CPT: Pharmacometrics & Systems Pharmacology最新文献_第3页

Toward Precision Dosing of Lamotrigine During Pregnancy: Physiologically Based Pharmacokinetic Modeling and Simulation.

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-02-24 DOI: 10.1002/psp4.70007

Yudie Qian, Wanhong Wu, Chengjie Ke, Siting Liu, Jiarui Chen, Yuying Chen, Xianzhong Guo, Weiwei Lin

{"title":"Toward Precision Dosing of Lamotrigine During Pregnancy: Physiologically Based Pharmacokinetic Modeling and Simulation.","authors":"Yudie Qian, Wanhong Wu, Chengjie Ke, Siting Liu, Jiarui Chen, Yuying Chen, Xianzhong Guo, Weiwei Lin","doi":"10.1002/psp4.70007","DOIUrl":"https://doi.org/10.1002/psp4.70007","url":null,"abstract":"Lamotrigine is a commonly used anti-seizure medication in pregnant women. However, its pharmacokinetics (PK) during pregnancy markedly change, increasing the frequency of seizures and endangering the safety of the mother and fetus. Meanwhile, insufficient PK data on lamotrigine during pregnancy hinders its dose adjustment. This study aimed to predict the maternal and fetal PK of lamotrigine and provide recommendations for dose adjustment. A physiologically based pharmacokinetic (PBPK) model of lamotrigine was constructed using PK-Sim and MoBi and validated with clinical data. The area under the steady-state concentration-time curve (AUC) for lamotrigine decreased by 66.5%, 71.1%, and 81.2% during early, mid, and late pregnancy, respectively, compared with non-pregnant conditions. To achieve effective exposure, three, three, and five times the baseline dose were recommended during early, mid, and late pregnancy, respectively. The fetal PK was best predicted using the isolated cotyledon perfusion method compared to the Caco-2 cell permeability and MoBi default methods. Based on the fetal risk concentration (4.87 mg/L), during early, mid, and late pregnancy, the maximum recommended once-daily dosage should not exceed 400, 500, and 700 mg, respectively, and the twice-daily dosage should not exceed 300, 400, and 600 mg, respectively. The significant decrease in lamotrigine exposure may increase the frequency of seizures in pregnant women. Therefore, prompt dose adjustment is recommended to control seizures while ensuring fetal safety.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pyridoxic Acid as Endogenous Biomarker of Renal Organic Anion Transporter Activity: Population Variability and Mechanistic Modeling to Predict Drug-Drug Interactions.

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-02-24 DOI: 10.1002/psp4.70005

Aarzoo Thakur, Sumathy Mathialagan, Emi Kimoto, Manthena V S Varma

{"title":"Pyridoxic Acid as Endogenous Biomarker of Renal Organic Anion Transporter Activity: Population Variability and Mechanistic Modeling to Predict Drug-Drug Interactions.","authors":"Aarzoo Thakur, Sumathy Mathialagan, Emi Kimoto, Manthena V S Varma","doi":"10.1002/psp4.70005","DOIUrl":"https://doi.org/10.1002/psp4.70005","url":null,"abstract":"Pyridoxic acid (PDA) was suggested as a potential endogenous biomarker to assess in vivo renal organic anion transporter (OAT) 1 and 3 activity. Here, we first investigated the population variability in the plasma baseline levels of PDA using data from five independent studies (conducted/supported by Pfizer), and subsequently developed mechanistic physiologically based pharmacokinetic (PBPK) model to assess its effectiveness in biomarker-informed drug-drug interaction (DDI) predictions. Meta-analysis suggested that the inter-individual variability in PDA plasma concentration was ~40% across all five studies (n = 71 subjects). While sex-dependent differences were not evident, the baseline plasma PDA levels were significantly higher (38%, p < 0.05) in White males compared to Japanese males. Correspondingly, the amount of PDA excreted in urine and renal clearance were significantly higher (p < 0.05) in Japanese males (1.5- and 2.2-fold, respectively), compared to White males. A PBPK model considering relative activity factor-based scaling of in vitro transport data indicated > 80% contribution by OAT3 to the renal clearance of PDA. The baseline plasma concentrations across multiple studies were recovered by the model; and using in vitro inhibition potency data, the model predicted effect of OAT inhibitors (probenecid, ritlecitinib and tafamidis) on PDA pharmacokinetics. Furthermore, DDIs with OAT3 object drug, furosemide, were well-predicted by the biomarker-informed PBPK model. PDA data and the modeling approach indicated lack of clinically-relevant OAT inhibition with ritlecitinib and tafamidis. Overall, this study presents PDA as a reliable biomarker to assess OAT3-mediated renal DDIs with moderate inter-subject and inter-study variability.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143491154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Disease–Drug–Drug Interaction of Imatinib in COVID-19 ARDS: A Pooled Population Pharmacokinetic Analysis

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-02-22 DOI: 10.1002/psp4.13299

Medhat M. Said, Job R. Schippers, Leila Atmowihardjo, Yingxue Li, Mick S. van der Plas, Harm J. Bogaard, Lieuwe D. J. Bos, Ron A. A. Mathôt, Jurjan Aman, Eleonora L. Swart, Imke H. Bartelink

{"title":"Disease–Drug–Drug Interaction of Imatinib in COVID-19 ARDS: A Pooled Population Pharmacokinetic Analysis","authors":"Medhat M. Said, Job R. Schippers, Leila Atmowihardjo, Yingxue Li, Mick S. van der Plas, Harm J. Bogaard, Lieuwe D. J. Bos, Ron A. A. Mathôt, Jurjan Aman, Eleonora L. Swart, Imke H. Bartelink","doi":"10.1002/psp4.13299","DOIUrl":"10.1002/psp4.13299","url":null,"abstract":"Prior pharmacokinetic (PK) analysis revealed that increased alpha-1-acid glycoprotein (AAG) levels are associated with decreased imatinib unbound fraction in coronavirus disease 2019 (COVID-19) patients. This study aimed to investigate the PK of total and unbound concentrations of imatinib and the metabolite N-desmethyl imatinib in hospitalized patients with different severities of COVID-19, and to assess the impact of critical illness and the potential drug–drug interaction with IL-6R inhibitors on imatinib exposure. Imatinib, N-desmethyl imatinib, and AAG were quantified from collected plasma samples. The PK data was further combined with previous data from COVID-19 patients and chronic myelogenous leukemia/gastrointestinal stromal tumor (CML/GIST) patients who received imatinib. A population PK analysis was conducted using a standard sequential approach. Unbound fraction in COVID-19 patients admitted to the intensive care unit (ICU) and treated with IL-6R inhibitors was significantly elevated compared to CML/GIST patients (4.66% vs. 3.54% [1.08%–8.51%]; p < 0.001), despite twofold increased AAG levels. Our findings on total and unbound concentration show that cotreatment with IL-6R inhibitor can lead to changes in metabolism and protein binding, suggesting similar implications for other highly protein bound drugs. Consequently, total concentrations may not accurately reflect unbound target site concentrations.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":"14 3","pages":"583-595"},"PeriodicalIF":3.1,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/psp4.13299","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476298","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}

引用次数: 0

Development of a Joint Tumor Size-Overall Survival Modeling and Simulation Framework Supporting Oncology Development Decision-Making.

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-02-21 DOI: 10.1002/psp4.70002

Herbert Struemper, Chetan Rathi, Morris Muliaditan, Sebastiaan C Goulooze, Richard C Franzese, Alejandro Mantero, Murad Melhem, Teun M Post, Sandra A G Visser

{"title":"Development of a Joint Tumor Size-Overall Survival Modeling and Simulation Framework Supporting Oncology Development Decision-Making.","authors":"Herbert Struemper, Chetan Rathi, Morris Muliaditan, Sebastiaan C Goulooze, Richard C Franzese, Alejandro Mantero, Murad Melhem, Teun M Post, Sandra A G Visser","doi":"10.1002/psp4.70002","DOIUrl":"https://doi.org/10.1002/psp4.70002","url":null,"abstract":"Tumor size-overall survival (TS-OS) models can support decision-making in oncology drug development by predicting long-term OS based on TS data from early data cuts and baseline patient factors. The current work describes the development of a TS-OS framework capable of predicting OS across a variety of treatment modalities and mechanisms of action in patients with non-small cell lung cancer from seven clinical studies. The presented framework jointly models TS with a bi-exponential Stein model and OS with an accelerated failure time log-normal survival model. In the corresponding link function between TS and OS, the most significant predictor of OS was the tumor growth rate (kg), applied via an Emax function. Time to tumor growth and baseline TS were additional TS predictors informing OS. Albumin, total protein, and neutrophil-to-lymphocyte ratio were selected from the tested baseline factors as the most significant predictors of OS. Significant baseline covariates for the TS model included number of target lesions on baseline TS, tumor PD-L1 expression on tumor shrinkage rate, and lactate dehydrogenase levels on kg. The TS-OS framework model adequately describes the OS distributions within this specific set of treatment modalities-chemotherapies, immuno-oncology treatments, and combinations thereof-using a single treatment-independent link function, supporting the use of the framework to support evaluation and design of future studies. Our findings contribute to a body of literature exploring and qualifying TS-OS modeling as a methodology capable of supporting and accelerating oncology drug development.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Tutorial on Conditional Simulations With a Tumor Size-Overall Survival Model to Support Oncology Drug Development. 利用肿瘤大小-总体生存模型进行条件模拟以支持肿瘤药物开发教程。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-02-21 DOI: 10.1002/psp4.70003

Sebastiaan C Goulooze, Morris Muliaditan, Richard C Franzese, Alejandro Mantero, Sandra A G Visser, Murad Melhem, Teun M Post, Chetan Rathi, Herbert Struemper

{"title":"Tutorial on Conditional Simulations With a Tumor Size-Overall Survival Model to Support Oncology Drug Development.","authors":"Sebastiaan C Goulooze, Morris Muliaditan, Richard C Franzese, Alejandro Mantero, Sandra A G Visser, Murad Melhem, Teun M Post, Chetan Rathi, Herbert Struemper","doi":"10.1002/psp4.70003","DOIUrl":"https://doi.org/10.1002/psp4.70003","url":null,"abstract":"The gold standard for regulatory approval in oncology is overall survival (OS). Because OS data are initially limited, early drug development decisions are often based on early efficacy endpoints, such as objective response rate and progression-free survival. Tumor size (TS)-OS models provide a framework to support decision-making on potential late-stage success based on early readouts, through leveraging TS data with limited follow-up and treatment-agnostic TS-OS link functions, to predict longer-term OS. Conditional simulations (also known as Bayesian forecasting) with TS-OS models can be used to simulate long-term OS outcomes for an ongoing study, conditional on the available TS and OS data at interim data cuts of the same study. This tutorial provides a comprehensive overview of the steps involved in using such conditional simulations to support better informed drug development decisions in oncology. The tutorial covers the selection of the TS-OS framework model; applying the TS-OS model to the interim data; performing conditional simulations; generating relevant output; as well as correct interpretation and communication of the output for decision making.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PBPK Modeling: Empowering Drug Development and Precision Dosing in China.

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-02-18 DOI: 10.1002/psp4.70004

Dongsheng Yang, Jian Li, Wen Yao Mak, Aole Zheng, Xiao Zhu, Qingfeng He, Yuzhu Wang, Xiaoqiang Xiang

{"title":"PBPK Modeling: Empowering Drug Development and Precision Dosing in China.","authors":"Dongsheng Yang, Jian Li, Wen Yao Mak, Aole Zheng, Xiao Zhu, Qingfeng He, Yuzhu Wang, Xiaoqiang Xiang","doi":"10.1002/psp4.70004","DOIUrl":"https://doi.org/10.1002/psp4.70004","url":null,"abstract":"Physiologically based pharmacokinetic (PBPK) modeling, a cornerstone of model-informed drug development and model-informed precision dosing, simulates drug disposition in the human body by integrating physiological, biochemical, and physicochemical parameters. While PBPK modeling has advanced globally since the 1970s, China's adoption of this technology has followed a distinctive path, characterized by accelerated growth over the past 2 decades. This review provides a comprehensive analysis of China's contributions to PBPK modeling, addressing knowledge gaps in publication trends, application domains, and platform preferences. A systematic literature search yielded 266 original PBPK research articles from PubMed up to August 08, 2024. The analysis revealed that drug disposition and drug-drug interaction studies constitute the largest proportion of PBPK analyses in China. Chinese universities and hospitals emerge as the leading contributors to PBPK research among institutions in China. Although established commercial PBPK platform such as GastroPlus and Simcyp remain popular within the Chinese pharmaceutical industry, open-source platforms like PK-Sim are gaining significant traction in PBPK applications across China. This review underscores the transformative potential of PBPK modeling in drug development within China, offering valuable insights into future directions and challenges in the field.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Enhanced Sensitivity to Tramadol in Diabetic Neuropathic Pain Compared to Nerve Compression Neuropathies: A Population PK/PD Model Analysis.

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-02-17 DOI: 10.1002/psp4.13315

Dain Chun, Parsshava Mehta, Serge Guzy, Brian Cicali, Gabriela R Lauretti, Vera L Lanchote, Valvanera Vozmediano, Natalia De Moraes

{"title":"Enhanced Sensitivity to Tramadol in Diabetic Neuropathic Pain Compared to Nerve Compression Neuropathies: A Population PK/PD Model Analysis.","authors":"Dain Chun, Parsshava Mehta, Serge Guzy, Brian Cicali, Gabriela R Lauretti, Vera L Lanchote, Valvanera Vozmediano, Natalia De Moraes","doi":"10.1002/psp4.13315","DOIUrl":"https://doi.org/10.1002/psp4.13315","url":null,"abstract":"Neuropathic pain, often associated with diabetic neuropathy or nerve compression injuries, arises from damage or dysfunction in the somatosensory nervous system. Tramadol, frequently prescribed for this pain, has its fraction unbound and that of its active metabolite (M1) significantly altered by diabetes. Yet, dosing adjustments for diabetic neuropathic pain remain underexplored. This study developed a comprehensive population pharmacokinetics/pharmacodynamics (PK/PD) model for tramadol and its major metabolites, focusing on diabetes's impact on PK and PK-PD relationship to identify optimal dosing regimens. Data from patients with chronic neuropathic pain on oral tramadol were used to develop enantiomer-specific population models, considering both total and unbound concentrations. Tramadol's PK was best described by a two-compartment model with Weibull absorption and linear elimination and a one-compartment model with enterohepatic circulation and first-pass metabolism for the active M1. Simulations showed higher unbound fractions of the active M1 in patients with type 1 and type 2 diabetes. Despite a 67% and 14% reduction in the AUC of total (1R,2R)-M1 in patients with type 1 and type 2 diabetes, respectively, the AUC of unbound (1R,2R)-M1 remained consistent. The unbound concentration of the active M1 required to achieve 50% of the maximum pain reduction (IC50) was lower in patients with diabetes, indicating increased sensitivity to the drug. This model-based approach provides valuable dosing guidance, suggesting once-daily dosing treatments in patients with diabetes and twice-daily dosing for patients with neuropathic pain secondary to nerve compression mechanisms.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Intranasal diamorphine population pharmacokinetics modeling and simulation in pediatric breakthrough pain

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-02-13 DOI: 10.1002/psp4.13186

Lianjin Cai, Jingchen Zhai, Beihong Ji, Fengyang Han, Taoyu Niu, Luxuan Wang, Junmei Wang

{"title":"Intranasal diamorphine population pharmacokinetics modeling and simulation in pediatric breakthrough pain","authors":"Lianjin Cai, Jingchen Zhai, Beihong Ji, Fengyang Han, Taoyu Niu, Luxuan Wang, Junmei Wang","doi":"10.1002/psp4.13186","DOIUrl":"10.1002/psp4.13186","url":null,"abstract":"Intranasal diamorphine (IND), approved for managing breakthrough pain in the UK, has been identified as an acceptable alternative offering effective, expedient, and less traumatic analgesia for children. However, the current dose regimen in pediatric populations relies on clinical expertise while the pharmacokinetics properties are poorly understood. This study aimed to develop diamorphine population pharmacokinetics (pop-PK) models and simulate the IND dosing in virtual pediatric subjects. An integrated four-compartment pop-PK model with first-order absorption and elimination provided an appropriate fit and characterized publicly available 385 concentration measurements of diamorphine, 6-monoacetylmorphine, and morphine collected from adults. Body weight allometry and renal function maturation (age) were incorporated into the final model, serving as two covariates. The estimated IND relative bioavailability was around 52% compared with intramuscularly injected diamorphine. Using this final model, the morphine plasma concentrations, as the active metabolite for pain relief, were simulated in virtual subjects. The utility of model extrapolation was supported by external verification with acceptable average fold errors of 1.06 ± 0.30 and 0.83 ± 0.07 for morphine maximum concentration and exposures. Meanwhile, the simulated morphine concentration–time profiles could recover the PK profiles observed in children after a single dose of IND. The model-based dosing simulations were therefore assessed in four children age groups to match the therapeutic window of morphine concentrations in steady state (10–20 μg/L). Our study demonstrates that the dose regimen of 0.3 mg/kg loading dose plus 0.1 mg/kg hourly maintenance dose is generally appropriate for multiple pediatric populations with breakthrough pain, in the view of PK.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":"14 3","pages":"435-447"},"PeriodicalIF":3.1,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/psp4.13186","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413726","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}

引用次数: 0

Analysis of C4 Concentrations to Predict Impact of Patient-Reported Diarrhea Associated With the Ileal Bile Acid Transporter Inhibitor Linerixibat

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-02-13 DOI: 10.1002/psp4.13300

Fernando Carreño, Rashmi Mehta, Andrea Ribeiro de Souza, Jon Collins, Brandon Swift

{"title":"Analysis of C4 Concentrations to Predict Impact of Patient-Reported Diarrhea Associated With the Ileal Bile Acid Transporter Inhibitor Linerixibat","authors":"Fernando Carreño, Rashmi Mehta, Andrea Ribeiro de Souza, Jon Collins, Brandon Swift","doi":"10.1002/psp4.13300","DOIUrl":"10.1002/psp4.13300","url":null,"abstract":"Linerixibat, an ileal bile acid transporter (IBAT) inhibitor, is being evaluated for the treatment of pruritus in primary biliary cholangitis (PBC). Diarrhea is commonly reported with this drug class as IBAT inhibition redirects bile acids (BA) to the colon. Serum 7-alpha-hydroxy-4-cholesten-3-one (C4) measurement is a validated method to identify BA diarrhea. To inform dose selection, we characterized the relationship between linerixibat dose, C4 levels, and patient-reported bother on the gastrointestinal symptom rating scale (GSRS) diarrhea question. A kinetic-pharmacodynamic model was developed using data from five Phase 1/2 trials, to describe the effect of linerixibat dose (1–180 mg) and regimen (once/twice daily) on C4 concentrations over time. GSRS data from patients with PBC and pruritus in the Phase 2b GLIMMER study (NCT02966834) were used to develop a proportional odds model to predict the probability of a score of 1–7 (no–very severe discomfort) to the question “Have you been bothered by diarrhea during the past week?” in relation to linerixibat dose. The two models were linked to describe the linerixibat dose-C4-diarrhea bother relationship. Models were validated using graphical and numerical assessment and visual predictive checks. Linerixibat caused dose-dependent increases in C4 until saturation (~180 mg total daily dose). Increased C4 concentrations trended with increased GSRS diarrhea scores. Simulations demonstrated increases in moderate-to-very severe (≥ 4) diarrhea scores with increasing linerixibat dose. Increases in patient-reported diarrhea scores were linerixibat dose-dependent. Selecting an optimal dose that maximizes linerixibat's ability to improve pruritus while minimizing patient-reported diarrhea bother is important to support treatment adherence.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":"14 3","pages":"596-605"},"PeriodicalIF":3.1,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/psp4.13300","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405974","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}

引用次数: 0

Quantitative Systems Pharmacology Model to Predict Target Occupancy by Bruton Tyrosine Kinase Inhibitors in Patients With B-Cell Malignancies.

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-02-12 DOI: 10.1002/psp4.13307

Oleg Demin, Ying Ou, Galina Kolesova, Dmitry Shchelokov, Alexander Stepanov, Veronika Musatova, Sri Sahasranaman, Yating Zhao, Xiangyu Liu, Zhiyu Tang, William D Hanley

{"title":"Quantitative Systems Pharmacology Model to Predict Target Occupancy by Bruton Tyrosine Kinase Inhibitors in Patients With B-Cell Malignancies.","authors":"Oleg Demin, Ying Ou, Galina Kolesova, Dmitry Shchelokov, Alexander Stepanov, Veronika Musatova, Sri Sahasranaman, Yating Zhao, Xiangyu Liu, Zhiyu Tang, William D Hanley","doi":"10.1002/psp4.13307","DOIUrl":"https://doi.org/10.1002/psp4.13307","url":null,"abstract":"The effectiveness of Bruton tyrosine kinase (BTK) inhibitors is influenced by the level of BTK occupancy in target tissues. In randomized phase 3 studies, progression-free survival (PFS) with zanubrutinib was superior to ibrutinib, whereas acalabrutinib was noninferior to ibrutinib in previously treated chronic lymphocytic leukemia. To establish a link between numerical differences in BTK occupancy and differentiated efficacy profiles among three covalent BTK inhibitors, quantitative systems pharmacology (QSP) modeling was employed. The model was developed to describe available clinical BTK occupancy data in patients with B-cell malignancies. Simulations of BTK occupancy were conducted for various clinical scenarios (e.g., dose interruption) and for bone marrow (BM), for which routine measurements are difficult. This model describes pharmacokinetics of BTK inhibitors; intracellular concentration of BTK inhibitors in peripheral blood mononuclear cells (PBMCs), BM, and lymph nodes (LNs); binding of BTK inhibitors with BTK; and BTK turnover rate. The model was validated using available clinical BTK occupancy data. Consistent with observed clinical data, the model predicted that zanubrutinib 160 mg twice daily resulted in higher median trough BTK occupancy in PBMCs, LNs, and BM compared with ibrutinib and acalabrutinib. Although the BTK occupancy differences at trough were relatively small between the BTK inhibitors, the differences were more pronounced after dose interruption. The current work underscores the importance of maintaining high BTK occupancy at steady-state trough and during treatment interruption to ensure maximal efficacy and provides an example of combining in vitro and clinical data to model receptor occupancy in tissues where measurements are challenging.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143406057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0