Clinical Pharmacokinetics最新文献

{"title":"Evaluation of the Potential for Cytochrome P450 and Transporter-Mediated Drug–Drug Interactions for Firsocostat, a Liver-Targeted Inhibitor of Acetyl-CoA Carboxylase","authors":"Elijah J. Weber, Islam R. Younis, Cara Nelson, Ann R. Qin, Timothy R. Watkins, Ahmed A. Othman","doi":"10.1007/s40262-024-01420-0","DOIUrl":"https://doi.org/10.1007/s40262-024-01420-0","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background and Objective</h3><p>Firsocostat is an oral, liver-targeted inhibitor of acetyl-CoA carboxylase in clinical development for the treatment of metabolic dysfunction-associated steatohepatitis. This work evaluated the potential drug–drug interactions (DDIs) of firsocostat as a victim and as a perpetrator, to inform concomitant medication use.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>In this phase I study, healthy participants (<i>n</i> = 13–30 in each of four cohorts) received firsocostat alone or in combination with either victims or perpetrators of cytochrome P450 (CYP) enzymes and drug transporters to evaluate firsocostat as both a victim and perpetrator of DDIs, respectively.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Overall, 80 participants completed the study. As a victim of DDI, firsocostat plasma exposure (area under the plasma concentration-time curve [AUC] from 0 to infinity [AUC_∝]) was 19-fold, 22-fold, 63%, and 38% higher when administered with single-dose rifampin 600 mg (organic anion transporting polypeptide [OATP] 1B1/B3 inhibitor), single-dose cyclosporine A 600 mg (OATP/P-glycoprotein/CYP3A inhibitor), multiple-dose probenecid 500 mg twice daily (evaluated as a uridine diphosphate glucuronosyltransferase [UGT] inhibitor), and multiple-dose voriconazole 200 mg twice daily (CYP3A inhibitor), respectively, compared with the administration of firsocostat alone. As a perpetrator of DDI, multiple-dose administration of firsocostat did not affect the exposure of midazolam 2 mg (CYP3A substrate) or drospirenone/ethinylestradiol 3 mg/0.02 mg (combined oral contraceptive). Study treatments were well-tolerated and all adverse events were mild.</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>Firsocostat can be administered with CYP3A and UGT inhibitors without dose adjustment. However, firsocostat should not be coadministered with strong OATP1B/3 inhibitors, such as rifampin and cyclosporine A. Firsocostat can be administered with CYP3A substrates or combined oral contraceptives without dose modification.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics and Pharmacodynamics of Systemic Corticosteroids in Autoimmune and Inflammatory Diseases: A Review of Current Evidence","authors":"Julia E. Möhlmann, Solaiman Ezzafzafi, Caroline A. Lindemans, Marc H. A. Jansen, Stefan Nierkens, Alwin D. R. Huitema, Matthijs van Luin","doi":"10.1007/s40262-024-01419-7","DOIUrl":"https://doi.org/10.1007/s40262-024-01419-7","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background and Objective</h3><p>Systemic corticosteroids have a long history of use in the treatment of autoimmune and inflammatory diseases. Both efficacy and safety show large interindividual variability (IIV), suggesting that corticosteroids may have the potential for individualised dosing strategies to optimise therapy. This systematic review aims to provide an overview of current evidence on the pharmacokinetic (PK) and pharmacodynamic (PD) relationships of systemic corticosteroids in patients with autoimmune and inflammatory diseases.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>A systematic literature search was conducted in PubMed and Embase for PK/PD studies of systemic corticosteroids in autoimmune and inflammatory diseases in humans published until December 2023. Studies were scored from 1 to 5 according to criteria for the levels of evidence, as inspired by the Oxford Centre for Evidence-Based Medicine.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Twelve studies (1981–2016) were included. The majority of these studies had a small sample size. The corticosteroids involved were prednisone, prednisolone, methylprednisolone and budesonide. Substantial IIV of corticosteroid PK was described in all studies. Evidence for a relationship between the PK of corticosteroids and efficacy was inconclusive and limited. However, there was some evidence for a relationship between the PK of prednisolone and the severity of Cushingoid features.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>There is insufficient evidence to draw firm conclusions on the potential associations between PK and clinical outcome of systemic corticosteroid treatment in autoimmune and inflammatory diseases. This is remarkable given the many decades that steroid drugs have been used in clinical care. Prospective research is recommended with robust and well-defined cohorts to fully quantify the PK/PD associations of corticosteroids.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142227712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated Population Pharmacokinetics of Daprodustat in Patients with Chronic Kidney Disease with Anemia","authors":"Kelly M. Mahar, Shuying Yang, Emir Mesic, Teun M. Post, Sebastiaan C. Goulooze","doi":"10.1007/s40262-024-01417-9","DOIUrl":"https://doi.org/10.1007/s40262-024-01417-9","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background and Objective</h3><p>Daprodustat is a first-in-class hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) approved in the USA for treatment of anemia owing to chronic kidney disease (CKD) in dialysis-dependent adults and in Japan for treatment of CKD in dialysis- and non-dialysis dependent adults. This analysis characterized the population pharmacokinetics (PopPK) of daprodustat in adults with CKD and evaluated the influence of intrinsic and extrinsic factors.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>This PopPK analysis included data from one phase 2B and four phase 3 studies comprising 707 CKD subjects dose titrated to prespecified target hemoglobin levels with daprodustat doses ranging from 1 to 24 mg once daily and 2 to 48 mg given three times a week (TIW). Model development leveraged a previous phase 1/2 PopPK model. Stepwise covariate analysis included 20 extrinsic and intrinsic factors. Model evaluation used standard goodness-of-fit and visual predictive checks.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Daprodustat PopPK was adequately characterized using a three-compartment distribution model with first-order elimination. The absorption phase was described using five transit compartments. Oral clearance and volume of distribution was 24.6 L/h and 26.9 L, respectively. Body weight dependence (with fixed allometric coefficients) of clearance and volume terms was a statistically significant covariate. Concomitant use of clopidogrel (moderate CYP2C8 inhibitor) decreased oral clearance, resulting in higher area under the plasma concentration-time curve (AUC) ratio of 1.59 (90% CI: 1.39–1.82), subjects’ dialysis status (non-dialysis versus dialysis) had an effect on absorption, with C_max ratio of 1.19 (90% CI: 1.09–1.30). None of the other investigated intrinsic or extrinsic covariates, including concomitant administration with phosphate binders, oral iron and acid reducing agents resulted in a significant change in daprodustat systemic exposure.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>The PopPK of daprodustat in the CKD population with anemia was adequately characterized. Allometrically-scaled body weight on clearance and volume, dialysis status on absorption and clopidogrel on clearance were statistically significant covariates.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142198702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dose Justification for Asciminib in Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia with and Without the T315I Mutation.","authors":"Francois Pierre Combes, Sherwin K B Sy, Ying Fei Li, Sebastien Lorenzo, Kohinoor Dasgupta, Shruti Kapoor, Matthias Hoch, Yu-Yun Ho","doi":"10.1007/s40262-024-01411-1","DOIUrl":"https://doi.org/10.1007/s40262-024-01411-1","url":null,"abstract":"<p><strong>Background and objective: </strong>Asciminib is approved in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) treated with ≥ 2 prior tyrosine kinase inhibitors. Here, we aimed to demonstrate similarity in efficacy/safety of asciminib 80 mg once daily (q.d.) versus 40 mg twice daily (b.i.d.) in patients with CML-CP without T315I mutation and support the use of the 200-mg b.i.d. dosage in patients harboring T315I, using model-informed drug development.</p><p><strong>Methods: </strong>Data were collected from 199 patients in the phase I (NCT02081378; 10-200 mg b.i.d. or 10-400 mg q.d.) and 154 patients in the phase III (NCT03106779; 40 mg b.i.d.) studies. Evaluations were based on population pharmacokinetics (PopPK) and exposure-response (efficacy/safety) analyses.</p><p><strong>Results: </strong>PopPK showed comparable exposure (area under the curve, AUC_0-24h) for 40 mg b.i.d. and 80 mg q.d. (12,638 vs 12,646 ng*h/mL); average maximum and minimum plasma concentrations for 80 mg q.d. were 1.61- and 0.72-fold those of 40 mg b.i.d., respectively. Exposure-response analyses predicted similar major molecular response rates for 40 mg b.i.d. and 80 mg q.d. (Week 24: 27.6% vs 24.8%; Week 48: 32.3% vs 30.6%). Results also established adequacy of 200 mg b.i.d. in patients with T315I mutation (Week 24: 20.7%; Week 48: 23.7%), along with a similar safety profile for all dose regimens.</p><p><strong>Conclusions: </strong>Similarity between 40 mg b.i.d. and 80 mg q.d. regimens was investigated, demonstrating similar and substantial efficacy with well-tolerated safety in patients without T315I mutation. The 200-mg b.i.d. dose was deemed safe and effective for patients with T315I mutation.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the Influence of Covariates on Axicabtagene Ciloleucel (axi-cel) Kinetics in Patients with Non-Hodgkin's Lymphoma.","authors":"Magali Chartier, Simone Filosto, Thomas Peyret, Manoj Chiney, Francesca Milletti, Justin Budka, Andre Ndi, Jinghui Dong, Saran Vardhanabhuti, Daqin Mao, Stephen Duffull, Michael Dodds, Rhine Shen","doi":"10.1007/s40262-024-01413-z","DOIUrl":"https://doi.org/10.1007/s40262-024-01413-z","url":null,"abstract":"<p><strong>Background and objective: </strong>Axicabtagene ciloleucel (axi-cel, Yescarta) is an autologous, anti-CD19, chimeric antigen receptor (CAR) T-cell therapy approved for patients with relapsed and refractory non-Hodgkin's lymphoma. Substantial inter-individual variability in cellular kinetics has been observed with CAR-T therapies and factors impacting CAR-T cellular kinetics remain poorly understood. This work reports a population cellular kinetic model of axi-cel in relapsed and patients with refractory non-Hodgkin's lymphoma and investigated the impact of covariates on early and late kinetic phases of CAR-T exposure.</p><p><strong>Methods: </strong>A population cellular kinetic model (NONMEM^® version 7.4) for axi-cel was developed using data from 410 patients (2050 transgene observations) after a single intravenous infusion of 2 × 10⁶ anti-CD19 CAR+ T cells/kg in patients with non-Hodgkin's lymphoma (ZUMA-1, ZUMA-5, and ZUMA-7 clinical studies). A large panel of covariates was assessed to decipher the variability of CAR-T cell kinetics including patient characteristics, product characteristics, and disease types.</p><p><strong>Results: </strong>Axi-cel cellular kinetics were well described by a piecewise model of cellular growth kinetics characterized by an exponential growth phase followed by a triphasic decline phase including a long-term persistence phase. The final cellular kinetic model retained in vitro doubling time during CAR-T cell manufacturing and total number of T cells infused as covariates impacting the duration of the growth phase, which, however, did not substantially influence maximum concentration, area under the concentration-time curve over the first 28 days, or long-term persistence. A statistically significant relationship was observed between maximum concentration and the probability to receive tocilizumab and/or corticosteroids.</p><p><strong>Conclusions: </strong>No covariates considered in this study were found to significantly and substantially predict the exposure profile of axi-cel. Tocilizumab and steroid use were related to maximum concentration, but they were used reactively to treat toxicities that are associated with a higher maximum concentration. Further CAR-T kinetic analyses should consider additional factors to explain the observed variability in cellular kinetics or help establish a dose-exposure relationship.</p><p><strong>Clinical trial registration: </strong>NCT02348216 (ZUMA-1), NCT03105336 (ZUMA-5), and NCT03391466 (ZUMA-7).</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application of Virtual Drug Study to New Drug Research and Development: Challenges and Opportunity.","authors":"Xiuqi Li, Shupeng Liu, Dan Liu, Mengyang Yu, Xiaofei Wu, Hongyun Wang","doi":"10.1007/s40262-024-01416-w","DOIUrl":"https://doi.org/10.1007/s40262-024-01416-w","url":null,"abstract":"<p><p>In recent years, virtual drug study, as an emerging research strategy, has become increasingly important in guiding and promoting new drug research and development. Researchers can integrate a variety of technical methods to improve the efficiency of all phases of new drug research and development, including the use of artificial intelligence, modeling and simulation for target identification, compound screening and pharmacokinetic characteristics evaluation, and the application of clinical trial simulation to carry out clinical research. This paper aims to elaborate on the application of virtual drug study in the key stages of new drug research and development and discuss the opportunities and challenges it faces in supporting new drug research and development.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Development and Application of a Physiologically Based Pharmacokinetic Model for Elagolix in the Adult and Adolescent Population.","authors":"Xinghai Zhang, Xuanxuan Wang, Rui Li, Chenning Zhang, Jianmin Du, Hengli Zhao, Qing Wen","doi":"10.1007/s40262-024-01415-x","DOIUrl":"https://doi.org/10.1007/s40262-024-01415-x","url":null,"abstract":"","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetics and Pharmacodynamics of Dalbavancin and C-Reactive Protein in Patients with Staphylococcal Osteoarticular Infections.","authors":"Pier Giorgio Cojutti, Sara Tedeschi, Eleonora Zamparini, Pierluigi Viale, Federico Pea","doi":"10.1007/s40262-024-01410-2","DOIUrl":"https://doi.org/10.1007/s40262-024-01410-2","url":null,"abstract":"<p><strong>Background and objective: </strong>Dalbavancin is increasingly used for the long-term treatment of chronic osteoarticular infections. A population pharmacokinetic/pharmacodynamic (PK/PD) analysis for assessing the relationship between dalbavancin exposure and C-reactive protein (C-RP) over time was conducted.</p><p><strong>Methods: </strong>Non-linear mixed-effect modeling was fitted to dalbavancin and C-RP concentrations. Monte Carlo simulations assessed the weekly percentage of C-RP reduction associated with different dosing regimens, starting from baseline to < 1 mg/dL.</p><p><strong>Results: </strong>A total of 45 patients were retrospectively included in the analysis. The PK of dalbavancin was described by a two-compartment model, and the PD of C-RP was described by an indirect turnover maximum inhibition model. The total dalbavancin concentration model estimate producing 50% of maximum C-RP production inhibition (IC₅₀) was 0.70 mg/L. Monte Carlo simulations showed that in patients with staphylococcal osteoarticular infections targeting total dalbavancin concentrations at > 14.5 mg/L at any time point may achieve C-RP production inhibition over time in > 95% of patients. Based on this, the findings showed that a cumulative dose of 3000 mg administered in the first 3 weeks may lead to a > 90% C-RP decrease versus baseline in approximately 5-6 weeks. In patients needing treatment prolongation, an additional 1500 mg dose after this period may maintain C-RP concentrations < 1 mg/dL for other 3 weeks.</p><p><strong>Conclusions: </strong>A decrease in C-RP is related to dalbavancin exposure in osteoarticular infections. Targeting dalbavancin plasma concentrations above the efficacy threshold may be associated with effective treatment.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine Learning Methods for Precision Dosing in Anticancer Drug Therapy: A Scoping Review.","authors":"Olga Teplytska, Moritz Ernst, Luca Marie Koltermann, Diego Valderrama, Elena Trunz, Marc Vaisband, Jan Hasenauer, Holger Fröhlich, Ulrich Jaehde","doi":"10.1007/s40262-024-01409-9","DOIUrl":"https://doi.org/10.1007/s40262-024-01409-9","url":null,"abstract":"<p><strong>Introduction: </strong>In the last decade, various Machine Learning techniques have been proposed aiming to individualise the dose of anticancer drugs mostly based on a presumed drug effect or measured effect biomarkers. The aim of this scoping review was to comprehensively summarise the research status on the use of Machine Learning for precision dosing in anticancer drug therapy.</p><p><strong>Methods: </strong>This scoping review was conducted in accordance with the interim guidance by Cochrane and the Joanna Briggs Institute. We systematically searched the databases Medline (via PubMed), Embase and the Cochrane Library for research articles and reviews including results published after 2016. Results were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist.</p><p><strong>Results: </strong>A total of 17 relevant studies was identified. In 12 of the included studies, Reinforcement Learning methods were used, including Classical, Deep, Double Deep and Conservative Q-Learning and Fuzzy Reinforcement Learning. Furthermore, classical Machine Learning methods were compared in terms of their performance and an artificial intelligence platform based on parabolic equations was used to guide dosing prospectively and retrospectively, albeit only in a limited number of patients. Due to the significantly different algorithm structures, a meaningful comparison between the various Machine Learning approaches was not possible.</p><p><strong>Conclusion: </strong>Overall, this review emphasises the clinical relevance of Machine Learning methods for anticancer drug dose optimisation, as many algorithms have shown promising results enabling model-free predictions with the potential to maximise efficacy and minimise toxicity when compared to standard protocols.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dosing Adjustments in Cases of Altered Plasma Protein Binding are Most Needed for Drugs with a Volume of Distribution Below 1.3 L/kg.","authors":"Florin M Musteata","doi":"10.1007/s40262-024-01403-1","DOIUrl":"10.1007/s40262-024-01403-1","url":null,"abstract":"<p><strong>Background: </strong>The present literature offers conflicting views on the importance of changes in plasma protein binding in clinical therapeutics. Furthermore, there are no methods to calculate a new dosing regimen when such changes occur.</p><p><strong>Methods: </strong>Previous models developed by Balaz et al. and Greenblat et al. were used to calculate a plasma protein binding (PPB) score for individual drugs based on the volume of distribution for total concentration and the bound fraction of drug. The models were further used to calculate a new drug dosing interval for cases of altered plasma protein binding. The equations apply best for drugs with fast absorption and fast distribution; they can be used as approximations for drugs with slow distribution by using the volume of distribution at steady state and the rate constant of the elimination phase.</p><p><strong>Results: </strong>The newly developed equations show that changes in plasma protein binding are relevant only for drugs with a positive PPB score; such drugs must have a volume of distribution for total concentration below 1.3 L/kg and high protein binding. It is further shown that the drug dosing interval should be reduced when the remaining fraction of plasma protein binding is below the PPB score.</p><p><strong>Conclusion: </strong>A new method to rank drugs according to the impact of changes in plasma protein binding on their pharmacokinetic profile was developed. The new method was applied to show that drugs with high PPB scores need reductions in their dosing interval when the level of protein binding decreases.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141751295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}