Clinical Pharmacokinetics最新文献

{"title":"Informing Sampling Design for Lung Distribution Studies Using a Pulmonary Population Minimal PBPK Model.","authors":"Haini Wen, Muhammad Waqas Sadiq, Markus Fridén, Jens M Hohlfeld, Lena E Friberg, Elin M Svensson","doi":"10.1007/s40262-026-01664-y","DOIUrl":"10.1007/s40262-026-01664-y","url":null,"abstract":"<p><strong>Background: </strong>Understanding intrapulmonary pharmacokinetics (PK) following inhalation remains a significant challenge in drug development and repurposing. Current lung sampling methods include bronchoalveolar lavage (BAL), biopsies, and the more recent bronchosorption technique, which enhances regional specificity while reducing potential quantification errors. This study aimed to develop a pulmonary population physiologically based pharmacokinetic (PBPK) model for inhaled salbutamol by integrating data from all three sampling techniques to improve PK predictions and to compare different sampling strategies to optimize future study designs.</p><p><strong>Methods: </strong>A population-based minimal PBPK model was developed using data from a previously published study (NCT03524066) investigating salbutamol's pulmonary and plasma PK in 13 healthy volunteers after inhalation. Simulations assessed the impact of permeability on pulmonary PK profiles and BAL-derived epithelial lining fluid (ELF)-to-plasma ratios using salbutamol as a reference compound. Stochastic simulation-estimation (SSE) methods were employed to assess the feasibility of different sampling strategies for estimating key parameters of the PBPK model. First, we evaluated using one or two sampling techniques within a single bronchoscopy session. Second, we compared uniform and staggered bronchosorption-based sampling strategies for drugs from different permeability categories.</p><p><strong>Results: </strong>The minimal PBPK model described pulmonary PK of salbutamol across the lung and estimated the unbound tissue-plasma partition coefficient for the lung ( <math><msub><mi>K</mi> <mrow><mtext>p</mtext> <mo>,</mo> <mtext>u</mtext> <mo>,</mo> <mtext>lung</mtext></mrow> </msub> </math> ) and the effective permeability ( <math><msub><mi>P</mi> <mtext>eff</mtext></msub> </math> ) of salbutamol as 11.0 and 0.543 m/h, respectively. Inter-individual variabilities (IIV) were found on plasma clearance and lung deposition fraction. No significant IIV was detected on <math><msub><mi>K</mi> <mrow><mtext>p</mtext> <mo>,</mo> <mtext>u</mtext> <mo>,</mo> <mtext>lung</mtext></mrow> </msub> </math> or <math><msub><mi>P</mi> <mtext>eff</mtext></msub> </math> . Simulations indicated that low-permeability drugs exhibited higher concentrations in the ELF, while high-permeability drugs accumulated more in lung tissues, after inhalation. Results from SSE showed that bronchosorption plus biopsy were the most informative two-technique combination and bronchosorption alone was the best single-technique option. Additionally, the optimal sampling strategy for both uniform and staggered sampling depended on drug permeability, with early time points favoured for high-permeability drugs and later or broader windows needed for low-permeability drugs.</p><p><strong>Conclusion: </strong>A pulmonary population PBPK model for inhaled salbutamol was developed by integrating detailed intrapulmonary data f","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1257-1272"},"PeriodicalIF":4.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13461897/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148344141","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":"Quantitative Pharmacology Justifying Ribociclib Dose in Early Breast Cancer.","authors":"Yan Ji, Craig Wang, Francois Pierre Combes, Yu-Yun Ho, Peter A Fasching, Michael Untch, Juan Pablo Zarate, John Crown","doi":"10.1007/s40262-026-01643-3","DOIUrl":"10.1007/s40262-026-01643-3","url":null,"abstract":"<p><strong>Background and objective: </strong>Ribociclib was recently approved for the treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative early breast cancer (EBC) at the starting dose of 400 mg orally once daily (3 weeks on/1 week off), following previous approval in hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer at the starting dose of 600 mg orally once daily (3 weeks on/1 week off). This study aims to characterize ribociclib pharmacokinetics and its relationship with QT interval corrected according to Fridericia's formula (QTcF) in patients with EBC and justify the dose in EBC.</p><p><strong>Methods: </strong>Data from several studies, including the pivotal phase III trial in patients with EBC and phase I-III trials in patients with advanced breast cancer and advanced cancer were analyzed. Ribociclib pharmacokinetics was characterized by non-compartmental or population pharmacokinetic analyses. The exposure-QTcF relationship was assessed by linear mixed-effects modeling. Neutropenia and QTcF data were compared by dose and population.</p><p><strong>Results: </strong>At the 400-mg dose, ribociclib steady-state clearance was ~ 20% higher in patients with EBC than patients with advanced cancer, suggesting differences in pharmacokinetics between populations. Steady-state mean area under the plasma concentration-time curve and maximum (peak) plasma drug concentration were ~ 50% lower and steady-state clearance was ~ 50% higher in patients with EBC receiving 400 mg compared with patients with advanced cancer and advanced breast cancer receiving 600 mg, attributed to differences in both dose and population. The pharmacokinetic-QTcF analysis showed that the patient population was a significant covariate in QTcF response. The model-estimated mean change from baseline in QTcF at steady-state maximum (peak) plasma drug concentration was substantially lower in patients with EBC receiving 400 mg (10.0 ms) versus in patients with advanced breast cancer receiving 600 mg (20.7-23.7 ms), likely due to the dose and pharmacokinetic exposure effect and the population effect. Patients with EBC receiving 400 mg experienced lower rates and severity of both neutropenia and QTcF prolongation than patients with advanced breast cancer receiving 600 mg.</p><p><strong>Conclusions: </strong>This integrative analysis characterized the ribociclib pharmacokinetic and exposure-QTcF relationship, revealed the population effect on both pharmacokinetic and QTcF response, and justified the 400-mg dose in EBC. This work illustrates the utility and impact of quantitative pharmacology in justifying different doses across different patient populations for oncology therapies.</p><p><strong>Clinical trial registration: </strong>NATALEE (NCT03701334, 2018-09-21); AMALEE (NCT03822468, 2019-01-28); MONALEESA-2 (NCT01958021, 2013-10-04); MONALEESA-3 (NCT02422615, 2015-04-01); MONALEESA-7 (NCT02278120, ","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1217-1228"},"PeriodicalIF":4.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13461666/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148301228","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":"Revisited Pharmacokinetic Profiles of Methylprednisolone in Plasma and Urine After Single and Multiple Oral Administrations: Relevance in Sports Drug Testing.","authors":"Sergi Coll, Claudia Bressan, Núria Monfort, Ana Aldea-Perona, Marcel Lí Carbó, Rosa Ventura","doi":"10.1007/s40262-026-01665-x","DOIUrl":"10.1007/s40262-026-01665-x","url":null,"abstract":"<p><strong>Background: </strong>The pharmacokinetic profiles of methylprednisolone (MP) in plasma and urine were evaluated after single and multiple oral doses. MP is prohibited in sports competitions when administered systemically (oral, injectable, or rectal administrations) whereas other routes remain permitted for therapeutic purposes.</p><p><strong>Objective: </strong>The aim of this study was to characterize the urinary MP excretion after oral administration to assess whether the current World Anti-Doping Agency minimum reporting level of 30 ng/mL in urine is appropriate for distinguishing permitted from prohibited administrations, as well as whether the recommended washout period is adequate. Another aim was to better define MP elimination kinetics and evaluate its systemic effects.</p><p><strong>Methods: </strong>Sixteen healthy male participants were enrolled and divided into two groups. One group received a single oral dose of 12 mg of MP, while the other received 12 mg daily for 3 consecutive days. Urine and blood samples were collected before, during, and after administration. Urine samples were analyzed for MP and 15 metabolites using a sensitive and selective liquid chromatography-tandem mass spectrometry method. Plasma samples were analyzed for unchanged MP and cortisol using liquid chromatography-tandem mass spectrometry. A pharmacokinetic analysis was performed using a one-compartment model with first-order absorption, combining plasma concentrations and urinary excretion data.</p><p><strong>Results: </strong>MP represented only a small proportion of the administered dose, confirming that metabolism is the main elimination pathway. After a single oral dose, urinary MP concentrations above 30 ng/mL were observed up to 12 h, while all samples collected later were below this concentration. After multiple dosing, most samples above 30 ng/mL were also found within 12 h, although a few participants still showed concentrations above the minimum reporting level in the 12 to 24 h period. All samples collected more than 24 h after the last dose were below 30 ng/mL. In plasma, MP reached peak concentrations around 1.6-2.3 h after administration and was not detectable 24 h after the last dose. Cortisol concentrations were markedly suppressed after dosing, with recovery to baseline within 24-48 h depending on the regimen.</p><p><strong>Conclusions: </strong>This study confirms that the current urinary minimum reporting level of 30 ng/mL is appropriate for detecting oral MP use while minimizing the risk of false adverse analytical findings. The results also support the adequacy of the current 3-day washout period. Modern liquid chromatography-tandem mass spectrometry analysis and combined plasma-urine pharmacokinetic modeling provided robust evidence that MP is rapidly eliminated, extensively metabolized, and associated with transient cortisol suppression after oral administration.</p><p><strong>Clinical trial registration: </strong>EudraCT nu","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1243-1256"},"PeriodicalIF":4.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13461668/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148315616","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":"Population Pharmacokinetic Analysis of Glecaprevir and Pibrentasvir in Pediatric Patients ≥ 3 to < 18 Years of Age with Genotypes 1-6 Chronic Hepatitis C Virus (HCV) Infection.","authors":"Neha Thakre, Denise Beck, Ahmed M Saeed, Doerthe Eckert, Mong-Jen Chen, Wei Liu, Hoi Kei Lon, Nael M Mostafa, Sven Mensing","doi":"10.1007/s40262-026-01637-1","DOIUrl":"10.1007/s40262-026-01637-1","url":null,"abstract":"<p><strong>Background: </strong>Mavyret, a combination medication of glecaprevir (GLE) and pibrentasvir (PIB), is approved to treat chronic and acute hepatitis C virus (HCV) (genotypes 1-6) infection in adults and pediatric patients ≥ 3 years old. To support approval, a two-part clinical trial was conducted in adolescents (≥ 12 to < 18 years) and children (≥ 3 to < 12 years) to identify the appropriate dosage and determine the efficacy and safety in pediatric patients.</p><p><strong>Objectives: </strong>Population pharmacokinetic (popPK) analyses reported herein aimed to (1) characterize the pharmacokinetic (PK) parameters of orally administered GLE and PIB and the sources of PK variability in pediatric patients and (2) support the use of a body weight-based pediatric GLE/PIB dose ratio of 50/20 mg in HCV-infected children.</p><p><strong>Methods: </strong>PopPK models were built for GLE and PIB independently using nonlinear mixed-effects modeling and utilized data collected from 126 pediatric patients. Demographic, pathophysiological, and treatment factors were investigated for their impact on GLE and PIB PK.</p><p><strong>Results: </strong>PopPK analyses of pediatric exposures confirmed comparable exposures to those of adults who achieved over 95% sustained virologic response (SVR12). The pediatric popPK model incorporated allometric body weight-based scaling and subsequently identified no covariate that significantly impacted GLE exposures. Similarly, no covariate beyond the specified allometric body weight scaling was identified to impact PIB exposures. The developed pediatric popPK models were able to describe the central tendency and variability of the data.</p><p><strong>Conclusion: </strong>These results supported the approval of body weight-based dosing regimens of GLE and PIB in children (< 45 kg) infected with any HCV genotype.</p><p><strong>Clinical trials: </strong>NCT03067129.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1061-1072"},"PeriodicalIF":4.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13356091/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148027541","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":"Renal or Hepatic Impairment Does Not Affect Pharmacokinetics, Safety, or Tolerability of Subcutaneous Cagrilintide.","authors":"Mette J F Nielsen, Niels-Peter Becker, Helene H Hansen Duus, Katrine Kirkeby, Viera Kupčová, Britt W Lauenborg, Benjamin Low, Olivia Svolgaard, Louise Witten","doi":"10.1007/s40262-026-01654-0","DOIUrl":"10.1007/s40262-026-01654-0","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background and objectives: &lt;/strong&gt;Cagrilintide is a long-acting amylin agonist under development as monotherapy for weight management and as a fixed-dose combination with the glucagon-like peptide-1 receptor agonist semaglutide (CagriSema) for weight management and treatment of type 2 diabetes. Two studies were conducted to assess the effects of renal or hepatic impairment on pharmacokinetics, safety and tolerability following single doses of cagrilintide.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;In both studies, adult participants were categorised into four groups on the basis of renal or hepatic function (normal function and mild, moderate or severe impairment) and received a single dose of cagrilintide 0.6 or 0.9 mg, respectively. The primary endpoint was area under the cagrilintide plasma concentration curve from time zero extrapolated to infinity (AUC&lt;sub&gt;0-∞&lt;/sub&gt;) from baseline (day 1) to day 36 (renal impairment study) or day 39 (hepatic impairment study). Other pharmacokinetic parameters included maximum observed cagrilintide plasma concentration (C&lt;sub&gt;max&lt;/sub&gt;), time to C&lt;sub&gt;max&lt;/sub&gt; (t&lt;sub&gt;max&lt;/sub&gt;) and safety.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The renal impairment study included 33 participants (normal function, n = 14; mild impairment, n = 7; moderate impairment, n = 7; severe impairment, n = 5) and the hepatic impairment study included 32 participants (normal function, n = 14; mild impairment, n = 7; moderate impairment, n = 7; severe impairment, n = 4). In both studies, total cagrilintide exposure (AUC&lt;sub&gt;0-∞&lt;/sub&gt;), C&lt;sub&gt;max&lt;/sub&gt; and other pharmacokinetic parameters were similar across groups with no consistent patterns observed with renal or hepatic impairment. Compared with normal renal function, the estimated ratio of the mean AUC&lt;sub&gt;0-∞&lt;/sub&gt; was 1.23 (90% confidence interval [CI], 0.91-1.66) in mild impairment, 1.18 (0.87-1.59) in moderate impairment and 1.21 (0.87-1.68) in severe impairment. Compared with normal hepatic function, the estimated ratio of the mean AUC&lt;sub&gt;0-∞&lt;/sub&gt; was 0.99 (0.89-1.11) in mild impairment, 1.01 (0.91-1.12) in moderate impairment and 1.11 (0.96-1.30) in severe impairment. Overall, 21 and 16 treatment-emergent adverse events (TEAEs) were reported in 11 and 9 participants in the renal and hepatic studies, respectively. In both studies, no serious TEAEs, TEAEs leading to study withdrawal or deaths were reported. No increase in number of adverse events with increasing renal or hepatic impairment was observed, and no new safety or tolerability findings with cagrilintide were identified with renal or hepatic impairment.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;In these studies, within the limitations of small sample sizes, no clinically relevant differences in cagrilintide pharmacokinetics were observed in participants with renal or hepatic impairment compared with those with normal function, suggesting that dose adjustment is not warranted for these populations. Cagrilintide was well-tolerated a","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1087-1099"},"PeriodicalIF":4.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13356073/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148142928","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":"Population Pharmacokinetic Modelling of Dolutegravir: A Narrative Review.","authors":"Émilie Pilote, Nancy L Sheehan, Amélie Marsot","doi":"10.1007/s40262-026-01653-1","DOIUrl":"10.1007/s40262-026-01653-1","url":null,"abstract":"<p><p>Dolutegravir-based regimens are part of the preferred regimens in all populations living with HIV, but dolutegravir's pharmacokinetics can vary greatly with factors such as drug-drug interactions (DDIs) and age. For example, DDIs between dolutegravir and rifamycins in countries with a high burden of HIV/tuberculosis co-infection present a major challenge. Attaining therapeutic concentrations is crucial for virologic success and to prevent resistance. Understanding dolutegravir pharmacokinetics and its sources of variability is essential to ensure adequate exposure in all individuals. Population pharmacokinetic (PopPK) modeling is a powerful tool for characterizing medication disposition. In this review, we aim to synthesize existing dolutegravir PopPK models, highlighting key pharmacokinetic parameters and covariate effects. A literature search was done on Medline and Embase databases from inception to November 18th, 2025. This review included 23 studies: 15 in adults, 4 in pediatrics, 2 in pregnancy (mothers and their newborn), and 2 in term neonates. Almost all models included allometric scaling, with body weight especially, on apparent clearance (CL/F) and/or apparent volume of distribution (Vd/F) parameters. When considering differences in body size, CL/F and Vd/F were similar across populations. The absorption rate constant (k_a) was higher in adults and presented high variability across populations. Other common covariates in adults and pediatrics were co-medications and background antiretrovirals. Data and tested covariates were limited in pregnant women and neonates. Study simulations and predefined target values indicated adequate recommended dolutegravir doses. Further characterization of dolutegravir PopPK in populations at risk of altered concentrations (e.g., preterm neonates, pediatrics, pregnancy, obesity, and older adults) is crucial to better understand dolutegravir pharmacokinetics in these populations as data are still limited.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"953-993"},"PeriodicalIF":4.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148351174","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: Model‑Based Alternative Dosing Strategies for Subcutaneous Nivolumab to Improve Cost Effectiveness.","authors":"Yan Wang, Laura H Bukkems, Rob Ter Heine, J G C van Hasselt, S L W Koolen, J J M A Hendrikx, Tom Van der Hulle, Ellen Kapiteijn, Juliette Zwaveling, Annemarie Becker, Michel M van den Heuvel, Willemijn S M E Theelen, Thijs H Oude Munnink, Egbert F Smit, Henk-Jan Guchelaar, Dirk Jan A R Moes","doi":"10.1007/s40262-026-01649-x","DOIUrl":"10.1007/s40262-026-01649-x","url":null,"abstract":"","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1113-1114"},"PeriodicalIF":4.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13356090/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147971166","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":"Impact of Preclinical Verification in Physiologically Based Pharmacokinetic Modelling for First-in-Human Predictions: Application of a Published Model Building Strategy for Five Compounds.","authors":"Claire Jackson, Rebecca H Graves, Thuy T Tran, Neil A Miller","doi":"10.1007/s40262-026-01655-z","DOIUrl":"10.1007/s40262-026-01655-z","url":null,"abstract":"<p><strong>Background and objective: </strong>Physiologically based pharmacokinetic modelling is routinely used in the pharmaceutical industry and has an impact on drug labels. New applications have emerged, one of which is first-in-human pharmacokinetic predictions. Scientists in this field often believe that verification of models in preclinical species is essential for accurate predictions, but consensus has not been reached and animal use across the industry deserves continual examination with the aim to reduce use.</p><p><strong>Methods: </strong>A published model-building strategy was used to assess the accuracy added by preclinical verification for human PK prediction. Three sequential approaches were explored using five compounds covering a range of physicochemical properties and chemical classes. Approach 1 (QSPR FIH prediction), uses parameter inputs predicted using in silico Quantitative Structure Property Relationship models; Approach 2 (In vitro FIH prediction), supplements predicted parameters with in vitro measurements where available data exist; Approach 3 (Verified FIH prediction), uses preclinical in vivo pharmacokinetic data to verify the in vitro measurements.</p><p><strong>Results: </strong>Preclinical verification models were able to provide predictions of first-in-human pharmacokinetics within two-fold of the observed data for all five compounds studied, which was a significant improvement compared with predictions using in silico or in vitro inputs without verification in preclinical species. In most cases, the predictions generated purely from structure were superior to those supplemented with in vitro data without preclinical validation. Prediction of human clearance via in vitro in vivo extrapolation proved challenging and was identified as the most common cause of poor predictions of human PK from in vitro data.</p><p><strong>Conclusions: </strong>The work here supports the continued considered use of preclinical verification in PBPK modelling.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1043-1059"},"PeriodicalIF":4.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13356094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147986912","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":"A Model-Informed Early Prediction of Methotrexate-Induced Acute Kidney Injury in Pediatric Patients with Osteosarcoma Using Real-World Data: A Multi-center Pharmacokinetic Study.","authors":"Patricia Rega, Jorge Morales Vallespin, Azucena Aldaz, Andrew Pappas, Paulo Caceres Guido, Manuel Azocar, Milena Villarroel, Jennifer L Pauley, Clinton F Stewart, Manuel Ibarra, Paula Schaiquevich","doi":"10.1007/s40262-026-01658-w","DOIUrl":"10.1007/s40262-026-01658-w","url":null,"abstract":"<p><strong>Background and objective: </strong>High-dose methotrexate is central to pediatric osteosarcoma treatment, but delayed elimination increases the risk of acute kidney injury, compromising treatment intensity. Current therapeutic drug monitoring often identifies toxicity too late for intervention. This study aimed to develop a population pharmacokinetic model using real-world data to identify early predictors of methotrexate-associated acute kidney injury.</p><p><strong>Methods: </strong>We conducted a multicenter study including 248 pediatric, adolescent, and young adult patients with osteosarcoma (1809 high-dose methotrexate courses) from referral centers in Argentina, Chile, Spain, and the USA. A population pharmacokinetic model was developed using Monolix. Early predictors of acute kidney injury were assessed using receiver operating characteristic curve analysis, and optimal sampling times earlier than those currently used in the clinics for rescue measures were explored through simulation.</p><p><strong>Results: </strong>A two-compartment population pharmacokinetic model adequately described the data up to 48 h after the start of infusion. Time-varying serum creatinine was included as a key covariate for methotrexate clearance. The alpha disposition half-life was the most accurate early predictor of moderate-to-severe acute kidney injury (area under the curve-receiver operating characteristic: 0.956 (95% confidence interval (CI) 0.914-0.998); threshold: 3.4 h (95% confidence interval 2.7-3.7), sensitivity: 0.94 [95% CI 0.81-1.0], and specificity: 0.96 [95% CI 0.73-0.99]). A two-point early sampling strategy (C4 and C8-11) precisely estimated alpha disposition half-life.</p><p><strong>Conclusions: </strong>Early identification of impaired methotrexate clearance is feasible using model-based metrics available within the first 11 h after the end of infusion by means of the alpha disposition half-life. This approach may guide supportive care offering a practical tool for model-informed precision dosing in pediatric patients with osteosarcoma.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1101-1112"},"PeriodicalIF":4.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148162094","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":"Partial Area Under the Curve: A Revelatory Story in Pharmacokinetics.","authors":"Maheshwari Periyasamy, Mirunalini Ravichandran","doi":"10.1007/s40262-026-01666-w","DOIUrl":"10.1007/s40262-026-01666-w","url":null,"abstract":"<p><p>Bioequivalence studies are important for a generic drug to enter the market. These studies mainly examine various pharmacokinetic parameters like C_max, AUC_0-T and AUC_0-∞. But at times, these parameters might not be sufficient to pick up essential kinetics. It is even possible to undertake the additional parameter along with the traditional pharmacometrics. This article gives an overview of one such parameter, partial area under the curve (pAUC), which captures specific time intervals of clinical relevance. The pAUC is especially useful for comparing specific formulations, determining bioequivalence in early or late stages, and assessing medicines with time-dependent therapeutic windows. When employed correctly, pAUC improves our understanding of temporal drug behaviour beyond what total AUC can provide, allowing for more precise and clinically meaningful pharmacokinetic assessments. This article is a review that describes how pAUC has been used in specific regulatory guidelines for drug products that have time-dependent exposures, which may impact the drug's pharmacodynamic properties. These product guidances have been issued by the US Food and Drug Administration (FDA), Health Canada, and European Medicines Agency (EMA). This article presents various viewpoints about pAUC in the mindset of regulators, researchers, and industrial experts.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"943-951"},"PeriodicalIF":4.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148351101","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}