Clinical Pharmacokinetics最新文献

{"title":"A Sequential Population Pharmacokinetic Model of Zilovertamab Vedotin in Patients with Hematologic Malignancies Extrapolated to the Pediatric Population.","authors":"Thijs J Zweers, Jos Lommerse, Eline van Maanen, Manash S Chatterjee","doi":"10.1007/s40262-024-01429-5","DOIUrl":"10.1007/s40262-024-01429-5","url":null,"abstract":"<p><strong>Background and objectives: </strong>Recently a number of antibody-drug conjugate (ADC) pharmacometric models have been reported in the literature, describing one or two ADC-related analytes. The objective of this analysis was to build a population pharmacokinetic (popPK) three-analyte ADC model to describe efficacy and safety of zilovertamab vedotin, an ROR1-targeting ADC conjugated to monomethyl auristatin E (MMAE).</p><p><strong>Methods: </strong>Data from a phase 1 study of zilovertamab vedotin in subjects with hematologic malignancies was used in a stepwise ADC modeling strategy based on the simplified ADC popPK model proposed by Gibiansky. This choice provided opportunity to model three analytes: conjugated monomethyl auristatin E (acMMAE), total monoclonal antibody (total mAb), and free MMAE. The model was extrapolated to the pediatric population using a clearance maturation function and accounting for weight dependent pharmacokinetic (PK) changes.</p><p><strong>Results: </strong>The simplified model provided a good structure to fit the adult acMMAE, total mAb, and free MMAE data. Analysis showed that MMAE was released through deconjugation of the payload and full proteolytic degradation of the acMMAE. Deconjugation was associated with an immediate release of MMAE, proteolytic clearance introduced a delay in the release of MMAE. Simulation of the model extrapolated to the pediatric population was the basis for pediatric dosing strategies for zilovertamab vedotin that were approved in the United States and European Union.</p><p><strong>Conclusions: </strong>The total mAb, acMMAE, and free MMAE model showed a good fit to the data. The pediatric population can match the acMMAE adult exposure at the same weight-based dose regimen without concerns that the toxic MMAE concentration will reach higher levels than found in adults.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1489-1499"},"PeriodicalIF":4.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496332","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":"Use of a PK/PD Model to Select Cetagliptin Dosages for Patients with Type 2 Diabetes in Phase 3 Trials.","authors":"Jinmiao Lu, Jiahong Zhao, Daosheng Xie, Juping Ding, Qiang Yu, Tong Wang","doi":"10.1007/s40262-024-01427-7","DOIUrl":"10.1007/s40262-024-01427-7","url":null,"abstract":"<p><strong>Background: </strong>Cetagliptin is a novel dipeptidyl peptidase-4 (DPP-4) inhibitor developed for the treatment of patients with type 2 diabetes (T2D). Several phase 1 studies have been conducted in China. Modelling and simulation were used to obtain cetagliptin dose for phase 3 trials in T2D patients.</p><p><strong>Methods: </strong>A pharmacokinetic (PK)/pharmacodynamic (PD) model and model-based analysis of the relationship between hemoglobin A1c (HbA1c) and dosage was explored to guide dose selection of cetagliptin for phase 3 trials. The PK/PD data were derived from four phase 1 clinical studies, and sitagliptin 100 mg was employed as a positive control in studies 1, 3, and 4.</p><p><strong>Results: </strong>The PK profiles of cetagliptin were well described by a two-compartment model with first-order absorption, saturated efflux, and first-order elimination. The final PD model was a sigmoid maximum inhibitory efficacy (E_max) model with the Hill coefficient. The final model accurately captured cetagliptin PK/PD, demonstrated by goodness-of-fit plots. Based on weighted average inhibition (WAI), the relationship between HbA1c and dose was well displayed. Cetagliptin 50 mg once daily or above as monotherapy or as add-on therapy appeared more effective in HbA1c reduction than sitagliptin 100 mg. Cetagliptin 50 mg or 100 mg once daily was selected as the dose for phase 3 trials of cetagliptin in T2D patients.</p><p><strong>Conclusions: </strong>The PK/PD model supports dose selection of cetagliptin for phase 3 trials. A model‑informed approach can be used to replace a dose-finding trial and accelerate cetagliptin's development.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1463-1476"},"PeriodicalIF":4.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375230","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":"Model-Informed Precision Dosing of Tacrolimus: A Systematic Review of Population Pharmacokinetic Models and a Benchmark Study of Software Tools.","authors":"Yannick Hoffert, Nada Dia, Tim Vanuytsel, Robin Vos, Dirk Kuypers, Johan Van Cleemput, Jef Verbeek, Erwin Dreesen","doi":"10.1007/s40262-024-01414-y","DOIUrl":"10.1007/s40262-024-01414-y","url":null,"abstract":"<p><strong>Background and objective: </strong>Tacrolimus is an immunosuppressant commonly administered after solid organ transplantation. It is characterized by a narrow therapeutic window and high variability in exposure, demanding personalized dosing. In recent years, population pharmacokinetic models have been suggested to guide model-informed precision dosing of tacrolimus. We aimed to provide a comprehensive overview of population pharmacokinetic models and model-informed precision dosing software modules of tacrolimus in all solid organ transplant settings, including a simulation-based investigation of the impact of covariates on exposure and target attainment.</p><p><strong>Methods: </strong>We performed a systematic literature search to identify population pharmacokinetic models of tacrolimus in solid organ transplant recipients. We integrated selected population pharmacokinetic models into an interactive software tool that allows dosing simulations, Bayesian forecasting, and investigation of the impact of covariates on exposure and target attainment. We conducted a web survey amongst model-informed precision dosing software tool providers and benchmarked publicly available tools in terms of models, target populations, and clinical integration.</p><p><strong>Results: </strong>We identified 80 population pharmacokinetic models, including 44 one-compartment and 36 two-compartment models. The most frequently retained covariates on clearance and distribution parameters were cytochrome P450 3A5 polymorphisms and body weight, respectively. Our simulation tool, hosted at https://lpmx.shinyapps.io/tacrolimus/ , allows thorough investigation of the impact of covariates on exposure and target attainment. We identified 15 model-informed precision dosing software tool providers, of which ten offer a tacrolimus solution and nine completed the survey.</p><p><strong>Conclusions: </strong>Our work provides a comprehensive overview of the landscape of available tacrolimus population pharmacokinetic models and model-informed precision dosing software modules. Our simulation tool allows an interactive thorough exploration of covariates on exposure and target attainment.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1407-1421"},"PeriodicalIF":4.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281375","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":"Coadministration of Cariprazine with a Moderate CYP3A4 Inhibitor in Patients with Schizophrenia: Implications for Dose Adjustment and Safety Monitoring.","authors":"Máté Szabó, Zoltán Hujber, Judit Harsányi, Balázs Szatmári, Zsófia B Dombi, Gabriella Magyar, Zsuzsanna Hegedűs, Piroska Ratskó, Gabriella Pásztor Mészáros, Ágota Barabássy","doi":"10.1007/s40262-024-01431-x","DOIUrl":"10.1007/s40262-024-01431-x","url":null,"abstract":"<p><strong>Background: </strong>Cariprazine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6.</p><p><strong>Aim: </strong>This study aimed to evaluate the effects of erythromycin, a moderate cytochrome P450 (CYP)3A4 inhibitor, on the pharmacokinetics of cariprazine in male patients with schizophrenia, and to assess the influence of CYP2D6 phenotypes on cariprazine metabolism.</p><p><strong>Methods: </strong>Forty-two patients received oral doses of 1.5 mg cariprazine alone for 28 days (to reach steady state), followed by a co-administration of cariprazine 1.5 mg daily with erythromycin 500 mg twice daily (BID) and Enterol 250 mg BID for 21 days, followed by a 14-day post-treatment period. Blood samples were collected at predefined time points and analysed for cariprazine, its two active metabolites: desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), and erythromycin using validated high performance liquid chromatography-tandem mass spectrometry methods. CYP2D6 phenotypes were determined by genotyping. The pharmacokinetic parameters were calculated using non-compartmental analysis.</p><p><strong>Results: </strong>Erythromycin increased the area under the curve (AUC_τ) and peak concentration (C_max) of Total cariprazine (cariprazine + DCAR + DDCAR) by about 40-50% but did not affect the time to peak concentration (T_max). The CYP2D6 phenotypes had no substantial effect on the pharmacokinetics of cariprazine and its metabolites, either alone or in combination with erythromycin. Cariprazine was well tolerated and safe.</p><p><strong>Conclusion: </strong>The findings suggest that co-administration of cariprazine with moderate CYP3A4 inhibitors may require dose adjustment or monitoring; however, pharmacogenetic testing for CYP2D6 is not necessary for optimising cariprazine therapy.</p><p><strong>Trial registration: </strong>Trial registration number (EudraCT Number): 2018-003721-28. Date of registration: 21-SEP-2018.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1501-1510"},"PeriodicalIF":4.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11522146/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"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":"32 1","pages":""},"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":"63 1","pages":""},"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":"2013 1","pages":""},"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":"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":"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":" ","pages":"1239-1249"},"PeriodicalIF":4.6,"publicationDate":"2024-09-01","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":"Extrapolation of the Efficacy and Pharmacokinetics of Belimumab to Support its Use in Children with Lupus Nephritis.","authors":"Richard Dimelow, Lia Liefaard, Yulia Green, Ryan Tomlinson","doi":"10.1007/s40262-024-01422-y","DOIUrl":"10.1007/s40262-024-01422-y","url":null,"abstract":"<p><strong>Background and objective: </strong>Lupus nephritis (LN), a severe manifestation of systemic lupus erythematosus, has greater severity in children versus adults. Belimumab is approved for systemic lupus erythematosus treatment in patients aged ≥ 5 years, and for active LN in adults in the European Union, China, Japan and Latin America, and patients aged ≥ 5 years in the USA. Low prevalence of paediatric active LN makes conducting a clinical study within a reasonable period unfeasible. We describe a model-based extrapolation of belimumab efficacy and pharmacokinetics from adults to children with LN to support US Food and Drug Administration approval of intravenous belimumab 10 mg/kg (administered every 4 weeks after the loading dose) in children (aged 5-17 years) with active LN.</p><p><strong>Methods: </strong>This concept assumed that disease progression, response to belimumab, exposure-response, and the target belimumab exposure for efficacy are similar across adult and paediatric systemic lupus erythematosus and LN, evaluated against the published literature for paediatric LN and belimumab systemic lupus erythematosus and LN clinical trial data in adults and children. A two-compartmental population pharmacokinetic model, previously developed for adults with LN, was used to extrapolate belimumab pharmacokinetics to children with LN.</p><p><strong>Results: </strong>The model captured the dependence of time-varying proteinuria on belimumab clearance, and therefore exposure. Sufficient target exposures for efficacy were achieved in children with active LN. A small proportion of children aged 5-11 years are predicted to have exposures below adult levels but no impact to efficacy is expected.</p><p><strong>Conclusions: </strong>Our model demonstrated that intravenous belimumab 10 mg/kg every 4 weeks is appropriate for children aged 5-17 years with active LN.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1313-1326"},"PeriodicalIF":4.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11450137/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physiologically Based Pharmacokinetic Modelling in Critically Ill Children Receiving Anakinra While on Extracorporeal Life Support.","authors":"Samuel Dubinsky, Abdullah Hamadeh, Carina Imburgia, Autumn McKnite, J Porter Hunt, Kristy Wong, Cassandra Rice, Joseph Rower, Kevin Watt, Andrea Edginton","doi":"10.1007/s40262-024-01424-w","DOIUrl":"10.1007/s40262-024-01424-w","url":null,"abstract":"<p><strong>Background and objective: </strong>Because of the pathophysiological changes associated with critical illness and the use of extracorporeal life support (ECLS) such as continuous renal replacement therapy (CRRT) and extracorporeal membrane oxygenation (ECMO), the pharmacokinetics of drugs are often altered. The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for anakinra in children that accounts for the physiological changes associated with critical illness and ECLS technology to guide appropriate pharmacotherapy.</p><p><strong>Methods: </strong>A PBPK model for anakinra was first developed in healthy individuals prior to extrapolating to critically ill children receiving ECLS. To account for the impact of anakinra clearance by the dialysis circuit, a CRRT compartment was added to the pediatric PBPK model and parameterized using data from a previously published ex-vivo study. Additionally, an ECMO compartment was added to the whole-body structure to create the final anakinra ECLS-PBPK model. The final model structure was validated by comparing predicted concentrations with observed patient data. Due to limited information in guiding anakinra dosing in this population, in-silico dose simulations were conducted to provide baseline recommendations.</p><p><strong>Results: </strong>By accounting for changes in physiology and the addition of ECLS compartments, the final ECLS-PBPK model predicted the observed plasma concentrations in an adolescent receiving subcutaneous anakinra. Furthermore, dosing simulations suggest that anakinra exposure in adolescents receiving ECLS is similar to that in healthy counterparts.</p><p><strong>Conclusion: </strong>The anakinra ECLS-PBPK model developed in this study is the first to predict plasma concentrations in a population receiving simultaneous CRRT and ECMO. Dosing simulations provided may be used to inform anakinra use in critically ill children and guide future clinical trial planning.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1343-1356"},"PeriodicalIF":4.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342871","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}