Clinical Pharmacokinetics最新文献

{"title":"TDM-Based Tailored Dosing of Durvalumab in Lung Cancer Patients: A Comprehensive Population Pharmacokinetic-Pharmacoeconomic Evaluation.","authors":"Fenna de Vries, Eric J F Franssen, Arthur A J Smit, Dirk Jan A R Moes, Anthonie J van der Wekken, Thijs Oude Munnink, Jeroen J M A Hendrikx, Daphne W Dumoulin, Stijn L W Koolen, Wietske Kievit, Michel M van den Heuvel, Rob Ter Heine","doi":"10.1007/s40262-025-01555-8","DOIUrl":"https://doi.org/10.1007/s40262-025-01555-8","url":null,"abstract":"<p><strong>Background: </strong>The increasing use of immune checkpoint inhibitors, such as durvalumab, places a significant financial burden on healthcare systems, strains hospital capacities, and contributes to environmental concerns.</p><p><strong>Objective: </strong>We aimed to develop alternative dosing strategies to optimize durvalumab administration, reduce unnecessary drug use, and ensure sustainable cancer care without sacrificing efficacy.</p><p><strong>Methods: </strong>Using the population pharmacokinetic model developed by the licensing holder, we designed two alternative dosing strategies for non-small cell lung cancer based on therapeutic drug monitoring. Adjustments were made to the dose or administration interval, following regulatory standards for in silico dose optimization. A pharmacoeconomic evaluation was conducted to estimate potential cost savings from a medical perspective.</p><p><strong>Results: </strong>Both alternative strategies achieved high exposure levels, with 98.1-99.0% of patients exceeding a predefined efficacy target, surpassing the 95.4% predicted by the license holder for the approved 10 mg/kg 2-weekly regimen. They also reduced overall drug exposure by 7-24% and eliminated drug wastage, resulting in an average annual cost reduction of €25,163 (22.9%) per patient.</p><p><strong>Conclusion: </strong>Therapeutic drug monitoring-guided adjustments for durvalumab offer a potentially cost-saving way to optimize drug use, reduce healthcare burdens, and lessen environmental impact while ensuring adequate patient exposure. Our proposal's evidence provides a solid basis for a non-inferiority study.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144706581","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 and Pharmacodynamics of Remimazolam.","authors":"Bas T de Jong, Douglas J Eleveld, Keira P Mason, Michel M R F Struys","doi":"10.1007/s40262-025-01548-7","DOIUrl":"https://doi.org/10.1007/s40262-025-01548-7","url":null,"abstract":"<p><p>Remimazolam is a benzodiazepine with a high affinity for the γ-aminobutyric acid type A-receptor thereby inducing sedation and amnesia. It is a short-acting drug, has a fast onset, short duration of action, and a predictable recovery profile. Remimazolam is metabolized mainly into CNS7054. In recent years, numerous population pharmacokinetic and combined pharmacokinetic/pharmacodynamic studies have been published. This narrative review aims to give an overview of and insight into pharmacokinetic/pharmacodynamic models and related clinical effects. Body weight, age and American Society of Anesthesiologists classification, sex, hepatic function, and extracorporeal circulation have been shown to significantly impact remimazolam pharmacokinetics. Body mass index, race, concomitant opioid administration, and a CNS7054-induced tolerance effect may be covariates. The labeling of remimazolam is not consistent worldwide as it has been approved for general anesthesia and/or sedation in different countries. To date, remimazolam is only approved by the intravenous route. Remimazolam has been approved for general anesthesia and/or sedation. The incidence of postoperative nausea and vomiting seems higher compared with propofol, yet pain on injection is less common. One study has published population pharmacokinetics in children. Reports on alternative methods to intravenous administration have been sparse.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144674017","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, Pharmacodynamics, and Urinary Recovery of Oral Mescaline Hydrochloride in Healthy Participants.","authors":"Lorenz Mueller, Aaron Klaiber, Laura Ley, Anna M Becker, Jan Thomann, Dino Luethi, Yasmin Schmid, Matthias E Liechti","doi":"10.1007/s40262-025-01544-x","DOIUrl":"https://doi.org/10.1007/s40262-025-01544-x","url":null,"abstract":"<p><strong>Background and objective: </strong>Mescaline is a classic serotonergic psychedelic with a long history of human use. The present study analyzed the pharmacokinetics, pharmacokinetic-pharmacodynamic relationship, and urinary recovery of oral mescaline hydrochloride.</p><p><strong>Methods: </strong>Data from 105 single-dose administrations (100-800 mg) in 49 participants from two phase I trials were analyzed with compartmental pharmacokinetics and pharmacokinetic-pharmacodynamic modeling. A one-compartment model with first-order absorption, elimination, and a lag time was used to describe mescaline plasma concentrations. Acute subjective effects, assessed by visual analog scales (range 0-100%), were modeled using a sigmoid E_max model linked to plasma concentrations via a first-order rate constant (k_e0).</p><p><strong>Results: </strong>Mescaline showed dose-proportional increases in total exposure and maximal concentrations, with a peak concentration reached within 2.0 h (geometric mean) and a half-life of 3.5 h across all doses. Mean model-predicted onset of \"any drug effect\" occurred around 1 hour post-dose. Maximum predicted effect intensity and duration increased with dose, from 13% and 2.8 h at 100 mg to 89% and 15 h at 800 mg. Over all conditions, 53% of the dose was excreted into urine unchanged, and 31% was excreted as the main metabolite 3,4,5-trimethoxyphenylacetic acid over 24-30 h.</p><p><strong>Conclusions: </strong>These findings provide the first detailed pharmacokinetic-pharmacodynamic characterization of mescaline in humans and indicate an oral bioavailability of at least 53%, limited by first-pass metabolism to 3,4,5-trimethoxyphenylacetic acid, followed by predominant renal elimination of both analytes.</p><p><strong>Clinical trial registration: </strong>ClinicalTrials.gov identifier: NCT04227756 and NCT04849013.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625484","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":"Revisiting Acyclovir Dosing for Adult Viral Encephalitis Using a Full Bayesian LeiCNS PBPK Modeling Approach.","authors":"Ming Sun, Martijn L Manson, Anne-Grete Märtson, Jacob Bodilsen, Elizabeth C M de Lange, Tingjie Guo","doi":"10.1007/s40262-025-01545-w","DOIUrl":"https://doi.org/10.1007/s40262-025-01545-w","url":null,"abstract":"<p><strong>Background and objective: </strong>Acyclovir is a primary treatment for central nervous system (CNS) infections caused by herpes simplex virus (HSV) and varicella-zoster virus (VZV). However, patient outcomes remain suboptimal, despite acyclovir treatment. Given the lack of alternative therapies, there is a pressing clinical need to revisit acyclovir dosing for viral encephalitis. This study aimed to evaluate current and alternative acyclovir dosing regimens using a Bayesian CNS physiologically based pharmacokinetic (PBPK) modeling approach.</p><p><strong>Method: </strong>A full Bayesian analysis was performed using LeiCNS3.0 model to describe acyclovir's CNS distribution. Simulations were performed for standard dosing (10 mg/kg TID) and various alternative dosing regimens. Drug efficacy was evaluated using 50%fT > IC₅₀ (50% of the dosing interval with drug concentration above IC₅₀) and C_min > IC₅₀ (minimum concentration of the drug exceeding IC₅₀). A toxicity threshold of 25 mg/L for plasma peak concentration was applied.</p><p><strong>Results: </strong>The standard regimen (10 mg/kg TID) achieved the 50%fT > IC₅₀ target but failed to consistently meet the C_min > IC₅₀ target, particularly for VZV. Alternative regimens of increasing the dosing frequency to QID or extending infusion durations to 1.5 h or 2 h improved efficacy while maintaining safety. Prolonged infusion durations reduced peak plasma concentration thus lowered toxicity risks CONCLUSIONS: The Bayesian CNS PBPK modeling approach demonstrated robust predictive capacity for CNS PK. Current acyclovir dosing regimens may be inadequate for treating HSV and VZV encephalitis. Alternative dosing strategies involving increased frequency or extended infusion durations appear more effective and safer. Future efforts should focus on refining the PK/pharmacodynamic (PD) relationship between acyclovir exposure and antiviral efficacy to improve therapeutic outcomes.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144616552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetic and Pharmacodynamic Modelling and Simulation for Nedosiran Clinical Development and Dose Guidance in Pediatric Patients with Primary Hyperoxaluria Type 1.","authors":"Steven Zhang, Pablo Gamallo, Verity Rawson","doi":"10.1007/s40262-025-01540-1","DOIUrl":"https://doi.org/10.1007/s40262-025-01540-1","url":null,"abstract":"<p><strong>Background and objectives: </strong>Nedosiran (Rivfloza^®) is an RNA interference (RNAi) therapy approved for individuals aged ≥ 2 years with primary hyperoxaluria type 1 (PH1), a rare autosomal-recessive disorder causing renal failure and systemic oxalosis. Nedosiran silences lactate dehydrogenase (LDH) mRNA in hepatocytes, reducing oxalate levels. This study evaluated the model-informed clinical development of nedosiran to support proposed doses in children aged 2 to < 12 years with PH1.</p><p><strong>Methods: </strong>A population pharmacokinetic/pharmacodynamic (Pop-PK/PD) model characterizing the plasma concentration-time profile of nedosiran and its effect on the spot urine oxalate-to-creatinine ratio (Uox/Cr) was developed using data from six trials. Simulations assessed spot Uox/Cr reduction in children aged 2 to < 12 years for the proposed dosing regimen versus those aged ≥ 12 years weighing ≥ 50 kg with similar renal function.</p><p><strong>Results: </strong>The datasets included 2087 PK (N = 148) and 668 spot Uox/Cr (N = 41, with PH1) observations. Body weight, estimated glomerular filtration rate (eGFR), and PH type were covariates in the PK model, with body weight in low and high percentiles affecting nedosiran exposures. Moderate renal impairment (eGFR 30-59 mL/min/1.73 m²) increased exposure, while only age was significant for baseline Uox/Cr in the PD model. Simulations showed similar Uox/Cr reduction and times to maximum effect in children aged 2 to < 12 years, treated once-monthly (Q1M) with 3.5 mg/kg, compared to those aged ≥ 12 years treated Q1M with 170 mg.</p><p><strong>Conclusions: </strong>Simulations based on the final Pop-PK/PD model support the 3.5 mg/kg Q1M dosing regimen in children aged 2 to < 12 years with PH1 and relatively intact kidney function (eGFR ≥30 mL/min/1.73 m²).</p><p><strong>Trial registration: </strong>Trials are registered at ClinicalTrials.gov with study numbers NCT03392896 (PHYOX1), NCT03847909 (PHYOX2), NCT04042402 (PHYOX3), and NCT05001269 (PHYOX8) and at EudraCT with study numbers 2018-003098-91 (PHYOX2) and 2018-003099-10 (PHYOX3).</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetic Analysis of an Octreotide Depot (CAM2029) in the Treatment of Acromegaly.","authors":"Anaïs Glatard, Sofia Friberg-Hietala, Lina Keutzer, Anna Hansson, Markus Johnsson, Fredrik Tiberg","doi":"10.1007/s40262-025-01522-3","DOIUrl":"10.1007/s40262-025-01522-3","url":null,"abstract":"<p><strong>Introduction: </strong>Octreotide is a first-generation somatostatin receptor ligand (SRL) approved for acromegaly treatment. CAM2029 is a sustained-release subcutaneous octreotide injection designed to improve treatment convenience for patients and bioavailability over alternative SRL treatments. The aim of this analysis was to characterise the pharmacokinetic (PK) properties of CAM2029.</p><p><strong>Methods: </strong>Using nonlinear mixed-effects modelling, 4098 observations from three trials, including 216 healthy participants and participants with acromegaly, were used to develop a population PK model of octreotide after administration of CAM2029 or immediate-release (IR) octreotide. Simulated octreotide plasma concentration profiles after administration of clinically justified dosing regimens of CAM2029 and octreotide IR were compared.</p><p><strong>Results: </strong>Octreotide disposition was best described by a two-compartmental distribution with a first-order elimination model. The rapid initial and slow subsequent drug release of CAM2029 was best characterised by two simultaneous first-order absorption processes, whereas octreotide IR absorption was described by a single first-order pathway. The model was qualified to describe octreotide concentrations and supported the robustness of dosing CAM2029 every 4 weeks (Q4W) ± 1 week. Simulations indicated that the average concentration during a dosing interval at steady state for 20 mg CAM2029 Q4W was similar to 0.25 mg octreotide IR every 8 h, but with reduced daily fluctuation.</p><p><strong>Conclusions: </strong>This population PK model supports the use of CAM2029 as a potential alternative treatment option to both octreotide IR and long-acting repeatable (LAR) for acromegaly treatment. The octreotide bioavailability for CAM2029 was similar to octreotide IR and approximately 5 to 6 fold higher than octreotide LAR, with a more rapid onset.</p><p><strong>Trial registrations: </strong>2020-002643-35 (EudraCT), NCT04076462 (date of registration: 3rd September 2019), NCT04125836 (date of registration: 14th October 2019).</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1079-1092"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12185581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141556","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":"Optimizing Nortriptyline Dosing: A Comparison between Pharmacogenetics-Based, Phenotype-Based, and Standard Dosing.","authors":"Cornelis F Vos, Marieke J H Coenen, Sophie E Ter Hark, Arnt F A Schellekens, Rob E Aarnoutse, Joost G E Janzing, Rob Ter Heine","doi":"10.1007/s40262-025-01528-x","DOIUrl":"10.1007/s40262-025-01528-x","url":null,"abstract":"<p><strong>Background and objective: </strong>Nortriptyline, a tricyclic antidepressant, has an important role in the pharmacotherapy of major depressive disorder (MDD). Individualized dosing approaches, such as pharmacogenetics-based and phenotype-based dosing, may enhance early achievement of therapeutic plasma concentrations, but their comparative accuracy has not been investigated. Our objective was to compare the accuracy of three nortriptyline dosing strategies: pharmacogenetics-based, phenotype-based, and standard dosing.</p><p><strong>Methods: </strong>Using pharmacokinetic modeling based on data from a randomized controlled trial, we assessed and compared the following dosing strategies: pharmacogenetics-based dosing depending on the cytochrome P-450 (CYP) 2D6 genotype, phenotype-based dosing determined by the plasma concentration measured after a single nortriptyline administration, and standard dosing (125 mg/day). A population pharmacokinetic model was developed to assess phenotype-based dosing recommendations. We evaluated the dosing strategies by comparing the number of participants with predicted therapeutic, subtherapeutic, and supratherapeutic plasma concentrations using Chi-squared (χ²) tests. Variability in plasma concentrations was assessed using F-tests.</p><p><strong>Results: </strong>Both pharmacogenetics-based (χ² (1) = 8.0, p = 0.01) and phenotype-based dosing (χ² (1) = 5.3, p = 0.02) significantly increased the likelihood of achieving therapeutic plasma concentrations compared with standard dosing while reducing plasma concentration variability. No significant difference was found in the prediction of therapeutic concentrations between the two individualized dosing strategies (χ² (1) = 0.33, p = 0.56).</p><p><strong>Conclusions: </strong>Pharmacogenetics-based and phenotype-based dosing demonstrate greater accuracy in predicting therapeutic nortriptyline plasma concentrations than standard dosing. Further research is warranted to explore the clinical application of model-informed precision dosing for nortriptyline and other psychotropic medications.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1071-1078"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12185566/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141554","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":"Author's Reply to Chan et al.: \"Ticagrelor is Associated with Increased Rosuvastatin Blood Concentrations in Patients Who Have Had a Myocardial Infarction\".","authors":"Tjaša Dermota, Borut Jug, Jurij Trontelj, Mojca Božič Mijovski","doi":"10.1007/s40262-025-01519-y","DOIUrl":"10.1007/s40262-025-01519-y","url":null,"abstract":"","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1137-1138"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126268","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 Pharmacology of Loop Diuretics in Critical Care.","authors":"Fiorenza Ferrari, Christian Zanza, Manfredi Tesauro, Yaroslava Longhitano, Raymond Planinsic, Antonio Voza, Jacopo Fumagalli, Vittorio Scaravilli, Giacomo Grasselli","doi":"10.1007/s40262-025-01524-1","DOIUrl":"10.1007/s40262-025-01524-1","url":null,"abstract":"<p><p>Loop diuretics are a cornerstone in the management of fluid overload in critically ill patients; however, their use is often complicated by variable pharmacokinetics and the phenomenon of diuretic resistance. This narrative review comprehensively examines the pharmacokinetic properties of loop diuretics and discusses the implications of altered pharmacokinetics due to factors such as organ dysfunction, fluid shifts, and concomitant medications, highlighting the challenges in achieving therapeutic targets. Furthermore, we explore the adverse events associated with loop diuretic administration, including electrolyte imbalances and ototoxicity. The review delves into the concept of diuretic resistance, exploring its multifactorial origins, including altered pharmacodynamics and increased compensatory mechanisms. Various strategies to overcome diuretic resistance are presented, including combination therapy with other diuretics, optimizing dosing regimens, and utilizing novel pharmacological agents. Given the complexity of loop diuretic therapy in critically ill patients, a tailored approach is crucial for optimizing fluid management and mitigating adverse effects. This review aims to inform clinicians about the nuances of loop diuretic use in critical care settings, providing insights into pharmacological strategies and clinical considerations essential for enhancing patient outcomes.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"987-997"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12185637/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186724","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":"Pharmacokinetics of Ivacaftor, Tezacaftor, Elexacaftor, and Lumacaftor in Special Cystic Fibrosis Populations: A Systematic Review.","authors":"Femke A Elzinga, Paul R V Malik, Onno W Akkerman, Bart L Rottier, Hester van der Vaart, Daan J Touw, Gerard H Koppelman, Paola Mian","doi":"10.1007/s40262-025-01507-2","DOIUrl":"10.1007/s40262-025-01507-2","url":null,"abstract":"<p><strong>Background and objective: </strong>Following the development of cystic fibrosis transmembrane conductance regulator (CFTR) modulators (ivacaftor, tezacaftor, elexacaftor, and lumacaftor), the prognosis for people diagnosed with cystic fibrosis (pwCF) has improved. Understanding the pharmacokinetics (PK) of CFTR modulators is crucial to provide optimal care, particularly in special cystic fibrosis (CF) populations such as pwCF with hepatic impairment, pancreatic insufficiency, those who are pregnant or lactating, or who are children. We aim to provide an overview of the PK of CFTR modulators in these populations.</p><p><strong>Methods: </strong>A systematic literature search was carried out in PubMed and Embase on 20 June 2024. Studies were considered relevant when information on PK or exposure of CFTR-modulating drugs was available.</p><p><strong>Results: </strong>PwCF with mild/moderate hepatic impairment do not exhibit substantially higher exposure to CFTR modulators compared with those without liver involvement or healthy individuals. Similarly, exocrine pancreatic insufficiency has no effect on the PK of CFTR modulators in adult pwCF. In contrast, pediatric pwCF are exposed to higher levels of CFTR modulators relative to adults, as children receive higher weight-based doses (mg/kg) to ensure equivalent therapeutic efficacy.</p><p><strong>Conclusions: </strong>The PK of CFTR modulators have been more extensively studied in adults, pwCF with mild/moderate hepatic impairment, and children. However, ensuring adequate dosing remains challenging. Knowledge gaps persist for adults with severe hepatic impairment (Child-Pugh Class C), children with CF-induced hepatic impairment, and pregnant or lactating pwCF. Future research addressing these gaps, through incorporating routine clinical data, is crucial for improving clinical guidelines and optimizing dosing regimens, thereby advancing towards evidence-based utilization of CFTR modulators.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"999-1046"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12185575/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119092","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}