CPT: Pharmacometrics & Systems Pharmacology最新文献

{"title":"Simultaneous Population PKPD Analysis of Belantamab Mafodotin, Soluble BCMA, and Serum M-Protein in Relapsed/Refractory Multiple Myeloma","authors":"John D. Clements,&nbsp;Inmaculada C. Sorribes,&nbsp;Josh Kaullen,&nbsp;Christine Neumar,&nbsp;Adekemi Taylor,&nbsp;Mun Sang Yue,&nbsp;Xi Chen,&nbsp;Herbert Struemper,&nbsp;Geraldine Ferron-Brady","doi":"10.1002/psp4.70337","DOIUrl":"10.1002/psp4.70337","url":null,"abstract":"<p>A simultaneous pharmacokinetic (PK)/pharmacodynamic (PD) analysis was conducted to characterize relationships between anti-B-cell maturation antigen (BCMA)-targeting antibody-drug conjugate, belantamab mafodotin, and longitudinal multiple myeloma (MM) disease markers (soluble BCMA [sBCMA], M-protein). Data from patients with relapsed/refractory MM receiving belantamab mafodotin monotherapy in the DREAMM-1 (NCT02064387), DREAMM-2 (NCT03525678), DREAMM-3 (NCT04162210), or DREAMM-5 (NCT04126200) trials were included. The dataset contained 510 patients with 15,860 PK and PD observations. Previous population PK and M-protein PD models were combined to create a new starting model. Overparameterization was reduced using sensitivity analyses to create a 2-compartment base model for belantamab mafodotin with a linear clearance component and target-mediated drug disposition assuming quasi-equilibrium between belantamab mafodotin and sBCMA binding. Free belantamab mafodotin affected M-protein elimination rate via a direct effect, and M-protein in turn scaled sBCMA synthesis rate. sBCMA was assumed to transfer into the central free sBCMA compartment through a reservoir compartment, allowing capture of observed differences in timescales. Stepwise covariate modeling led to the final model, which contained eight covariate effects (baseline sBCMA, albumin, body weight, and sex on belantamab mafodotin clearance; baseline body weight and sex on belantamab mafodotin central volume of distribution; extramedullary disease at screening and baseline sBCMA on M-protein death rate constant). Simulations of belantamab mafodotin doses/schedules showed concentrations of free sBCMA and M-protein decreased as free and total belantamab mafodotin increased with higher doses. The PKPD model captured the clearance of belantamab mafodotin and the highly dynamic interactions between belantamab mafodotin PK, M-protein, and sBCMA.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":"15 10","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13624289/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PMxAgent: An Agentic Platform for Pharmacometrics","authors":"Peter Bloomingdale,&nbsp;Antari Khot","doi":"10.1002/psp4.70325","DOIUrl":"10.1002/psp4.70325","url":null,"abstract":"<p>AI agents are transforming computational workflows, yet pharmacometric analyses remain manual, relying on significant data wrangling, custom scripts, and specialized software. We present PMxAgent, an open-source agentic platform for developing and deploying specialized agent-callable pharmacometric tools. The platform uses Docker to orchestrate an R-based API server alongside a Python-based model context protocol (MCP) server, which automatically generates agent-callable tools from OpenAPI specifications, making pharmacometric functions discoverable and usable by AI agents. To exemplify pharmacometric applications, five tools were developed: non-compartmental analysis (NCA) using PKNCA, exposure-response (ER) modeling, pharmacokinetic (PK) simulation using mrgsolve, data standardization (DATA), and generation of population PK datasets from the nlmixr2lib model library (LIBRARY). As a proof-of-concept case study, PMxAgent orchestrated a multistep pharmacometric workflow, consisting of a PK simulation of 60 subjects across three dose groups, NCA to derive individual exposure metrics, and ER analysis. To evaluate analytical accuracy and reproducibility, the agentic NCA workflow was benchmarked against four frontier AI agents across 182 drugs and 1820 simulated subjects, using PKanalix as reference. PMxAgent's NCA accuracy (98.3%) matched or exceeded that of all frontier agents evaluated. PMxAgent produced deterministic, reproducible results in contrast to GPT and Claude agents that performed NCA by generating new code each run. PMxAgent was demonstrated using two MCP-compatible AI agents (Cursor and Claude Code) and is designed to integrate with any AI agent supporting the MCP protocol. PMxAgent provides an extensible foundation for integrating pharmacometric tools into human-supervised AI-driven workflows while ensuring reproducibility, transparency, and detailed documentation required for model-informed drug development.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":"15 10","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/psp4.70325","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development, Early Verification and Application of a North American Pediatric PBPK Model, Comparison With the North European Pediatric Population","authors":"Trevor N. Johnson,&nbsp;Fiskani Kondowe,&nbsp;Joyce van der Heijden,&nbsp;Saskia N. de Wildt,&nbsp;Iain Gardner,&nbsp;Karen Rowland Yeo","doi":"10.1002/psp4.70344","DOIUrl":"10.1002/psp4.70344","url":null,"abstract":"<p>Physiologically based pharmacokinetic (PBPK) models are increasingly used in pediatric drug development and matching such models to the target population is an important consideration. A US pediatric PBPK model was developed incorporating four sub-groups describing physiology and enzymatic/transporter levels for White, African American, Hispanic/Latino and Asian subjects. Virtual populations could then be created reflecting the demographics of the clinical study design. Ten different drugs (14 studies) were used to verify the pediatric PBPK model performance. Predicted PK parameters showed reasonable agreement with observed data, 50% of the predicted: observed values were within 0.8–1.25-fold, 74% within 0.67–1.5-fold, and 97% within 0.5–2-fold. There was minimal difference for most drugs in performance between the mixed US and North European pediatric populations. This was partly due to reported studies having low numbers of subjects and under-representation of some ethnicities. Power calculations showed that to detect a pharmacokinetic difference for the CYP3A4/5 substrates midazolam, sirolimus and tacrolimus between African American and White American children with a power of 80%, 25, 18 and 12 subjects respectively, in each group would be needed. Developing adult and pediatric PBPK models to closely match study populations is important due to their increased regulatory use and with the move to their application in personalized medicine. Such models may also help to bridge some of the ethnic differences not captured in pediatric clinical studies due to the low numbers of subjects.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":"15 10","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/psp4.70344","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149029635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Practical Tutorial on Physics-Informed Networks for Pharmacometrics and Quantitative Systems Pharmacology","authors":"Nazanin Ahmadi Daryakenari,&nbsp;Mohammad Kohandel","doi":"10.1002/psp4.70343","DOIUrl":"10.1002/psp4.70343","url":null,"abstract":"<p>Inverse problems in pharmacometrics and quantitative systems pharmacology (QSP) often involve sparse, noisy data, limited measurable states, and complex dynamical systems. Traditional parameter estimation methods can struggle with ill-posed problems, stiffness, discontinuities, and gray-box scenarios where only part of the system dynamics is known or observable. This tutorial provides an end-to-end, reproducible workflow for applying physics-informed neural networks (PINNs) to PK/PD/QSP inverse problems and gray-box discovery tasks. We present three worked case studies: (1) constant parameter recovery in a three-state compartmental system, (2) gray-box discovery of an unknown right-hand-side function, and (3) inference of a time-varying chemotherapy efficacy function under partial observation. For each, we provide implementation guidance, validation checks, and practical advice on collocation design, feature expansion, optimizer selection, numerical precision, constraint enforcement, loss weighting, and residual-based attention. We also discuss when to consider newer architectures such as Kolmogorov–Arnold networks (KANs) as drop-in alternatives to standard multilayer perceptrons. All code and notebooks are provided through our <span>PhINs</span> library, short for Pharmacometrics-Informed Networks, and are publicly available at https://github.com/NazAhmadi/PhINs/.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":"15 10","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13597951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149024011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetics of Topical Timolol Maleate Gel in Healthy Volunteers and Infants With Superficial Infantile Hemangioma","authors":"Li Li,&nbsp;Yanming Li,&nbsp;Fan Hu,&nbsp;Deming Wang,&nbsp;Ning Sun,&nbsp;Qingheng Meng,&nbsp;Qin Yu,&nbsp;Ling Xu,&nbsp;Libo Zhao,&nbsp;Lin Ma","doi":"10.1002/psp4.70334","DOIUrl":"10.1002/psp4.70334","url":null,"abstract":"<p>Although timolol ophthalmic solutions or hospital-compounded formulations have been used off-label for the treatment of superficial infantile hemangioma (IH), no topical timolol formulation has been developed specifically for this indication. This study was the first to develop a population pharmacokinetic (popPK) model for topical timolol maleate gel and to perform exploratory exposure–safety analyses. Data from Phase I–III clinical trials in healthy adults and infants with proliferative superficial IH were used to develop the popPK model. Potential covariate effects on the pharmacokinetics were investigated, and exploratory relationships between timolol exposure and safety outcomes were assessed. A total of 810 plasma concentration measurements from 138 subjects (24 healthy adults and 114 infants) were included in the popPK analysis. Timolol pharmacokinetics were well described by a one-compartment model with first-order absorption and elimination. No significant covariates influencing clearance were identified. No apparent associations were identified between timolol exposure and the evaluated safety outcomes. Overall, systemic exposure following administration of this topical timolol maleate gel formulation was limited, supporting its favorable safety profile in infants with superficial IH. These quantitative findings may help guide its rational clinical use.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":"15 10","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13591220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149012119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Quantitative Systems Pharmacology Model of Human Leucine Metabolism","authors":"J. Cody Herron,&nbsp;Anna Sher,&nbsp;Yingbo Ma,&nbsp;Elisabeth Roesch,&nbsp;Sebastian Miculța-Câmpeanu,&nbsp;Christopher Rackauckas,&nbsp;Kevin J. Filipski,&nbsp;Rachel Roth Flach,&nbsp;Theodore R. Rieger,&nbsp;Cynthia J. Musante,&nbsp;Richard Allen","doi":"10.1002/psp4.70328","DOIUrl":"https://doi.org/10.1002/psp4.70328","url":null,"abstract":"<p>Branched-chain amino acids (BCAAs) are essential dietary components that humans cannot synthesize. Altered BCAA levels have been associated with biomarkers or potential risk factors in several metabolic disorders, including insulin resistance, type 2 diabetes, obesity, and cardiovascular disease. However, the underlying mechanisms regulating BCAA metabolism and how cellular or signaling modifications may alter BCAA levels are yet to be fully elucidated. To investigate the fate of plasma and intracellular leucine, we developed a mathematical model of human leucine metabolism. Through a virtual population approach, the model was constructed based on known biology and data and calibrated to fit available acute leucine and α-ketoisocaproic acid (KIC) clinical challenge data in healthy subjects. The rate-limiting step of BCAA catabolism is oxidative decarboxylation by branched-chain α-ketoacid dehydrogenase (BCKDH), a process that is negatively regulated by phosphorylation by branched-chain α-ketoacid dehydrogenase kinase (BDK). Recent preclinical studies have reported that inhibition of BDK leads to significant lowering of plasma BCAA levels. Modeling predicts that the magnitude of reduction observed in plasma BCAA and BCKA levels upon BDK inhibition may require incorporation of an additional regulatory mechanism, such as feedback on leucine and KIC uptake into tissues. This leucine systems model has implications for drug discovery and development, enables a mechanistic understanding of clinical data, and could be used as a tool for the design and analysis of therapeutic modifications of leucine and KIC metabolism.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":"15 10","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/psp4.70328","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148981479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating CRRT as a Virtual Organ Into Physiologically Based Pharmacokinetic Modeling to Optimize Antimicrobial Dosing in Septic Patients","authors":"Yuanming Xing,&nbsp;Yijing Zhang,&nbsp;Chuqi Bai,&nbsp;Yulan Qiu,&nbsp;Chuhui Wang,&nbsp;Lei Chen,&nbsp;Taotao Wang,&nbsp;Jiaojiao Chen","doi":"10.1002/psp4.70338","DOIUrl":"https://doi.org/10.1002/psp4.70338","url":null,"abstract":"<p>Continuous renal replacement therapy (CRRT) extracorporeal drug removal, sepsis-related pathophysiological alterations, and reduced pathogen susceptibility to antimicrobials can lead to treatment failure in septic patients undergoing CRRT, highlighting the urgent need for precision dosing. This study aimed to develop a physiologically based pharmacokinetic (PBPK) modeling framework to characterize antimicrobial pharmacokinetics and support dosing optimization in septic patients undergoing CRRT. Drug-specific PBPK models were established in healthy adults and extrapolated to septic patients by scaling four pathophysiological parameters in PK-Sim. A CRRT compartment was subsequently incorporated in MoBi as a clearance organ and parameterized by modality and intensity to construct a PBPK framework for septic patients undergoing CRRT. Vancomycin, meropenem, and ceftazidime-avibactam were selected as representative antimicrobial agents for model development and validated by graphical comparison with reported data, fold error, and geometric mean fold error (GMFE). The final PBPK model adequately captured the observed data, with predicted area under concentration-time curve and maximum concentration within 0.5–2.0-fold of observed values and GMFE &lt; 2 for all three antimicrobial agents. The validated model simulated pharmacokinetic profiles of 1000 virtual patients across glomerular filtration rate (GFR) values of 0–30 mL/min, five CRRT modalities, and CRRT intensities of 20–40 mL/kg/h, allowing quantification of their relative impact on drug exposure and guiding dosing optimization. The results showed that both GFR and CRRT intensity influenced drug exposure, with GFR showing a greater contribution. Overall, this study provides a quantitative method for predicting antimicrobial exposure and supports model-informed precision dosing in septic patients undergoing CRRT.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":"15 9","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/psp4.70338","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148942961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Semi-Mechanistic Joint Population Pharmacokinetic Modeling of the Novel Antituberculosis Drug Sorfequiline and Its Metabolite M3 in Healthy Volunteers","authors":"Jose M. Calderin,&nbsp;Jerry Nedelman,&nbsp;David H. Salinger,&nbsp;Thanakorn Vongjarudech,&nbsp;Paolo Denti,&nbsp;Elin M. Svensson","doi":"10.1002/psp4.70331","DOIUrl":"10.1002/psp4.70331","url":null,"abstract":"<p>Sorfequiline is a novel diarylquinoline in development for treatment of tuberculosis. In vitro data suggest metabolism via CYP3A4, carrying the potential for presystemic metabolism and drug–drug interactions. Its major metabolite, M3, is pharmacologically active. We developed a semi-mechanistic joint population pharmacokinetic model of sorfequiline and M3 in healthy volunteers. Data were pooled from two studies (CL-001 and CL-002). CL-001 comprised a single-ascending-dose part (10–800 mg suspension fasted plus 100 mg fed), a multiple-ascending-dose part (25, 75, or 200 mg/day for 14 days, fed), and a relative bioavailability assessment including 100 mg in tablet form under fed and fasted conditions. In CL-002, fed participants received 200 mg/day suspension for 8 days followed by 165 mg/day for 4 days. Plasma concentrations were quantified using HPLC–MS/MS, and pharmacokinetic modeling and simulations were conducted in NONMEM. A three-compartment disposition model for both analytes, with transit-compartment absorption, adequately described the data. A fraction of the dose was assumed to be absorbed as M3 due to gut first-pass metabolism. This fraction was 46% (95% CI: 41%–50%) in fasted and 15% (13%–19%) in fed participants. Overall bioavailability decreased by 46% (32%–61%) at fasted doses ≥ 400 mg. Model-based simulations showed that exposures for all investigated regimens remained below safety reference values. Food reduced the fraction of sorfequiline dose absorbed as M3, likely due to limited gut first-pass metabolism. The developed model provides an initial platform for future pharmacokinetic/pharmacodynamic analyses and simulation of both analytes' exposures under drug–drug interaction scenarios.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":"15 9","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/psp4.70331","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148929198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of Integrated Parent–Metabolite Pharmacokinetic Model With Apparent Presystemic Metabolism to Characterize the Disposition of Alverine","authors":"Ara Cho,&nbsp;Hyeon-Cheol Jeong,&nbsp;MinJu Kim,&nbsp;Inkyung Cho,&nbsp;Hyeon-Jeong Na,&nbsp;Kyong-Cheol Ko,&nbsp;Yoon-Jee Chae,&nbsp;Kyeong-Ryoon Lee","doi":"10.1002/psp4.70342","DOIUrl":"https://doi.org/10.1002/psp4.70342","url":null,"abstract":"<p>Alverine is an antispasmodic agent characterized by extensive metabolism, and systemic exposure is largely driven by its metabolites. However, conventional parent–metabolite pharmacokinetic models typically assume metabolite formation solely from the systemic parent compound, which may not adequately capture route-dependent differences in metabolite exposure. This study aimed to develop an integrated parent–metabolite pharmacokinetic model to simultaneously describe alverine and its three major metabolites (M1, M2, and M3) in mice following intravenous (IV) and per-oral (PO) administration. Plasma concentration–time data were analyzed using a stepwise nonlinear mixed-effects model. Alternative structural models were evaluated to account for route-dependent metabolite appearance. Distinct route-dependent differences were observed in alverine metabolite exposure, with substantially higher levels following PO administration, particularly for M2, despite limited parent exposure. A model without presystemic metabolism, which assumed parent-derived formation alone, failed to adequately describe these data, leading to an overprediction of early parent concentrations. The final model incorporated presystemic metabolism for M1 and M3, significantly improving model fit (ΔOFV = −138.10) and providing an adequate description of both parent and metabolite profiles across routes. These findings suggest that systemic metabolite exposure following oral dosing is strongly influenced by presystemic processes that cannot be captured by parent-driven formation alone. The proposed model provides a parsimonious structural framework to account for these effects without requiring detailed mechanistic information. This approach may be broadly applicable to compounds exhibiting metabolite-dominant exposure and highlights the importance of flexible structural models in pharmacometric analyses of route-dependent pharmacokinetics.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":"15 9","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/psp4.70342","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148943078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 Brensocatib in Adult and Adolescent Patients With Non-Cystic Fibrosis Bronchiectasis","authors":"Helen Usansky,&nbsp;Anthony Cammarata,&nbsp;ChongHua Li,&nbsp;Sam Au Yeung,&nbsp;Christopher M. Rubino,&nbsp;Lin Wang,&nbsp;Ariel Teper,&nbsp;Carlos Fernandez,&nbsp;Kevin Mange","doi":"10.1002/psp4.70340","DOIUrl":"10.1002/psp4.70340","url":null,"abstract":"<p>Brensocatib, a competitive and reversible oral DPP1 inhibitor, at 10 and 25 mg significantly reduced pulmonary exacerbation burden, and 25 mg also reduced lung function decline vs. placebo in patients with non-cystic fibrosis bronchiectasis, hereafter bronchiectasis, in ASPEN (NCT04594369). A population pharmacokinetic (PPK) model was developed to support brensocatib dose selection for adults and adolescents. Data from 11 clinical trials were pooled for analysis. The covariate model was developed via a stepwise approach. Clinical relevance of statistically significant covariates was assessed by simulated brensocatib exposure at steady state in various subgroups with different characteristics relative to a reference subject (healthy White male, 49 years, 70 kg, fasted, no concomitant medications). Covariate effects on brensocatib PK were evaluated. From 291 healthy participants and 807 patients, 11,643 brensocatib plasma concentrations were used for PPK model construction. Body weight was integrated using standard allometric scaling coefficients of 0.75 on total and intercompartment clearance (CL/F and Q/F) and 1.0 on central and peripheral volume of distribution (Vc/F and Vp/F). Statistically significant covariates included hepatic impairment, sex, race, and co-medication use (strong CYP3A and Pgp modulators) on CL/F; age on Vc/F; food effect on Ka; and co-medications (strong CYP3A and Pgp inhibitors) on relative bioavailability. Disease populations, renal impairment, and tablet formulations were not statistically significant covariates. The PPK model provided a robust fit to observed brensocatib concentration time profiles in bronchiectasis patients. No identified covariates were clinically relevant. This analysis supported brensocatib dosage of 10 and 25 mg in patients with bronchiectasis ≥ 12 years without dose adjustment.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":"15 9","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/psp4.70340","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148911054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}