The Journal of Clinical Pharmacology最新文献

{"title":"Influence of Disease Type and Activity on Adalimumab Exposure in Children with Inflammatory Rheumatic Diseases","authors":"Klervi Golhen PharmD, PhD,&nbsp;Tatjana Welzel MD,&nbsp;Andrew Atkinson PhD,&nbsp;Gilbert Koch PhD,&nbsp;Dominic Braem PhD,&nbsp;Johannes van den Anker MD, PhD,&nbsp;Andreas Woerner MD,&nbsp;Marc Pfister MD,&nbsp;Verena Gotta PhD","doi":"10.1002/jcph.70045","DOIUrl":"10.1002/jcph.70045","url":null,"abstract":"<p>Understanding adalimumab pharmacokinetics (PK) in pediatric inflammatory rheumatic diseases (PIRD) could facilitate individualized treatment strategies. This pharmacometric (PMX) analysis, utilizing prospectively collected data, aimed to develop a PMX model investigating associations between disease-specific factors and adalimumab exposure in PIRD. PK data originating from a prospective two-center study including 36 children with PIRD (weight IQR: 33-55 kg) receiving subcutaneous adalimumab (IQR: 30-40 mg biweekly; n = 28 at steady state, n = 8 after first dose, i.e., treatment naïve) were analyzed. A total of 72 adalimumab concentrations were available for PMX analysis, measured at 1-9 days and 10-14 days post-dose. In addition to disease type (juvenile idiopathic arthritis [JIA] vs idiopathic uveitis) and disease activity (inactive/mild/minimal/moderate/severe), associations between methotrexate (MTX) co-administration and duration of adalimumab treatment with apparent clearance (CL/F) were investigated. A one-compartment model with standard allometric scaling adequately described adalimumab concentration–time data, with higher inter-individual variability in apparent clearance (63%). CL/F showed trends of association with disease type (52% higher in JIA vs idiopathic uveitis, <i>P</i> &lt; .1), disease activity (12% higher in active vs inactive disease, <i>P</i> &lt; .1), and duration of adalimumab (higher with longer duration, <i>P</i> &lt; 0.1) but not MTX co-administration (n.s.). However, none of these factors could be incorporated into the model with sufficient precision, except for bodyweight. While this PMX analysis suggests disease-specific factors may influence adalimumab exposure in children with PIRD, additional prospective studies are warranted to further characterize influence of disease-specific factors on drug exposure and their effects on drug response with goal to facilitate implementation of personalized dosing strategies in pediatric rheumatology.</p><p>What is already known on this topic\u0000\u0000 </p><p>What this study adds\u0000\u0000 </p><p>How this study might affect research, practice, or policy\u0000\u0000 </p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 10","pages":"1234-1245"},"PeriodicalIF":0.0,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144133346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetics and Exposure–Response Relationships of Etrolizumab in Patients with Moderately-to-Severely Active Crohn's Disease","authors":"Anita Moein PhD,&nbsp;Jakob Ribbing PhD,&nbsp;Moustafa M. A. Ibrahim PhD,&nbsp;Wenhui Zhang PhD,&nbsp;Nastya Kassir PharmD, PhD","doi":"10.1002/jcph.70043","DOIUrl":"10.1002/jcph.70043","url":null,"abstract":"<p>This study aimed to characterize the pharmacokinetics (PK) of etrolizumab, an IgG1-humanized monoclonal anti-β7 integrin antibody, and assess its exposure–response (ER) relationship for key clinical outcomes in patients with moderately-to-severely active Crohn's disease. ER analyses were based on data from Phase 3 BERGAMOT trial, which evaluated etrolizumab at 105 or 210 mg during induction phase and 105 mg during maintenance phase. Population pharmacokinetic analysis was performed to characterize etrolizumab PK and identify influential covariates. ER analyses were conducted at end of induction and maintenance for clinical remission, endoscopic improvement, and endoscopic remission. ER modeling was performed using logistic regression, and full covariate model was used to examine the impact of baseline covariates on clinical outcomes. Pharmacokinetics of etrolizumab was best characterized using a two-compartment model with first-order absorption, demonstrating a time-dependent decrease in clearance. Typical maximum reduction of clearance was 22.0% (95% CI: 20.5%-23.5%) with onset half-life of 3.45 (95% CI: 2.84-4.04) weeks. Baseline body weight, albumin, and C-reactive protein were the most impactful covariates for etrolizumab exposure. Based on population PK results, trough concentration at Week 4 of induction was selected as exposure metric. Etrolizumab exposure–response slope was significant (<i>P</i> &lt; .05) for clinical remission, endoscopic improvement, and endoscopic remission final models in maintenance phase, but none of final ER models of induction phase. For all induction ER endpoints, tumor necrosis factor (TNF)-naive patients had significantly higher probability of a favorable outcome at end of induction compared to TNF-experienced patients. In summary, exposure–response was more evident at end of maintenance than at end of induction.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 10","pages":"1208-1219"},"PeriodicalIF":0.0,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70043","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144121213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of Analysis of Covariance and Analysis of Variance in Pharmacokinetic Similarity Studies","authors":"Brett A. Martini MPH,&nbsp;Ping Ji PhD,&nbsp;Jiang Liu PhD,&nbsp;Jan-Shiang Taur PhD,&nbsp;Jianmeng Chen PhD, MD,&nbsp;Suresh Doddapaneni PhD,&nbsp;Chandrahas Sahajwalla PhD,&nbsp;Sarah J. Schrieber PharmD","doi":"10.1002/jcph.70041","DOIUrl":"10.1002/jcph.70041","url":null,"abstract":"<p>The aim of this study was to evaluate the impact of demographic covariates on pharmacokinetic (PK) similarity assessment. A total of 30 PK similarity studies were analyzed to compare the use of analysis of covariance (ANCOVA) and analysis of variance (ANOVA). Trial simulations were conducted to further compare the two statistical approaches by varying sample size and covariates. Our analyses showed that ANCOVA and ANOVA were generally comparable in establishing PK similarity between the two products in the PK similarity studies. However, ANCOVA was observed to produce narrower confidence intervals and thus demonstrate higher power, particularly when the sample size was small.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 10","pages":"1322-1327"},"PeriodicalIF":0.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144095421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating Tranexamic Acid Dosing Strategies for Postpartum Hemorrhage: A Population Pharmacokinetic Approach in Pregnant Individuals","authors":"Allison Dunn PharmD, MS,&nbsp;Mina Felfeli BS,&nbsp;Sebastian M. Seifert MD,&nbsp;Sixtine Gilliot PhD,&nbsp;Anne-Sophie Ducloy-Bouthors MD,&nbsp;Haleem Shakur-Still ,&nbsp;Amber Geer ,&nbsp;Stanislas Grassin-Delyle PhD,&nbsp;Naomi L. Luban MD,&nbsp;Johannes N. van den Anker MD, PhD,&nbsp;Jogarao V. S. Gobburu PhD,&nbsp;Ian Roberts MD, PhD,&nbsp;Homa K. Ahmadzia MD, MPH","doi":"10.1002/jcph.70031","DOIUrl":"10.1002/jcph.70031","url":null,"abstract":"<p>Tranexamic acid (TXA) is used for the treatment and occasionally prevention of postpartum hemorrhage (PPH); however, questions still remain regarding dosing regimen optimization. This study evaluated TXA pharmacokinetic (PK) data from four clinical trials (NCT: 04274335, 03287336, 00872469, and 02797119) conducted in pregnant participants receiving intravenous, intramuscular, or oral TXA to prevent or treat PPH. The goal of this analysis was to comprehensively characterize TXA PK in a large, heterogeneous population of pregnant individuals to (1) assess the need for weight-based dosing and (2) compare exposure target attainment for alternative routes of administration. A population PK analysis was performed using nonlinear mixed-effects modeling in Pumas, and a stepwise approach was implemented to select the structural model and identify significant covariates. A total of 211 pregnant participants who received between 0.35 and 4 g of TXA intravenously, orally, or intramuscularly offered 1303 TXA plasma concentrations for model development. A two-compartment model with first-order elimination and first-order absorption for both intramuscular and oral administration best described the disposition of TXA. Actual body weight was the only statistically significant covariate identified, but inclusion into the model did not explain a substantial amount of the observed variability. Simulations of virtual pregnant individuals indicated minimal differences in TXA exposure between fixed and weight-based dosing regimens, supporting the use of fixed dosing. Intramuscular TXA was additionally found to be a viable alternative to intravenous administration, achieving similar target exposure metrics.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 10","pages":"1262-1272"},"PeriodicalIF":0.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12226878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144095425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetics of Alfentanil in Children","authors":"Lorena Medina-Aymerich PhD,&nbsp;Ngoc (Betty) Ngo PharmD,&nbsp;Daniel Gonzalez PharmD, PhD,&nbsp;Chi D. Hornik PharmD,&nbsp;Amira Al-Uzri MD, MCR,&nbsp;Rachel G. Greenberg MD, MB, MHS,&nbsp;Sarah G. Anderson MS,&nbsp;Elizabeth H. Payne PhD,&nbsp;Sitora Turdalieva MS,&nbsp;Stephen J. Balevic MD, PhD,&nbsp;the Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee","doi":"10.1002/jcph.70044","DOIUrl":"10.1002/jcph.70044","url":null,"abstract":"<p>Alfentanil is an opioid analgesic and anesthetic agent used in surgical procedures. Despite its widespread use in children, the U.S. Food and Drug Administration label lacks specific dosing recommendations for those under 12 years. A population pharmacokinetic analysis was performed using NONMEM (v7.5) to characterize alfentanil's disposition in children. The study included 58 plasma concentrations from 42 patients who received intravenous alfentanil as part of usual care. Median age was 7.57 years (range: 0.33-17.80) and median dosing was 12.5 mcg/kg (range: 4-43). A one-compartment model with first-order elimination best described alfentanil's pharmacokinetics. Among body size measures, total body weight (WT) significantly influenced clearance (CL [L/h]) = 7.42 × (WT/70)^0.75) and volume of distribution (V [L]) = 12.6 × (WT/70)1). Inter-individual variability decreased after the inclusion of WT, coefficients of variation were reduced from 104% to 58% and from 169% to 83%, for CL and V, respectively. The final model facilitated simulations to achieve target efficacious analgesic and anesthetic concentrations. For analgesia, an initial 10 mcg/kg bolus (for the first hour) followed by an 8 mcg/kg/h infusion (starting at 1 h) achieved the efficacious targeted concentrations (10-100 ng/mL). For procedures that typically require minimal or moderate sedation, a 25 mcg/kg bolus followed by a 20 mcg/kg/h infusion (starting at 5 min) achieved the targeted concentrations (50-200 ng/mL, depending on the procedure). These regimens should be prospectively evaluated to ensure their safety and confirm their efficacy. Overall, this study provides valuable insights into pharmacokinetics and dosing of alfentanil in children.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 10","pages":"1220-1233"},"PeriodicalIF":0.0,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144081402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Hepatic or Renal Impairment on Pharmacokinetics of Fruquintinib","authors":"Martha Gonzalez BSc,&nbsp;Zhao Yang PhD,&nbsp;William Schelman MD, PhD,&nbsp;Thomas C. Marbury MD,&nbsp;Juan C. Rondon MD, JD, CPI,&nbsp;William Smith MD,&nbsp;Xiaofei Zhou PhD,&nbsp;Neeraj Gupta PhD,&nbsp;Caly Chien PhD","doi":"10.1002/jcph.70040","DOIUrl":"10.1002/jcph.70040","url":null,"abstract":"<p>Fruquintinib (FRUZAQLA^TM) is a highly selective tyrosine kinase inhibitor of all three vascular endothelial growth factor receptors (-1, -2, and -3). Two Phase 1, open-label, single-dose studies investigated the impact of hepatic or renal impairment on the pharmacokinetics and tolerability of fruquintinib. Participants with moderate renal impairment (creatinine clearance [CrCl] 30-59 mL/min; eight participants) and matched healthy controls (eight participants for each study) received fruquintinib 5 mg. Participants with moderate hepatic impairment (Child–Pugh B; eight participants) and severe renal impairment (CrCl 15-29 mL/min; eight participants) received fruquintinib 2 mg. Pharmacokinetic samples were collected over 240 h. Fruquintinib pharmacokinetics were similar between participants with moderate hepatic impairment and healthy controls; geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for maximum plasma concentration (C_max), area under the plasma concentration–time curve from 0 to time of last measurable concentration (AUC_0-t), and AUC from 0 to infinity (AUC_0-inf) were 1.04 (0.87-1.24), 0.89 (0.64-1.23), and 0.91 (0.66-1.26), respectively. Fruquintinib pharmacokinetics were similar between participants with severe or moderate renal impairment and healthy controls. Compared with healthy controls, the respective GMRs (90% CIs) for C_max, AUC_0-t, and AUC_0-inf for participants with severe renal impairment were 0.89 (0.78-1.03), 0.97 (0.83-1.14), and 1.01 (0.85-1.19), and for participants with moderate renal impairment were 0.95 (0.78-1.15), 1.06 (0.89-1.26), and 1.07 (0.89-1.28). Fruquintinib was generally well tolerated. These results support fruquintinib use without dose adjustment (5 mg daily, 3 weeks on, and 1 week off) in patients with moderate hepatic impairment or moderate to severe renal impairment.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 10","pages":"1273-1285"},"PeriodicalIF":0.0,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70040","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144046496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physiologically Based Pharmacokinetic Modeling to Predict Nicotine Pharmacokinetics of Nicotine Pouches Under Naturalistic Use Conditions","authors":"Ali Salehi PhD,&nbsp;Mohamadi A. Sarkar PhD, FCP,&nbsp;Jennifer H. Smith PhD,&nbsp;Ali A. Rostami PhD","doi":"10.1002/jcph.70038","DOIUrl":"10.1002/jcph.70038","url":null,"abstract":"<p>Adult users of traditional tobacco products like combustible cigarettes (CC) or moist smokeless tobacco (MST) products can reduce exposure to toxicants by switching to potentially less harmful alternatives such as tobacco-free nicotine pouches (NP). Nicotine exposure assessment is an important consideration to determine the switching potential of NPs. These measurements are often conducted using randomized clinical studies. However, characterizing nicotine exposure under real-world use conditions can further inform these assessments. We propose a framework based on physiologically based pharmacokinetic (PBPK) modeling that integrates typical use patterns and clinical pharmacokinetic (PK) data to predict nicotine exposure under actual use conditions. A tissue permeation model precedes the PBPK modeling and is characterized by two physiological parameters, nicotine diffusivity, and effective tissue thickness, which were determined and validated using literature data. A product-specific tissue uptake fraction was determined by regression of nicotine pharmacokinetics measured under controlled use conditions and applied consistently for alternative use scenario analyses. Nicotine PK profiles were predicted under various use scenarios for cigarette smoking or MST use and compared to that from the use of two NPs, namely on!^® and on! PLUS™ NPs (Test Products). The nicotine PK parameters predicted under real-world use conditions were not higher for Test Products relative to cigarettes or MST. The proposed modeling here can further inform nicotine exposure under actual use conditions. PBPK modeling can be a fit-for-purpose tool for predicting nicotine exposure under various use scenarios.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 10","pages":"1297-1309"},"PeriodicalIF":0.0,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70038","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144054942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Can Methotrexate Monotherapy Achieve Clinical Remission in Patients with Active Rheumatoid Arthritis? A Model-Based Meta-Analysis","authors":"Shengyang Chen MD,&nbsp;Yangrui Wu MD,&nbsp;Wei Huang MD,&nbsp;Jianxing Zhou MD,&nbsp;Zipeng Wei MD,&nbsp;Xuemei Wu PhD","doi":"10.1002/jcph.70039","DOIUrl":"10.1002/jcph.70039","url":null,"abstract":"<p>This study utilized model-based meta-analysis (MBMA) to systematically assess the efficacy of methotrexate (MTX) monotherapy in improving rheumatoid arthritis (RA) symptoms and function. The assessment was based on indicators such as Disease Activity Score 28 (DAS28), Health Assessment Questionnaire, and American College of Rheumatology (ACR) criteria. Additionally, the study investigated the impact of dosage, disease duration, and serum markers—C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)—on treatment efficacy. A systematic review of randomized controlled trials yielded data from 69 studies involving 7999 patients. Efficacy models for DAS28, ACR20, and ACR50 were developed to explore the impact of time and dosage, with simulations conducted to predict outcomes at 12 weeks. Results showed that the maximum reduction in DAS28 (Emax) was −54.90% (RSE: 13%), with an ET50 of 20.6 weeks (RSE: 26%). For ACR20 and ACR50, Emax values were 70.3% (RSE: 3%) and 49.4% (RSE: 24%), with ET50s of 6.69 (RSE: 7%) and 27.3 (RSE: 37%) weeks, respectively. Neither dosage nor patient-specific factors like disease duration, CRP, or ESR significantly influenced efficacy. MTX is effective in the early treatment of RA but often fails to achieve remission in patients.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 10","pages":"1310-1321"},"PeriodicalIF":0.0,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70039","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144026592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Systematic Evaluation of the Dosing Regimens for Approved Targeted Therapies and Immune Checkpoint Inhibitors in Metastatic Renal Cell Carcinoma From a Project OPTIMUS Perspective","authors":"Zhiyuan Tan MSc,&nbsp;Swantje Völler PhD,&nbsp;Aymara Sancho-Araiz PhD,&nbsp;Catherijne A. J. Knibbe PharmD, PhD,&nbsp;Dirk Jan A. R. Moes PharmD, PhD","doi":"10.1002/jcph.70035","DOIUrl":"10.1002/jcph.70035","url":null,"abstract":"<p>Targeted therapies and immune checkpoint inhibitors (ICIs) have significantly improved survival outcomes in metastatic renal cell carcinoma (mRCC) but are often associated with high rates of adverse events, leading to dose reductions or treatment discontinuation. The FDA's recent initiative, Project OPTIMUS, emphasizes the importance of optimizing dosing regimens in oncology clinical development, and moves beyond the conventional maximum tolerated dose approach. In this study, we aimed to review and redefine the approved dosing strategies for targeted therapies and ICIs in mRCC from the Project OPTIMUS perspective, including pazopanib, axitinib, cabozantinib, sunitinib, everolimus, and nivolumab. A comprehensive summary of FDA clinical pharmacology reviews and clinical studies performed in routine clinical practice was conducted, alongside model-informed simulations of pharmacokinetic profiles with approved and alternative regimens. Results demonstrated that actual tolerated doses in clinical practice were 46.1% to 86% lower than the approved dosages, with up to 75% of patients requiring dose adjustments. Model-informed simulations suggested that for most targeted therapies, a 14%-50% dose reduction maintained comparable efficacy while improving tolerability. For nivolumab, simulations confirmed adequate drug exposure with the approved flat dose regimens, without an increase of adverse effects. In conclusion, we identified optimized dosing regimens that could improve drug tolerability while maintaining efficacy for approved targeted therapies and ICIs in mRCC. We suggest that these optimized dosing regimens should be considered for use in clinical practice and that the optimal exposure range should be included in drug labels to support pharmacokinetically guided dose individualization in clinical practice.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 10","pages":"1187-1207"},"PeriodicalIF":0.0,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70035","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144065158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Physiologically Based Modeling Approach to Evaluate Intravenous Levetiracetam Dosing in Term and Preterm Neonates","authors":"Alexis Johnson BS, MS,&nbsp;Nolan Thomas BS,&nbsp;Max Blumenthal BS,&nbsp;Chrysanthy Ikonomidou MD, PhD,&nbsp;Sin Yin Lim PharmD, MS","doi":"10.1002/jcph.70037","DOIUrl":"10.1002/jcph.70037","url":null,"abstract":"<p>Seizures are the most common neurologic emergency in neonates and are associated with significant morbidity and mortality. Current first-line pharmacotherapy, phenobarbital, is associated with serious adverse effects, including impairment of the developing brain. Levetiracetam is a well-tolerated alternative; however, its use is limited because its optimal dosing in neonates remains unknown. Additionally, limited knowledge of levetiracetam pharmacokinetics in neonates, especially preterm neonates, means they generally receive the same weight-based dosing. This may put preterm neonates at risk of increased adverse events or insufficient drug effects. This study developed a physiologically based pharmacokinetic (PBPK) model for levetiracetam in term and preterm neonates to evaluate their pharmacokinetic differences. After accounting for the physiological changes, a 1.56-fold increase in drug tissue distribution was needed to represent the increased volume of distribution of levetiracetam in neonates. In term neonates, scaling renal clearance from children based on estimated glomerular filtration rate required a 61% increase to accurately describe renal clearance. Additionally, allometric scaling to extrapolate metabolic clearance required age-dependent corrections to account for the reduced metabolic clearance. In preterm neonates, extrapolated renal clearance was approximately equal to observed total clearance, suggesting renal clearance as the sole elimination route. Consistently, predicted metabolic clearance approached zero when the postmenstrual age was &lt;37.5 weeks. Our simulations showed that common intravenous levetiracetam dosing regimens resulted in higher plasma concentrations in more premature neonates or those with reduced kidney function. In preterm neonates, these regimens may result in plasma concentrations exceeding toxicity thresholds, indicating a need for lower weight-based dosing.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 10","pages":"1246-1261"},"PeriodicalIF":0.0,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70037","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}