Clinical Pharmacokinetics最新文献

{"title":"Population Pharmacokinetics of Intravenous Vitamin C in Adults with Sepsis: A Sub-study of the LOVIT Trial.","authors":"Salmaan Kanji, María Patricia Hernández-Mitre, Hugues Blain, Neill K J Adhikari, Francois Lamontagne, Marie-Claude Battista, Julie Ménard, Sheila Sprague, Marie-Hélène Masse, Jason A Roberts","doi":"10.1007/s40262-026-01648-y","DOIUrl":"10.1007/s40262-026-01648-y","url":null,"abstract":"<p><strong>Background and objectives: </strong>High-dose intravenous vitamin C was associated with increased harm in adults with sepsis requiring vasopressors in the large international LOVIT trial. This population pharmacokinetic sub-study of LOVIT aimed to characterise the pharmacokinetics of vitamin C and explore associations with patient characteristics and outcomes.</p><p><strong>Methods: </strong>Patients who enrolled in the LOVIT trial were randomized to receive 50 mg/kg vitamin C every 6 hours for 96 hours or placebo. Blood samples were collected on study Days 1, 3, and 7 for plasma vitamin C quantification. Population pharmacokinetic modeling was performed, with relevant patient and treatment-related factors tested as covariates. Internal validation was conducted using bootstrap resampling (n = 1000). Univariable and multivariable analyses explored associations between 28-day mortality and patient characteristics, as well as the relationship between vitamin C exposure and severity of illness.</p><p><strong>Results: </strong>A total of 464 samples from 161 patients who were randomized to vitamin C were analysed. The median age was 64 (interquartile range [IQR] 56-72) years, weight 82 (IQR, 70-94) kg, and APACHE II score 24 (IQR, 18-29); 65.2% were male. A one-compartment model best described the data, with clearance (CL) significantly influenced by CKD-EPI eGFR and APACHE II score. Population mean estimates for clearance and volume of distribution were 3.37 L/h and 45.06 L, respectively. The model was internally validated and demonstrated to be robust and stable. Although greater vitamin C exposure was observed among non-survivors versus survivors (median 1900.5 [IQR 1191.8-2548.2] vs 1017.8 [IQR 630-1836.7] mg·h/L; p < 0.001), only age (odds ratio [OR] 1.063; 95% confidence interval [CI] 1.024-1.104, p = 0.001) and APACHE II score (OR 1.079; 95% CI 1.005-1.158, p = 0.036) were independently associated with 28-day mortality. Severity of illness was also predictive of vitamin C exposure.</p><p><strong>Conclusions: </strong>Vitamin C pharmacokinetics are highly variable between individuals. Some of this variability can be explained by changes in glomerular filtration and APACHE II score as a measure of illness severity. Although non-survivors had greater vitamin C exposure than survivors, exposure was not independently associated with mortality.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1205-1216"},"PeriodicalIF":4.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148292985","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":"How Feasible is the Use of Saliva for Antiviral Therapeutic Drug Monitoring? A Systematic Review and Analysis.","authors":"Cassandra Weng-Yan Lai, Suzanne A M Wenker, Paul W Groundwater, Justin Beardsley, Gaurav Sutrave, Ricky Hao Chen, Anne-Grete Märtson, Jan-Willem C Alffenaar","doi":"10.1007/s40262-026-01675-9","DOIUrl":"10.1007/s40262-026-01675-9","url":null,"abstract":"<p><strong>Background and objective: </strong>Immunosuppressed patients are susceptible to serious viral infections, often necessitating antiviral prophylaxis and/or treatment. Therapeutic drug monitoring (TDM) has been proposed to optimise drug exposure and clinical outcomes and is typically performed on full blood/plasma samples. Saliva offers a less invasive, patient-friendly approach, and this systematic review aims to assess the feasibility of saliva-based assays for antiviral TDM.</p><p><strong>Methods: </strong>We conducted a search on MEDLINE, EMBASE and ClinicalTrials.gov databases, governmental regulatory websites and conference abstracts. Primary studies reporting both saliva and plasma concentrations of antivirals used forprophylaxis or treatment of opportunistic viral infections were included. Physicochemical properties of eachantiviral were compiled from PubChem and DrugBank to predict salivary excretion. Feasibility classifications were defined as follows: (1) likely, (2) possible, (3) unlikely, (4) unclear but possible, (5) unclear but unlikely.</p><p><strong>Results: </strong>We included nine studies in our review. (Val)acyclovir and favipiravir were considered possibly feasible for saliva-based TDM, whereas molnupiravir and oseltamivir were unclear but possible. Nirmatrelvir was deemed unclear but unlikely. For other included antivirals, no primary studies were available, however, physicochemical profiles suggest that salivary penetration may be feasible for some agents but limited for others.</p><p><strong>Conclusion: </strong>Studies documenting both saliva and plasma concentrations were scarce, and data was inconsistent. Findings from clinical studies sometimes contradicted predictions of penetration based on drug properties, suggesting that other factors, such as drug transporters, may significantly influence the salivary excretion of antivirals. Future robust, standardised investigations are required to confirm the clinical utility of saliva-based TDM. Feasibility is therefore currently inconclusive, but preliminary evidence is promising.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1155-1172"},"PeriodicalIF":4.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13461875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148677258","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":"Correction: Population Pharmacokinetic-Pharmacodynamic Relationships of Sarilumab Using Disease Activity Score 28‑Joint C‑Reactive Protein and Absolute Neutrophil Counts in Patients with Rheumatoid Arthritis.","authors":"Lei Ma, Christine Xu, Anne Paccaly, Vanaja Kanamaluru","doi":"10.1007/s40262-026-01656-y","DOIUrl":"10.1007/s40262-026-01656-y","url":null,"abstract":"","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1273-1274"},"PeriodicalIF":4.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13461850/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419335","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":"Blood Never Lies: The PopPK-Based Lie Detector.","authors":"Sahira Chaiben, Peggy Gandia, Béatrice Duly-Bouhanick, Lauriane Goldwirt, Didier Concordet","doi":"10.1007/s40262-026-01652-2","DOIUrl":"10.1007/s40262-026-01652-2","url":null,"abstract":"<p><strong>Background and objective: </strong>Accurate assessment of drug adherence is essential for long-term oral therapies, where self-administration is unsupervised. Conventional tools such as self-reports, electronic monitors, and even therapeutic drug monitoring often fail to detect non-adherence. Population pharmacokinetic modeling improves objectivity but typically relies on a single analyte, which may still miss hidden non-adherence. We propose a bi-analyte population pharmacokinetic-based approach that uses both the parent drug and a metabolite with distinct pharmacokinetics to enhance adherence detection and reconstruct likely dosing histories.</p><p><strong>Methods: </strong>A literature review identified spironolactone and its metabolite canrenone as suitable candidates, based on long-term use and an available population pharmacokinetic model capturing distinct elimination profiles. Virtual patients were simulated under steady-state assumptions, then exposed to various adherence scenarios. A modified Metropolis-Hastings algorithm jointly estimated individual pharmacokinetic parameters and dosing patterns by analyzing simulated drug and metabolite concentrations. The probability of taking 0, 1, or 2 tablets per day was inferred, and a posterior adherence probability was derived from the posterior distribution to quantify adherence likelihood. A receiver operating characteristic analysis was used to evaluate diagnostic performance.</p><p><strong>Results: </strong>The combined use of parent and metabolite improved non-adherence detection compared with either alone, particularly for recent missed doses. Trough concentrations outperformed peak concentrations, especially when patients did not compensate with extra doses.</p><p><strong>Conclusions: </strong>This probabilistic bi-analyte approach enhances non-adherence detection and is adaptable to other pharmacokinetic settings where distinct profiles and low model variability are present.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1193-1204"},"PeriodicalIF":4.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13461949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148257478","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":"Clinical Pharmacokinetics and Pharmacodynamics of the IL-1 Receptor Antagonist Anakinra: A Systematic Review.","authors":"Jia Li, Megan Clark, David K Metz, Marcel F Nold, Carl M J Kirkpatrick","doi":"10.1007/s40262-026-01667-9","DOIUrl":"10.1007/s40262-026-01667-9","url":null,"abstract":"<p><strong>Background and objective: </strong>Anakinra, an interleukin-1 receptor antagonist (IL-1Ra), has been used clinically for over 20 years, with growing interest in repurposing it across diverse indications. However, clinical dosing strategies for anakinra are variable, with limited pharmacokinetic (PK)/pharmacodynamic (PD) knowledge across patient populations and administration routes available. This systematic review aimed to summarise clinical PK and PD characteristics of anakinra and identify research gaps.</p><p><strong>Methods: </strong>A systematic search of Medline, Embase, and other databases was conducted to identify clinical studies reporting the PK, PD, efficacy, and safety of anakinra. Following the application of predefined inclusion and exclusion criteria, 26 articles were included in the review. Extracted data from these studies were converted into uniform units to enable cross-study comparison, and a descriptive synthesis was performed. All included studies were assessed for risk of bias.</p><p><strong>Results: </strong>Data were categorised into three groups: noncompartmental analysis (NCA) PK parameters, model-informed PK/PD parameters, and exposure-response (ER) relationships. Across all studies, anakinra demonstrated linear PK following both intravenous (IV) and subcutaneous (SC) administration, with high SC bioavailability and flip-flop kinetics. Covariate analyses from NCA and PK models consistently identified body weight and renal function as key determinants of anakinra PK variability, with clearance increasing with body weight and decreasing with worsening renal function. ER analyses identify a potential target exposure corresponding to an average steady-state concentration (C_avg,ss) of 0.4 mg/L, equivalent to a steady-state area under the concentration-time curve (AUC_{0-24 h,ss}) of 9.6 mg·h/L. However, available anakinra paediatric clinical PK data are sparse, limiting definitive age-based comparisons. Existing PK models of anakinra lacked incorporation of endogenous IL-1Ra kinetics, and do not currently describe diverse patient populations, with only one population PK/PD model identified. Furthermore, currently available data are insufficient to validate the target exposure of anakinra across the full continuum spanning PK, PD, clinical outcomes, and safety.</p><p><strong>Conclusions: </strong>Overall, this review highlights substantial gaps in the clinical PK/PD knowledge on anakinra, and model robustness. Future studies, integrating physiologically informed covariates, improved biomarker strategies, and comprehensive ER data, are essential to support model-informed dosing for anakinra repurposing across populations and administration routes. These would facilitate the safety and efficacy of anakinra therapy across diverse populations.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1131-1153"},"PeriodicalIF":4.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13461743/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148403840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physiologically Based Pharmacokinetic (PBPK) Modeling of Antidepressants: A Scoping Review of Existing Models, Applications, and Software Tools.","authors":"Rebecca Leyla Huber, Oliver Scherf-Clavel","doi":"10.1007/s40262-026-01668-8","DOIUrl":"10.1007/s40262-026-01668-8","url":null,"abstract":"<p><p>Physiologically based pharmacokinetic models are a valuable tool for simulating antidepressant pharmacokinetics in patient groups that are often underrepresented in clinical trials. Clinical data on antidepressant use in vulnerable populations such as geriatric patients or pregnant women remain limited, making safe and personalized treatment challenging. The objective of this review was to systematically evaluate existing physiologically based pharmacokinetic models for antidepressants, their applications, and the modeling software platforms used, in order to identify relevant research gaps and highlight future needs for model development. A scoping review was conducted in accordance with Preferred Reporting Items for Scoping Reviews (PRISMA-ScR) guidelines. Seven electronic databases were systematically searched. Data on the modeled drug, model applications, and software platforms were extracted and evaluated. A total of 60 studies met the inclusion criteria. The availability of physiologically based pharmacokinetic models across antidepressants was heterogeneous. Paroxetine, fluvoxamine, and venlafaxine were most frequently modeled (n = 10 each), whereas few or no models exist for substances such as mirtazapine (n = 1) or milnacipran (n = 0). The main application areas were drug-drug interactions (n = 18), pregnancy (n = 14), and drug-(drug-)gene interactions (n = 13). Pediatric populations and specific ethnic groups were rarely addressed. SimCyp® Simulator was the most used modeling platform, followed by PK-Sim®/Mobi®, GastroPlus®, and R®/RStudio®. Although physiologically based pharmacokinetic models for antidepressants are increasingly available, they focus on a limited number of drugs and applications. Substantial evidence gaps remain, particularly for vulnerable patient populations.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1115-1130"},"PeriodicalIF":4.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13461864/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148403869","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":"Correction: Population Pharmacokinetic Analysis of Enalapril and Enalaprilat in Newly Treated Children with Heart Failure: Implications for Safe Dosing of Enalapril (LENA Studies).","authors":"Melina Steichert, Willi Cawello, Stephanie Laeer","doi":"10.1007/s40262-026-01677-7","DOIUrl":"10.1007/s40262-026-01677-7","url":null,"abstract":"","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1275"},"PeriodicalIF":4.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13461759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618071","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":"ALBI Grade is a Determinant of Lenvatinib Pharmacokinetics, Efficacy, and Toxicities in Japanese Patients with Hepatocellular Carcinoma.","authors":"Kosuke Suzuki, Yumi Otoyama, Natsumi Matsumoto, Yusuke Masuo, Yoko Nakajima, Ikuya Sugiura, Takahiro Fuji, Erika Nomura, Yuki Ichikawa, Yuu Shimozuma, Manabu Uchikoshi, Momoka Hayano, Mayuko Hanano, Remi Murase, Chika Mitomori, Kiyoshi Oka, Masashi Sakaki, Yukio Kato, Hitoshi Yoshida, Ken-Ichi Fujita","doi":"10.1007/s40262-026-01662-0","DOIUrl":"10.1007/s40262-026-01662-0","url":null,"abstract":"<p><strong>Background and objective: </strong>The doses of lenvatinib for patients with hepatocellular carcinoma (HCC) are determined using the Child-Pugh classification and body weight. Because lenvatinib is highly bound to plasma albumin (98.6%), patients with low plasma albumin levels and hepatic lenvatinib clearance may exhibit a high unbound fraction and/or concentration of lenvatinib in the plasma to alter efficacy and toxicity. This study exploratorily and prospectively examined the effects of baseline albumin-bilirubin (ALBI) on systemic exposure to unbound lenvatinib and lenvatinib clinical responses in patients with HCC.</p><p><strong>Patients and methods: </strong>Patients with HCC who received lenvatinib were enrolled. Total- and unbound-base dose-normalized area under the plasma concentration-time curve (AUCt/dose and AUCu/dose, respectively) were determined. Progression-free survival (PFS) and toxicities were evaluated.</p><p><strong>Results: </strong>Forty-one patients were enrolled between May 2020 and January 2024. AUCu/dose, but not AUCt/dose, was significantly negatively correlated with ALBI score (P = 0.00699). Patients with ALBI grade ≥ 2b had significantly higher AUCu/dose than those with < 2b (mean ± SD, 0.00602 ± 0.00268 vs. 0.00390 ± 0.00168 h/L, P = 0.0131). Child-Pugh class was associated with AUCu/dose (P = 0.0312); however, among Child-Pugh classification components, albumin only was associated with the AUCu/dose. Multivariate Cox proportional hazards analysis identified ALBI grade ≥ 2b as risk factor for shorter PFS (P = 0.0000521; hazard ratio 9.43; 95% confidence interval 3.18-28.0). ALBI grade ≥ 2b, but not Child-Pugh class, showed a significantly higher incidence of lenvatinib-induced toxicity grades ≥ 2 than ALBI grade < 2b (87.0 vs. 55.6%, P = 0.0357).</p><p><strong>Conclusion: </strong>The study exploratorily found that baseline ALBI grade was associated with lenvatinib AUCu/dose and clinical responses.</p><p><strong>Trial registration number: </strong>UMIN000057138 (registered on February 27, 2025).</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1229-1241"},"PeriodicalIF":4.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13461857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148307325","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":"Elranatamab Population Pharmacokinetics and Exposure-Response for Cytokine Release Syndrome in Patients with Relapsed or Refractory Multiple Myeloma.","authors":"Jennifer E Hibma, Donald Irby, Alan Liu, Mohamed Elmeliegy, Lindsay E King, David Gifondorwa, Sibo Jiang, Kamrine E Poels, Pooneh Soltantabar, Hoi-Kei Lon, Blerta Shtylla, Diane Wang, Jason H Williams, Timothy Nicholas","doi":"10.1007/s40262-026-01663-z","DOIUrl":"10.1007/s40262-026-01663-z","url":null,"abstract":"<p><strong>Background and objective: </strong>A population pharmacokinetics (PopPK) model was developed for elranatamab, a bispecific antibody targeting both B-cell maturation antigen (BCMA) and cluster of differentiation 3 (CD3), to characterize the PopPK of elranatamab and guide clinical development. Elranatamab is approved in several countries for the treatment of relapsed or refractory multiple myeloma.</p><p><strong>Methods: </strong>The PopPK model incorporated data from four clinical studies and described both free and total elranatamab as well as soluble BCMA (sBCMA) using a semi-mechanistic two-compartment target-binding model. In total there were 13,233 observations from 321 participants who received intravenous (IV) or subcutaneous (SC) elranatamab monotherapy with doses ranging from 0.1 to 1000 µg/kg.</p><p><strong>Results: </strong>Elranatamab exhibited approximately linear PK over the dose range evaluated (i.e., 6-76 mg SC), with limited cellular target-mediated drug disposition and generally proportional exposure, with modest deviations at very high baseline sBCMA. None of the potential covariates evaluated, including age, sex, body weight, baseline sBCMA, and immunogenicity, were found to be clinically significant predictors of elranatamab exposure. Exposure-response analyses identified early peak exposure and tumor burden as key predictors of cytokine release syndrome (CRS), primarily after the first step-up dose. Simulations supported restarting treatment without re-priming after dose interruptions of up to 12 weeks.</p><p><strong>Conclusion: </strong>These findings support the approved fixed-dose regimen and provide a framework for clinical management of elranatamab in relapsed or refractory multiple myeloma.</p><p><strong>Clinical trial registration: </strong>NCT03269136, NCT04798586, NCT04649359, NCT05014412.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1173-1192"},"PeriodicalIF":4.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13461831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148249550","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":"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":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The minimal PBPK model described pulmonary PK of salbutamol across the lung and estimated the unbound tissue-plasma partition coefficient for the lung ( &lt;math&gt;&lt;msub&gt;&lt;mi&gt;K&lt;/mi&gt; &lt;mrow&gt;&lt;mtext&gt;p&lt;/mtext&gt; &lt;mo&gt;,&lt;/mo&gt; &lt;mtext&gt;u&lt;/mtext&gt; &lt;mo&gt;,&lt;/mo&gt; &lt;mtext&gt;lung&lt;/mtext&gt;&lt;/mrow&gt; &lt;/msub&gt; &lt;/math&gt; ) and the effective permeability ( &lt;math&gt;&lt;msub&gt;&lt;mi&gt;P&lt;/mi&gt; &lt;mtext&gt;eff&lt;/mtext&gt;&lt;/msub&gt; &lt;/math&gt; ) 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 &lt;math&gt;&lt;msub&gt;&lt;mi&gt;K&lt;/mi&gt; &lt;mrow&gt;&lt;mtext&gt;p&lt;/mtext&gt; &lt;mo&gt;,&lt;/mo&gt; &lt;mtext&gt;u&lt;/mtext&gt; &lt;mo&gt;,&lt;/mo&gt; &lt;mtext&gt;lung&lt;/mtext&gt;&lt;/mrow&gt; &lt;/msub&gt; &lt;/math&gt; or &lt;math&gt;&lt;msub&gt;&lt;mi&gt;P&lt;/mi&gt; &lt;mtext&gt;eff&lt;/mtext&gt;&lt;/msub&gt; &lt;/math&gt; . 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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;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}