conclusion: We could develop a 2D-QSAR model for Kp value with the highest accuracy using a few in vitro experimental data and physicochemical descriptors.
背景:目前对基于生理的药代动力学(PBPK)模型的需求日益增加。许多化合物的新药申请(NDA)都是通过PBPK模型提交的,以实现高效的药物开发。组织-等离子体分配系数(Kp)是PBPK模型描述微分方程的关键参数。然而,由于在组织中测量药物浓度比在血浆中测量困难得多,因此很难通过实验获得Kp值。目的:许多研究人员都在寻找计算机方法来代替实验。目前,大多数Kp预测模型都使用体外和体内参数作为解释变量。我们想到了可以提高可预测性的物理化学描述符。因此,我们的目标是建立Kp的二维定量构效关系(2D-QSAR)模型,使用物理化学描述符而不是体内实验数据作为解释变量。方法:根据已发表的方法(Yun et al.),使用20倍交叉验证将我们的模型与传统模型进行比较。药理学杂志,2014(1):1- 4。我们使用随机森林算法,这是已知的2D-QSAR模型的最佳预测器之一。最后,我们结合了最小的体外实验值和理化描述符。在此基础上,建立了利用少量体外参数和理化描述符预测Kp值的方法;这是一个多模态模型。结果:该模型的准确性优于常规模型。本研究结果表明,多模态对2D-QSAR模型是有用的[RMSE和双重误差%:0.66和42.2% (Berezohkovsky), 0.52和52.2% (Rodgers), 0.65和34.6% (Schmitt), 0.44和61.1%(已发表模型),0.41和62.1%(传统模型),0.39和64.5%(多模态模型)]。结论:利用少量体外实验数据和理化描述符,可以建立精度最高的Kp值2D-QSAR模型。
{"title":"Development of a 2D-QSAR Model for Tissue-to-Plasma Partition Coefficient Value with High Accuracy Using Machine Learning Method, Minimum Required Experimental Values, and Physicochemical Descriptors.","authors":"Koichi Handa, Seishiro Sakamoto, Michiharu Kageyama, Takeshi Iijima","doi":"10.1007/s13318-023-00832-w","DOIUrl":"https://doi.org/10.1007/s13318-023-00832-w","url":null,"abstract":"<p><strong>Background: </strong>The demand for physiologically based pharmacokinetic (PBPK) model is increasing currently. New drug application (NDA) of many compounds is submitted with PBPK models for efficient drug development. Tissue-to-plasma partition coefficient (K<sub>p</sub>) is a key parameter for the PBPK model to describe differential equations. However, it is difficult to obtain the K<sub>p</sub> value experimentally because the measurement of drug concentration in the tissue is much harder than that in plasma.</p><p><strong>Objective: </strong>Instead of experiments, many researchers have sought in silico methods. Today, most of the models for K<sub>p</sub> prediction are using in vitro and in vivo parameters as explanatory variables. We thought of physicochemical descriptors that could improve the predictability. Therefore, we aimed to develop the two-dimensional quantitative structure-activity relationship (2D-QSAR) model for K<sub>p</sub> using physicochemical descriptors instead of in vivo experimental data as explanatory variables.</p><p><strong>Methods: </strong>We compared our model with the conventional models using 20-fold cross-validation according to the published method (Yun et al. J Pharmacokinet Pharmacodyn 41:1-14, 2014). We used random forest algorithm, which is known to be one of the best predictors for the 2D-QSAR model. Finally, we combined minimum in vitro experimental values and physiochemical descriptors. Thus, the prediction method for K<sub>p</sub> value using a few in vitro parameters and physicochemical descriptors was developed; this is a multimodal model.</p><p><strong>Results: </strong>Its accuracy was found to be superior to that of the conventional models. Results of this research suggest that multimodality is useful for the 2D-QSAR model [RMSE and % of two-fold error: 0.66 and 42.2% (Berezohkovsky), 0.52 and 52.2% (Rodgers), 0.65 and 34.6% (Schmitt), 0.44 and 61.1% (published model), 0.41 and 62.1% (traditional model), 0.39 and 64.5% (multimodal model)].</p><p><strong>Conclusion: </strong>We could develop a 2D-QSAR model for K<sub>p</sub> value with the highest accuracy using a few in vitro experimental data and physicochemical descriptors.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9794837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}