CPT: Pharmacometrics & Systems Pharmacology最新文献_第2页

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":"https://doi.org/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":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"https://doi.org/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":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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

PBPK-Led Assessment of Antimalarial Drug Concentrations in Breastmilk: A Strategy for Optimal Use of Prediction Methods to Guide Decision Making in an Understudied Population.

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-02-11 DOI: 10.1002/psp4.13311

Lisa M Almond, Khaled Abduljalil, Amita Pansari, Beata Kusmider, Hannah M Jones, Karen Rowland Yeo, Iain Gardner, Muhammad Faisal, Anne Claire Marrast, Myriam El Gaaloul, Jörg J Möhrle, Nada Abla

{"title":"PBPK-Led Assessment of Antimalarial Drug Concentrations in Breastmilk: A Strategy for Optimal Use of Prediction Methods to Guide Decision Making in an Understudied Population.","authors":"Lisa M Almond, Khaled Abduljalil, Amita Pansari, Beata Kusmider, Hannah M Jones, Karen Rowland Yeo, Iain Gardner, Muhammad Faisal, Anne Claire Marrast, Myriam El Gaaloul, Jörg J Möhrle, Nada Abla","doi":"10.1002/psp4.13311","DOIUrl":"https://doi.org/10.1002/psp4.13311","url":null,"abstract":"Treatment of breastfeeding mothers with malaria is challenging due to the lack of information describing drug exposure in milk and the daily dose to the breastfed infant. Physiologically based pharmacokinetic (PBPK) modeling was used to predict milk-to-plasma (M/P) ratios, infant daily doses (IDD) and relative infant doses (RID) for five antimalarials with clinical lactation data (chloroquine, pyrimethamine, piperaquine, mefloquine and primaquine). In all cases, RID was correctly categorized as above or below the WHO proposed cut-off of 10% using two prediction models. Predicted M/P ratios were within 2-fold of observations for 63% of studies using both models (75% and 100% were within 3-fold for Models 1 and 2, respectively). M/P ratios, IDD and RID were predicted prospectively for seven antimalarials. RID was < 10% for amodiaquine, dihydroartemisinin, proguanil, and pyronaridine, and > 10% for lumefantrine and tafenoquine. For atovaquone, RID was > 10% with Model 1 but not Model 2. Predicted IDD were considerably lower than licensed doses for infants except for lumefantrine (Model 2) and tafenoquine (not licensed in < 2 years). Predictions were sensitive to drug properties (plasma protein binding and lipophilicity) and milk properties (creamatocrit and pH). This analysis demonstrates the utility of PBPK to predict milk exposure in the absence of clinical lactation information. These prediction methodologies can be used, alongside any licensed dosing information for < 1 year-olds, to evaluate whether a clinical lactation study is necessary and to inform drug label or policy recommendations. The ultimate goal is to better inform optimal treatment for lactating women supporting malaria eradication.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390307","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

Comparing Scientific Machine Learning With Population Pharmacokinetic and Classical Machine Learning Approaches for Prediction of Drug Concentrations.

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-02-07 DOI: 10.1002/psp4.13313

Diego Valderrama, Olga Teplytska, Luca Marie Koltermann, Elena Trunz, Eduard Schmulenson, Achim Fritsch, Ulrich Jaehde, Holger Fröhlich

{"title":"Comparing Scientific Machine Learning With Population Pharmacokinetic and Classical Machine Learning Approaches for Prediction of Drug Concentrations.","authors":"Diego Valderrama, Olga Teplytska, Luca Marie Koltermann, Elena Trunz, Eduard Schmulenson, Achim Fritsch, Ulrich Jaehde, Holger Fröhlich","doi":"10.1002/psp4.13313","DOIUrl":"https://doi.org/10.1002/psp4.13313","url":null,"abstract":"A variety of classical machine learning (ML) approaches has been developed over the past decade aiming to individualize drug dosages based on measured plasma concentrations. However, the interpretability of these models is challenging as they do not incorporate information on pharmacokinetic (PK) drug disposition. In this work we compare drug plasma concentraton predictions of well-known population PK (PopPK) modeling with classical machine learning models and a newly proposed scientific machine learning (MMPK-SciML) framework. MMPK-SciML allows to estimate PopPK parameters and their inter-individual variability (IIV) using multimodal covariate data of each patient and does not require assumptions about the underlying covariate relationships. A dataset of 541 fluorouracil (5FU) plasma concentrations as example for an intravenously administered drug and a dataset of 302 sunitinib and its active metabolite concentrations each as example for an orally administered drug were used for analysis. Whereas classical ML models were not able to describe the data sufficiently, MMPK-SciML allowed us to obtain accurate drug plasma concentration predictions for test patients. In case of 5FU, goodness-of-fit shows that the MMPK-SciML approach predicts drug plasma concentrations more accurately than PopPK models. For sunitinib, we observed slightly less accurate drug concentration predictions compared to PopPK. Overall, MMPK-SciML has shown promising results and should therefore be further investigated as a valuable alternative to classical PopPK modeling, provided there is sufficient training data.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373536","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

Elucidating Contributions of Drug Transporters/Enzyme to Nonlinear Pharmacokinetics of Grazoprevir by PBPK Modeling With a Cluster Gauss-Newton Method.

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-02-07 DOI: 10.1002/psp4.13314

Takashi Yoshikado, Yasunori Aoki, Ryo Nakamura, Saeko Shida, Yuichi Sugiyama, Koji Chiba

{"title":"Elucidating Contributions of Drug Transporters/Enzyme to Nonlinear Pharmacokinetics of Grazoprevir by PBPK Modeling With a Cluster Gauss-Newton Method.","authors":"Takashi Yoshikado, Yasunori Aoki, Ryo Nakamura, Saeko Shida, Yuichi Sugiyama, Koji Chiba","doi":"10.1002/psp4.13314","DOIUrl":"https://doi.org/10.1002/psp4.13314","url":null,"abstract":"Grazoprevir (GZR), a direct-acting agent for hepatitis C virus, is recognized as a substrate for organic anion transporting polypeptide 1B (OATP1B), cytochrome P450 3A (CYP3A), and P-glycoprotein (P-gp). The objective of the present study was to elucidate the contribution of these molecules to the nonlinear pharmacokinetics of GZR using a physiologically based pharmacokinetic (PBPK) model. Utilizing plasma concentration-time profiles of GZR derived from reported dose-escalation (50-800 mg) clinical studies and cumulative excretion data, around 10 parameters, including Michaelis constants (Km) for OATP1B, CYP3A, and P-gp, were estimated via a cluster Gauss-Newton method (CGNM). Parameter combinations that could reproduce the clinical data of GZR were obtained; however, discrepancies were noted between the in vivo estimated Km and the corresponding in vitro Km. Next, by incorporating the in vitro Km values into our PBPK-CGNM analyses utilizing a penalized parameter method, newly obtained parameter combinations appropriately reflected both the in vivo and in vitro observations. Particularly regarding OATP1B, while saturation of uptake was not clearly observed in the in vitro experiments without human serum albumin (HSA), Km values capable of explaining in vivo saturation were obtained under physiological HSA concentrations. By estimating the extent of saturation for each molecule in the liver and intestine and conducting sensitivity analyses of the Km values, it was inferred that OATP1B3 contributed the most to the nonlinearity of plasma GZR concentrations, followed by P-gp. In conclusion, the PBPK-CGNM, supplemented by penalized in vitro parameters, was shown to be effective for analyzing complex pharmacokinetics involving drug transporters and enzymes.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370692","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

Population Pharmacokinetics and Exposure-Response of Subcutaneous Atezolizumab in Patients With Non-Small Cell Lung Cancer.

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-02-05 DOI: 10.1002/psp4.13310

Phyllis Chan, Stephanie N Liu, Nathalie Gosselin, Zacharie Sauve, Mathilde Marchand, Alyse Lin, Luis Herraez-Baranda, James Zanghi, Esther Shearer-Kang, Xiaoyan Liu, Benjamin Wu, Pascal Chanu

{"title":"Population Pharmacokinetics and Exposure-Response of Subcutaneous Atezolizumab in Patients With Non-Small Cell Lung Cancer.","authors":"Phyllis Chan, Stephanie N Liu, Nathalie Gosselin, Zacharie Sauve, Mathilde Marchand, Alyse Lin, Luis Herraez-Baranda, James Zanghi, Esther Shearer-Kang, Xiaoyan Liu, Benjamin Wu, Pascal Chanu","doi":"10.1002/psp4.13310","DOIUrl":"https://doi.org/10.1002/psp4.13310","url":null,"abstract":"IMscin001 is a two-part dose-finding (Phase Ib) and -confirmation (Phase III) study to evaluate atezolizumab pharmacokinetics of subcutaneous (SC) compared with intravenous (IV) administration in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). The objectives of the current analyses were to characterize the population pharmacokinetics (popPK) of atezolizumab and to determine the relationship between atezolizumab exposure and safety and efficacy endpoints in IMscin001. A previously validated IV popPK model was extended to add SC absorption parameters using SC and IV data from Phase Ib and Phase III of IMscin001 (N = 435), and covariate effects were investigated on the SC absorption parameters. The exposure-response (ER) investigation was performed using SC data following 1875 mg every three weeks (q3w) administration in the Phase III portion of IMscin001 (N = 246). The clinical endpoints were objective response rate, progression-free survival, or overall survival for efficacy, serious adverse events, special interest adverse events, Grades 3-5 adverse events, infusion-related reaction, or injection site reactions for safety. Atezolizumab SC absorption was characterized by a first-order absorption with a bioavailability of 71.8% and an absorption rate constant of 0.304 day-1. The extended popPK model was adequate to predict atezolizumab PK after IV and SC administrations and to predict individual exposure metrics. For all efficacy and safety endpoints, atezolizumab exposure was not statistically significant (p-value > 0.05) in the ER models. The non-inferior popPK exposure and flat ER results supported atezolizumab SC dose at 1875 mg q3w.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188531","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