Clinical Pharmacokinetics最新文献

{"title":"Effect of Hepatic Impairment or Renal Impairment on the Pharmacokinetics of Aficamten.","authors":"Donghong Xu, Justin D Lutz, Punag Divanji, Jianlin Li, Youcef Benattia, Adrienne Griffith, Stephen B Heitner, Stuart Kupfer, Polina German","doi":"10.1007/s40262-025-01481-9","DOIUrl":"https://doi.org/10.1007/s40262-025-01481-9","url":null,"abstract":"<p><strong>Background and objective: </strong>Aficamten, a small-molecule, selective cardiac myosin inhibitor, is under development for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (oHCM). Aficamten is primarily eliminated by hepatic metabolism with renal excretion playing a minor role. The objective of this investigation was to evaluate the pharmacokinetics (PK) of aficamten in moderate hepatic impairment or mild to moderate renal impairment to inform dosing recommendations in HCM patients with mild or moderate hepatic impairment or mild to moderate renal impairment.</p><p><strong>Methods: </strong>The impact of hepatic impairment on the PK of single-dose aficamten 20 mg was evaluated in a phase 1 single-dose, open-label, parallel-group study, in healthy participants with moderate (n = 8) hepatic impairment (Child-Pugh B classification) versus participants with normal hepatic function (n = 8). Safety was monitored throughout. The effect of renal impairment on aficamten PK was assessed using population PK (PopPK) modelling of phase 2/3 clinical data in patients with oHCM.</p><p><strong>Results: </strong>Aficamten PK was similar in participants with moderate hepatic impairment and those with normal hepatic function. No serious or severe treatment-emergent adverse events or clinically significant laboratory abnormalities were reported. There were no clinical meaningful differences in aficamten exposure in patients with oHCM with mild or moderate renal impairment and those with normal renal function.</p><p><strong>Conclusions: </strong>No clinically relevant changes in aficamten PK were observed in participants with moderate hepatic impairment. Population PK analysis indicated mild or moderate renal impairment and had no statistically or clinically significant impact on aficamten PK in patients with oHCM. Aficamten dose adjustment may not be necessary in patients with mild or moderate hepatic or renal impairment.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188156","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":"Clinical Pharmacokinetics of Oral ALZ-801/Valiltramiprosate in a 2-Year Phase 2 Trial of APOE4 Carriers with Early Alzheimer's Disease.","authors":"John A Hey, Jeremy Y Yu, Susan Abushakra, Jean F Schaefer, Aidan Power, Pat Kesslak, Jijo Paul, Martin Tolar","doi":"10.1007/s40262-025-01482-8","DOIUrl":"https://doi.org/10.1007/s40262-025-01482-8","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;ALZ-801/valiltramiprosate is an oral, small-molecule inhibitor of β-amyloid (Aβ) oligomer formation in late-stage development as a potential disease-modifying therapy for Alzheimer's disease (AD). ALZ-801, a valine-conjugated prodrug, is rapidly converted to tramiprosate after oral dosing. Upon conversion to tramiprosate, it generates a single metabolite, 3-sulfopropanoic acid (3-SPA). Both tramiprosate and 3-SPA are active anti-Aβ oligomer agents that mediate ALZ-801's central mechanism of action (MOA). We summarize herein the pharmacokinetics (PK) of ALZ-801 in apolipoprotein ε4 (APOE4) carrier subjects with early AD from a phase 2 trial.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;The ALZ-801 phase 2 study was designed to evaluate longitudinal effects of ALZ-801 (265 mg BID) on plasma, cerebrospinal fluid (CSF) and volumetric magnetic resonance imaging (MRI) AD biomarkers, and clinical outcomes over 104 weeks in APOE4 carriers with early AD. Eighty-four subjects (31 APOE4/4 homozygotes and 53 APOE3/4 heterozygotes) with positive CSF biomarkers of amyloid and tau pathology were enrolled. The phase 2 study included a substudy of 24 subjects to provide 8-h steady-state PK at 65 weeks. Sparse PK samples were also analyzed. The relationships between plasma PK exposure and clinical characteristics [i.e., sex, APOE genotype, age, body mass index (BMI), estimated glomerular filtration rate (eGFR), concomitant acetylcholinesterase inhibitor (AChEI) use, and tablet lot] were evaluated.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The steady-state plasma PK results were closely aligned with the previous 2-week PK in the ALZ-801 phase 1b study in APOE4 carrier subjects with AD, as well as a phase 1 7-day PK study in heathy elderly volunteers. Following oral dosing, ALZ-801 was rapidly converted to the active moieties, tramiprosate and 3-SPA. The intersubject variability in plasma drug levels was low, confirming the superior performance of ALZ-801 versus oral tramiprosate tablet (150 mg BID) from the earlier tramiprosate phase 3 trials. Correlation analysis versus clinical characteristics showed that plasma exposures (Cmax and AUC8h) for ALZ-801, tramiprosate, and 3-SPA were not affected by sex, APOE genotype, age, BMI, concomitant AChEI use, or tablet lot. Plasma exposures of both tramiprosate and 3-SPA, but not ALZ-801, were inversely correlated with eGFR, in line with renal excretion as the primary route of elimination. ALZ-801 was well tolerated without new safety signals or events of amyloid-related imaging abnormalities (ARIA).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;The steady-state PK profile of oral ALZ-801 in subjects with early AD was not affected by sex, APOE genotype, age, BMI, concomitant use of AChEI, or tablet lot. The inverse relationship of plasma exposures of tramiprosate and 3-SPA, but not ALZ-801, versus eGFR is consistent with renal clearance as the primary route of elimination for tramiprosate and 3-SPA (active moieties), and wi","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188132","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":"Solubility-Limited Absorption Identified by a Simplified PBPK Model for the Prediction of Positive Food Effect for BCS II/IV Drugs.","authors":"Karine Rodriguez-Fernandez, José David Gómez-Mantilla, Suneet Shukla, Victor Mangas-Sanjuán, Sheila Annie Peters","doi":"10.1007/s40262-025-01472-w","DOIUrl":"https://doi.org/10.1007/s40262-025-01472-w","url":null,"abstract":"","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078736","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":"Evaluation of Solubility-Limited Absorption as a Surrogate to Predicting Positive Food Effect of BCS II/IV Drugs.","authors":"Karine Rodriguez-Fernandez, José David Gómez-Mantilla, Suneet Shukla, Peter Stopfer, Peter Sieger, Victor Mangas-Sanjuán, Sheila Annie Peters","doi":"10.1007/s40262-025-01473-9","DOIUrl":"https://doi.org/10.1007/s40262-025-01473-9","url":null,"abstract":"<p><strong>Introduction and objective: </strong>Physiologically based pharmacokinetic (PBPK) models are increasingly used to predict food effect (FE) but model parameterization is challenged by in vitro-in vivo (IVIV) disconnect and/or parameter nonidentifiability. To overcome these issues, we propose a simplified PBPK model, in which all solubility-driven processes are lumped into a single parameter, solubility, which is optimized against observed concentration-time data.</p><p><strong>Methods: </strong>A set of commercially available biopharmaceutical classification system (BCS) II/IV compounds was selected to measure the solubility in a fasted state simulated intestinal fluid (FaSSIF) medium. The compounds were ranked from the lowest to the highest dose-adjusted FaSSIF solubility (FaSSIF/D) value and subdivided into three areas based on an upper and a lower limit: drugs with FaSSIF/D > upper limit having no FE, drugs with FaSSIF/D < lower limit having FE, and drugs between the limits said to be in the sensitivity range (SR), for which we tested the hypothesis that solubility-limited absorption (SLA) identified by simplified PBPK model can reliably predict positive FE if their exposures are not impacted by gut efflux or gut metabolism.</p><p><strong>Results: </strong>We demonstrate, using a subset of drugs within SR for which PBPK models were available, that drugs with SLA exhibited a positive FE, while those with no SLA did not show FE.</p><p><strong>Conclusions: </strong>This proposal allows for a reliable binary prediction of FE to enable timely decisions on the need for pilot FE studies as well as the timing of pivotal FE studies.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078732","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":"Identifying the Optimal Sampling Strategy for the Bayesian Estimation of Vancomycin AUC_0-24 in Adult Hematologic Cancer Patients.","authors":"Alexandre Duong, Jessica Le Blanc, Denis Projean, Amélie Marsot","doi":"10.1007/s40262-025-01478-4","DOIUrl":"10.1007/s40262-025-01478-4","url":null,"abstract":"<p><strong>Background and objective: </strong>The latest consensus recommends using the ratio between the area under the curve over 24 h (AUC_0-24) and minimal inhibitory concentration (MIC) as the therapeutic target for vancomycin in clinical practice, with a Bayesian approach and population pharmacokinetic (popPK) model being particularly recommended. While using both post-dose peak concentration (C_peak) and pre-dose concentration (C_trough) is more accurate than C_trough alone, the optimal sampling strategy for estimating AUC_0-24 is still unclear. The objective of this study was to determine the best sampling time(s) to estimate AUC_0-24 using the Bayesian approach in these specific adult hematologic cancer patients.</p><p><strong>Methods: </strong>A virtual population (n = 7000) was simulated based on the distribution of the significant covariates (ideal body weight and estimated glomerular filtration rate) from the population used to develop the previous pharmacokinetic model. The dosing regimens from the Le Blanc et al. nomogram were used to generate, with NONMEM^® (v.7.5), simulated pharmacokinetic (PK) profiles of one loading dose followed by three maintenance doses (steady state). Strategies involving two samples taken during earlier maintenance doses and one sample taken at steady state were tested using the Bayesian approach to predict PK parameters. These strategies were then evaluated for their ability to predict AUC_0-24 at steady state (AUC_0-24,ss) RESULTS: For single-sample strategies, a sample taken anytime from 4 h post-dose can estimate AUC_0-24,ss with precision similar to C_trough (R² ≈ 0.75), regardless of renal function (R² ≈ 0.73-0.77). For two-sample strategies, taking samples at least midway through the dosing interval provides the highest precision for estimating AUC_0-24,ss during the first two maintenance doses (R² ≈ 0.75-0.77). In both strategies, using C_peak did not yield as precise results as sampling midway through the dosing interval or at C_trough.</p><p><strong>Conclusion: </strong>This study is the first to test multiple limited sampling strategies using a dosing nomogram stratified by renal function. The results show that vancomycin sampling can extend beyond traditional C_peak and C_trough without compromising the accuracy of maximum a posteriori Bayesian estimation of AUC_0-24,ss, thereby providing an opportunity to investigate these limited sampling strategies combined with model-informed precision dosing in a clinical setting.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"297-305"},"PeriodicalIF":4.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001291","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":"Clinical Pharmacokinetics of N,N-Dimethyltryptamine (DMT): A Systematic Review and Post-hoc Analysis.","authors":"K V van der Heijden, M E Otto, J W Schoones, M J van Esdonk, L G J M Borghans, J G C van Hasselt, J M A van Gerven, G Jacobs","doi":"10.1007/s40262-024-01450-8","DOIUrl":"10.1007/s40262-024-01450-8","url":null,"abstract":"<p><strong>Background and objective: </strong>N,N-Dimethyltryptamine (DMT) is currently being studied for its therapeutic potential in various psychiatric disorders. An understanding of its pharmacokinetics (PK) is essential to determine appropriate dose ranges in future clinical studies. We conducted a systematic literature review on the PK of DMT.</p><p><strong>Methods: </strong>Clinical studies that administered known amounts of DMT and reported PK data and/or parameters in humans were included. Additionally, raw PK data were requested from authors and/or extracted from publications.</p><p><strong>Results: </strong>In total, 219 references were retrieved, of which 13 publications were included, covering eight distinct datasets. All studies administered DMT intravenously in various infusion schemes, except for one intramuscular administration. High variability in dose-normalized exposure parameters and differences in exposure for bolus versus infusion administration were observed. DMT is extensively redistributed to other tissues, based on its biphasic elimination profile and high volume of distribution in the terminal elimination phase (range 123-1084 L). It is eliminated rapidly, with a half-life of 4.8-19.0 min and clearance of 8.1-46.8 L/min. This is a result of the rapid metabolization of DMT to indole-3-acetic acid (IAA), which is also reflected in the fact that the time of maximum concentration of IAA is similar to that of DMT.</p><p><strong>Conclusion: </strong>This review demonstrates that the PK of DMT in humans have been characterized to a limited extent, and publications lack details with regards to demographics, absolute doses, and PK parameters. Additional studies are necessary to investigate high intersubject variability and differences in exposure following bolus or prolonged infusion. Addressing these issues is essential for the development of DMT as a pharmacotherapeutic in neuropsychiatry.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"215-227"},"PeriodicalIF":4.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11782443/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001288","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 Apixaban in End-Stage Kidney Disease Patients with Atrial Fibrillation Receiving Haemodialysis.","authors":"Celine Konecki, Mark L Lipman, Thomas A Mavrakanas, Zoubir Djerada","doi":"10.1007/s40262-025-01476-6","DOIUrl":"10.1007/s40262-025-01476-6","url":null,"abstract":"<p><strong>Background and objective: </strong>Apixaban is increasingly being used for stroke prevention in patients with end-stage kidney disease with atrial fibrillation undergoing haemodialysis, but no pharmacostatistical model is available for dosage adjustment. This study aimed to develop a population pharmacokinetic model of apixaban in these patients to characterise its dialytic clearance and determine optimal dosing regimens and discontinuation timing before surgery.</p><p><strong>Methods: </strong>Patients received 2.5 mg of apixaban twice daily for 9 days, followed by 5 mg twice daily for 8 days after a 5-day washout period (NCT02672709). Apixaban concentrations were measured on and off dialysis. A population pharmacokinetic model was developed using parametric and non-parametric methods. Simulations were performed to assess plasmatic exposure and the time to reach clinically relevant apixaban concentrations after treatment discontinuation for seven dosing regimens and 13 dialysis schedules.</p><p><strong>Results: </strong>A total of 289 apixaban concentrations were measured, including 85 during haemodialysis. The best model was a two-compartment model with first-order elimination. Dialytic clearance was estimated at 1.20 L/h with high inter-individual variability. Apixaban daily exposure was proportional to the total daily dose, independent of dosing frequency and dialysis timing. The standard discontinuation period of 48-72 h before surgery was insufficient to achieve clinically negligible concentrations in patients undergoing haemodialysis.</p><p><strong>Conclusions: </strong>We propose the first pharmacokinetic model to characterise apixaban clearance in patients with end-stage kidney disease with atrial fibrillation undergoing haemodialysis. Simulations suggest that dialysis timing is not critical for monitoring apixaban, and the discontinuation period before surgery should be extended beyond current recommendations.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"307-321"},"PeriodicalIF":4.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143032378","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 Optimization of Vancomycin in Pediatric Post-Cardiac Surgery Patients: A Population Pharmacokinetic Modeling Study.","authors":"J Kamp, D J E Wannet, E P Buddingh, J van Prehn, H E Bunker-Wiersma, J J van Wattum, R H Klein, P P Roeleveld, D J A R Moes","doi":"10.1007/s40262-024-01463-3","DOIUrl":"10.1007/s40262-024-01463-3","url":null,"abstract":"<p><strong>Background and objective: </strong>Vancomycin is a glycopeptide antibiotic used for the treatment of severe gram-positive infections. Despite decades of clinical experience, optimized dosing for vancomycin in pediatric populations still warrants further investigation. Patients admitted to the pediatric intensive care unit (PICU) after cardiac surgery are often treated with vancomycin in case of (suspected) infection. However, vancomycin dosing in this population is often challenging due to fluctuations in volume status, (temporarily) compromised renal function or the use of diuretics or extracorporeal membrane oxygenation (ECMO). The main objective of this study was to describe vancomycin pharmacokinetics (PK) in pediatric cardiac surgery patients. Secondary objectives were to potentially optimize vancomycin dosing and to assess the suitability of the model to be used for model informed precision dosing (MIPD).</p><p><strong>Methods: </strong>A retrospective cohort study was performed with patients admitted to the PICU of the Leiden University Medical Center. Clinical data from post-cardiac surgery PICU patients receiving intravenous vancomycin between January 2020 and December 2023 were included in the analysis. Patients received vancomycin 10 mg/kg 4 times daily (qid), after which a trough concentration was generally sampled just before the fourth dose. Pharmacokinetic data were used to develop a population PK model by using a non-linear mixed effects modeling approach (NONMEM). In addition, potential covariates such as renal function, body weight (BW) and post-menstrual age were tested. The final model was used for vancomycin dose optimization using Monte Carlo simulations.</p><p><strong>Results: </strong>In total, 193 pediatric post-cardiac surgery patients, contributing a total of 706 vancomycin blood samples were included. The 2-compartmental population PK model best described the data. Renal function and BW were identified as significant and clinically relevant covariates on vancomycin PK. Model parameters were: elimination clearance: 4.01 L/min at 70 kg; intercompartmental clearance: 0.425 L/min at 70 kg; central volume of distribution: 56.1 L/70 kg; and peripheral volume of distribution: 21.7 L/70 kg (fixed). Dose simulations suggested a non-linear dosing algorithm, with relatively lower per kg dose for increasing BW to be optimal for our population. Furthermore, the model was considered to be suitable for the (a posteriori) prediction of future vancomycin serum concentrations.</p><p><strong>Conclusion: </strong>We successfully developed a population PK model for vancomycin in post-cardiac surgery children. Vancomycin PK were shown to be significantly influenced by serum creatinine and BW. Furthermore, we suggest a new vancomycin dosing regimen based on allometric scaling. The developed PK model can be used for model informed precision dosing of vancomycin in pediatric post-cardiac surgery patients.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"243-255"},"PeriodicalIF":4.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876207","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":"All You Need to Know About Allometric Scaling: An Integrative Review on the Theoretical Basis, Empirical Evidence, and Application in Human Pharmacology.","authors":"Daan W van Valkengoed, Elke H J Krekels, Catherijne A J Knibbe","doi":"10.1007/s40262-024-01444-6","DOIUrl":"10.1007/s40262-024-01444-6","url":null,"abstract":"<p><p>Scaling approaches are used to describe or predict clearance for paediatric or obese populations from normal-weight adult values. Theoretical allometry assumes the existence of a universal bodyweight-based scaling relationship. Although theoretical allometry is highly disputed, it is commonly applied in pharmacological data analyses and clinical practice. The aim of the current review is to (1) increase pharmacologists' understanding of theoretical allometry to better understand the (implicit) assumptions and (dis)advantages and (2) highlight important methodological considerations with the application of this methodology. Theoretical allometry originated in an empirical, and later debated, observation by Kleiber of a scaling exponent of 0.75 between basal metabolic rate and body mass of mammals. The mathematical framework of West, Brown, and Enquist provides one possible explanation for this value. To date, multiple key assumptions of this framework have been disputed or disproven, and an increasing body of evidence is emerging against the existence of one universal allometric exponent. The promise of ease and universality of use that comes with theoretical approaches may be the reason they are so strongly sought after and defended. However, ecologists have suggested that the theory should move from a 'Newtonian approach', in which physical explanations are sought for a universal law and variability is of minor importance, to a 'Darwinian approach', in which variability is considered of primary importance for which evolutionary explanations can be found. No scientific support was found for the application of allometry for within-species scaling, so the application of basal metabolic rate-based scaling principles to clearance scaling remains unsubstantiated. Recent insights from physiologically based modelling approaches emphasise the interplay between drugs with different properties and physiological variables that underlie drug clearance, which drives the variability in the allometric scaling exponent in the field of pharmacology. To deal with this variability, drug-specific or patient-specific adaptations to theoretical allometric scaling are proposed, that introduce empiric elements and reduce the universality of the theory. The use of allometric scaling with an exponent of 0.75 may hold empirical merit for paediatric populations, except for the youngest individuals (aged ≤ 5 years). Nevertheless, biological interpretations and extrapolation potential attributed to models based on 0.75 allometric scaling are theoretically unfounded, and merits of the empirical application of this function should, as for all models, always be supported by appropriate model validation procedures. In this respect, it is not the value of the allometric exponent but the description and prediction of individual clearance values and drug concentrations that are of primary interest.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"173-192"},"PeriodicalIF":4.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11782306/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791070","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":"Improving Understanding of Fexofenadine Pharmacokinetics to Assess Pgp Phenotypic Activity in Older Adult Patients Using Population Pharmacokinetic Modeling.","authors":"Frédéric Gaspar, Celestin Jacost-Descombes, Pauline Gosselin, Jean-Luc Reny, Monia Guidi, Chantal Csajka, Caroline Samer, Youssef Daali, Jean Terrier","doi":"10.1007/s40262-024-01470-4","DOIUrl":"10.1007/s40262-024-01470-4","url":null,"abstract":"<p><strong>Background and objective: </strong>Fexofenadine is commonly used as a probe substrate to assess P-glycoprotein (Pgp) activity. While its use in healthy volunteers is well documented, data in older adult and polymorbid patients are lacking. Age- and disease-related physiological changes are expected to affect the pharmacokinetics of fexofenadine. This study aims to investigate the pharmacokinetics of fexofenadine in hospitalized older adult patients as a potential marker of Pgp activity, using data from the OptimAT study (ClinicalTrials.gov identifier: NCT03477331).</p><p><strong>Methods: </strong>Population pharmacokinetic (popPK) modeling was conducted using data from 449 hospitalized patients with a median age of 71 years (range: 25-97) and 10 healthy volunteers (median age: 23 years, range: 20-36). Fexofenadine plasma concentrations were analyzed using a refined two-compartment model with sequential zero/first-order absorption, while investigating the impact of covariates such as age, renal function, and Pgp inhibitors on fexofenadine pharmacokinetics.</p><p><strong>Results: </strong>Age, renal insufficiency, and Pgp inhibitors significantly influenced fexofenadine exposure. Renal function was a key factor, with AUC_0-6 increasing by 79% in mild-to-moderate and by 154% in moderate-to-severe renal impairment compared with normal renal function. Co-administration of Pgp inhibitors led to a 35% increase in AUC_0-6. Across chronic kidney disease (CKD) stages, age, and Pgp inhibitor status, fexofenadine AUC_0-6 ratio ranged from 1.15 (stage 1, 20-30 years) to 4.59 (stage 5, 91-100 years, with Pgp inhibitors), relative to a reference subject of 20 years, normal renal function, and no Pgp inhibitors.</p><p><strong>Conclusion: </strong>Clinicians should consider the risk of Pgp substrate accumulation in older adults, particularly those with advanced renal impairment. We propose typical values stratified by age and renal function to assist in interpreting Pgp phenotyping using fexofenadine exposure, thereby supporting drug optimization in this population. Further studies are needed to explore underlying mechanisms, such as reduced Pgp activity or expression.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"275-283"},"PeriodicalIF":4.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11782438/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142964055","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}