CPT: Pharmacometrics & Systems Pharmacology最新文献

{"title":"A Unified Whole Lung PBK Model for Inhalational Uptake of Gases and Aerosols in Men.","authors":"Norman Nowak, Sylvia E Escher, Katharina Schwarz","doi":"10.1002/psp4.70117","DOIUrl":"https://doi.org/10.1002/psp4.70117","url":null,"abstract":"<p><p>Assessing the risk or benefit of an inhaled substance is challenging due to the variety of forms it can take (gas, vapor, particle, or droplet) and the complex biological processes involved in its uptake and retention. Physiologically based kinetic (PBK) models offer an alternative to in vivo experiments. However, PBK models for inhalational uptake are to date either designed for gases/vapors or airborne particulates, often with only low regional compartmentalization. The here-presented, newly developed model combines both applications. Its mechanisms are an amalgamation of PBK and non-PBK models integrated into a multicompartmental description of the human lung to include the relevant uptake and clearance processes in the different lung regions, of which macrophage-mediated dissolution is novel to PBK modeling. The model was designed to use a minimal number of substance-specific input parameters, which can be derived from in vitro assays or in silico methods. Model predictions for hypothetical substances with varying physicochemical properties were performed, along with rudimentary sensitivity analyses to identify the most important parameters for gases/vapors and particles. This novel PBK model combines all these aspects and provides in silico predictions of systemic and local lung concentrations, reducing uncertainty in risk assessments and supporting drug development. It serves as a valuable tool to translate nominal ambient air doses into effective localized doses within the lung.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225070","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}

{"title":"Population Pharmacokinetic and Pharmacodynamic Modeling for the Prediction of the Extended Amlitelimab Phase 3 Dosing Regimen in Atopic Dermatitis.","authors":"Gilles Tiraboschi, Kim Papp, Thomas Bieber, Stephan Weidinger, Lisa Beck, Chih-Hung Lee, John T O'Malley, Karl Yen, Charlotte Bernigaud, David Fabre, Fabrice Hurbin","doi":"10.1002/psp4.70121","DOIUrl":"https://doi.org/10.1002/psp4.70121","url":null,"abstract":"<p><p>Amlitelimab is a fully human, nondepleting, anti-OX40 ligand monoclonal antibody being investigated for the treatment of moderate-to-severe atopic dermatitis (AD) in adults and adolescents. Population pharmacokinetic (PopPK) and pharmacokinetic/pharmacodynamic-Eczema Area and Severity Index (PopPK/PD-EASI) models were used to inform dosing regimen selection for amlitelimab phase 3 trials. The PopPK model was developed using phase 1 (healthy volunteers) and phase 2 (participants with AD) trial data, including individual exposure variables from the STREAM-AD phase 2b trial following subcutaneous amlitelimab doses ranging from 62.5 to 250 mg given every 4 weeks (Q4W). The PopPK model was used to compute exposures for an extended dosing regimen of 250 mg Q12W (with 500 mg loading dose [+LD]). The PopPK/PD-EASI model was developed from phase 2 trials to predict treatment responses (EASI values) with selected dosing scenarios. Finally, the dose for individuals with lower body weight (i.e., < 40 kg) was determined. Utilizing the PopPK model, the amlitelimab 250 mg Q12W + LD computed exposures were between the exposures of 62.5 mg Q4W and 250 mg Q4W + LD efficacious doses in the STREAM-AD trial. Using the PopPK/PD-EASI model, the simulated efficacy for dosing scenarios of 250 mg Q12W + LD regimen from initiation or 250 mg Q4W + LD for 24 weeks followed by Q12W to Week 60 was similar to continuous 250 mg Q4W. Simulations identified that a twofold dose reduction would allow participants < 40 kg to achieve amlitelimab exposures within the range observed in participants ≥ 40 kg on 250 mg Q4W or Q12W. These results support evaluation of a Q12W dosing regimen for adults and adolescents in phase 3 trials.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205708","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}

{"title":"Population Pharmacokinetic Analysis of Datopotamab Deruxtecan (Dato-DXd), a TROP2-Directed Antibody-Drug Conjugate, in Patients With Advanced Solid Tumors.","authors":"Ying Hong, Sophie Peigné, Υuzhuo Pan, Sofia Friberg Hietala, Anna McLaughlin, Naoyuki Tajima, Deise Uema, Hong Zebger-Gong, Zoey Tang, Diansong Zhou, Malaz Abutarif, Τushar Garimella","doi":"10.1002/psp4.70118","DOIUrl":"https://doi.org/10.1002/psp4.70118","url":null,"abstract":"<p><p>Datopotamab deruxtecan (Dato-DXd) is a trophoblast cell surface antigen 2 (TROP2)-directed antibody-drug conjugate (ADC) developed for the treatment of advanced or metastatic solid tumors. Dato-DXd demonstrated promising antitumor activity and a manageable safety profile in the first-in-human Phase 1 study TROPION-PanTumor01. The present work established population pharmacokinetic models for Dato-DXd and DXd in patients with advanced solid tumors, using data from three clinical studies. The final Dato-DXd model was a two-compartment model with both linear (CL_linDatoDXd) and nonlinear elimination. CL_linDatoDXd was the major elimination pathway for Dato-DXd doses ≥ 4 mg/kg, whereas nonlinear clearance was necessary to capture the concentration-dependent clearance at lower doses. Body weight was added as a mechanistic covariate with a fixed allometric exponent of 0.75 (estimated value: 0.80) on clearance and estimated exponents on volumes of distribution. The final model for DXd was a one-compartment model with linear clearance (CL_DXd). The release of DXd was equal to the total elimination rate of Dato-DXd and was found to be time-dependent within and between cycles, as previously observed for other ADCs. For a typical 66 kg male patient, CL_linDatoDXd was 0.386 L/day, central volume of distribution V_cDatoDXd was 3.06 L, CL_DXd was 2.66 L/day, and V_cDXd was 25.1 L. Covariate analysis identified body weight as the most influential covariate on Dato-DXd and DXd exposure. These findings support the weight-based dosing strategy and indicate no dose adjustments are warranted based on the covariates evaluated.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205678","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}

{"title":"Using Virtual Patients to Evaluate Dosing Strategies for Bispecifics With a Bell-Shaped Efficacy Curve.","authors":"Jana L Gevertz, Irina Kareva","doi":"10.1002/psp4.70105","DOIUrl":"https://doi.org/10.1002/psp4.70105","url":null,"abstract":"<p><p>Bispecific antibodies can be broadly divided into two categories: those that are pharmacologically active as either dimers bound to a single target or as trimers bound to both targets, and those that are only active as trimers. Dose selection of trimer-based bispecifics poses a unique challenge, as toxicity increases with dose, but efficacy does not. Instead, trimer-driven bispecifics have a bell-shaped efficacy curve, for which both under- and over-dosing can cause a decrease in efficacy. To address the challenge of dose selection for trimer-based bispecifics, we develop a semi-mechanistic pharmacokinetic/pharmacodynamic model of one such bispecific, teclistamab. By introducing variability in key patient-specific parameters, we find that the currently selected phase II recommended dose of 1.5 mg/kg administered subcutaneously weekly falls within the calculated optimal range for maximizing concentration of the pharmacologically active trimer for a broad population. We next explore different strategies for patient stratification based on pre-treatment levels of measurable biomarkers. We discover that significantly more variability across subpopulations is predicted when the drug is administered every 2 weeks as compared to weekly administration, and that higher doses generally result in more interpatient variability. Further, the pharmacologically active trimers are predicted to be maximized at different doses for different subpopulations. These findings underscore the potential for model-supported patient stratification based on measurable biomarkers, offering a middle ground between population-level approaches and fully personalized medicine.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191391","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}

{"title":"A Model-Based Meta-Analysis of Pembrolizumab Effects on Patient-Reported Quality of Life: Advancing Patient-Centered Oncology Drug Development.","authors":"Yiqin Zou, Yimeng Sun, Sudhamshu Ravva, Lynne I Wagner, Jiawei Zhou","doi":"10.1002/psp4.70106","DOIUrl":"https://doi.org/10.1002/psp4.70106","url":null,"abstract":"<p><p>Pembrolizumab is an immune checkpoint inhibitor that has been approved for more than 20 different indications and has shown great survival benefits in various types of cancer. However, the reported benefits of pembrolizumab in patients' quality of life (QoL) have been inconsistent across different studies and different types of cancer. As oncology drug development increasingly emphasizes patient-centered care, patient-reported outcomes (PROs), particularly patient-reported QoL, are recognized as important clinical endpoints. To characterize the effects of pembrolizumab on patient-reported QoL, we conducted a model-based meta-analysis (MBMA) of published clinical trials evaluating pembrolizumab across different types of cancer. The longitudinal EORTC QLQ-C30 GHS/QOL data were extracted in our analysis as QoL scores. A population model was developed to characterize the longitudinal QoL trajectories and quantify both treatment toxicity and efficacy. Out of more than 300 screened studies, only 20 reported longitudinal EORTC QLQ-C30 QoL data. Among these, 8 studies reported no between-group differences in QoL outcomes between pembrolizumab and control arms. However, our modeling revealed that pembrolizumab was associated with greater toxicity but improved long-term QoL. Notably, our approach identified treatment effects on QoL that were not detected by traditional statistical analyses in the original publications. In summary, our study demonstrates that MBMA combined with population modeling enables more accurate evaluation of longitudinal PROs data, overcoming the limitations of conventional methods. This approach offers a robust framework for integrating patient-centered outcomes into oncology drug development and supports the broader use of PROs data in regulatory and clinical decision-making.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198648","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}

{"title":"PD-1-Cis IL-2R Agonism Determines the Predicted Pharmacological Dose Range for the Immunocytokine Eciskafusp Alfa (PD1-IL2v).","authors":"Lucy G Hutchinson, Thomas D Lewin, Laura Lauener, Meret Martin-Facklam, Merlind Muecke, Volker Teichgraeber, Laura Codarri Deak","doi":"10.1002/psp4.70112","DOIUrl":"https://doi.org/10.1002/psp4.70112","url":null,"abstract":"<p><p>Binding in cis-configuration to the PD-1 receptor (PD-1) and IL-2 <math> <semantics><mrow><mi>βγ</mi></mrow> <annotation>$$ beta gamma $$</annotation></semantics> </math> receptor (IL-2R <math> <semantics><mrow><mi>βγ</mi></mrow> <annotation>$$ beta gamma $$</annotation></semantics> </math> ) has been shown to lead to differentiation of CD8 T cells to better effectors, which is anticipated to drive efficacy of the immune-targeted cytokine eciskafusp alfa, or PD1-IL2v. Here we present a geometrically driven mathematical formulation informed by in vitro and early clinical data which enables prediction of doses at which cis-binding is at its highest, and explains observed differences in concentration-time profiles for patients who had recent exposure to other anti-PD-1 molecules compared with those who had not. Furthermore, binding in cis-configuration is expected to follow a \"bell-shaped\" relationship with drug concentration such that high concentrations may lead to reduced benefit/risk ratio compared with concentrations around the peak of the bell-shape. Model simulations identify patient cohorts for whom the upper limit of the pharmacological dosing range may be defined by either undesirable off-tumor target engagement or a decrease in on-tumor cis-binding.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181798","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}

{"title":"Evaluation and Mitigation of Time-Dependent Confounding Effects in Conventional Exposure-Response Analyses for Oncology Drugs.","authors":"Xuefen Yin, Ye Xiong, Youwei Bi, Xin Wei, Hong Zhao, Elimika Pfuma Fletcher, Rajanikanth Madabushi, Amal Ayyoub, Hao Zhu, Stephan Schmidt, Jiang Liu","doi":"10.1002/psp4.70119","DOIUrl":"https://doi.org/10.1002/psp4.70119","url":null,"abstract":"<p><p>Conventional exposure-response (E-R) analyses, such as logistic regression and time-to-event analysis using summary exposure metrics, are often conducted in oncology using data from the pivotal trial(s) with a single dose level to support dosing decisions. However, these E-R analyses, affected by multiple confounding factors, may mischaracterize true E-R relationships, potentially limiting their utility in dosing decisions. This study investigates potential mischaracterization in such analyses influenced by the following time-dependent confounding factors: exposure accumulation, dose modification patterns, and event onset time. We used a simulation-based approach to evaluate two E-R scenarios: ER1, where event time generated with a Weibull distribution is not affected by drug exposure, and ER2, where the response is driven by drug exposure via a joint PK-tumor size model. Our analyses indicate that when using time-dependent exposure metrics (e.g., average concentration till event/censoring), exposure accumulation tends to induce an inverse E-R trend, while dose modifications (interruptions/reductions) likely induce a positive E-R trend. Simulations suggest that employing static exposure metrics (e.g., first-cycle or steady-state) minimizes these biases. Additionally, adopting an Emax model aligned with the underground truth in ER2 in the E-R analyses could reduce bias. When significant dose modifications are present, including relevant data from a dose-range study and employing modified methods for time-dependent exposure derivation may help mitigate bias. Overall, using multiple exposure metrics (including static ones) to assess E-R consistency and interpreting the potential causal effects with totality of evidence (including dose-response results) should be implemented to better inform dosing decisions.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148023","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}

{"title":"Model-Informed Drug Development of Subcutaneous Nivolumab: Comparison of Pharmacokinetic Analysis Methodologies Using Clinical Trial Simulation.","authors":"Yue Zhao, Heather Vezina, Zheyi Hu, Anna Kondic, Li Zhu, Amit Roy","doi":"10.1002/psp4.70120","DOIUrl":"https://doi.org/10.1002/psp4.70120","url":null,"abstract":"<p><p>A subcutaneous formulation of nivolumab was evaluated in the phase III study CheckMate 67T (NCT04810078). The co-primary pharmacokinetic exposure endpoints, time-averaged serum concentration over the first 28 days (C_avgd28), and steady-state trough concentration (C_minss) were determined through population pharmacokinetic analysis as compared to conventional non-compartmental analysis (NCA). We proposed a model-based approach to determine subcutaneous and intravenous nivolumab exposures in CheckMate 67T, leveraging extensive prior pharmacokinetic data across various tumor types. The robustness of this model-informed drug development (MIDD) approach was assessed via clinical trial simulations. Concentration-time profiles in randomly sampled patients with renal cell carcinoma receiving second-line systemic therapy were simulated for subcutaneous/intravenous nivolumab. Population pharmacokinetic parameters, sampled from the joint parameter uncertainty distribution, were applied in simulations based on the CheckMate 67T design. Two population pharmacokinetic approaches-the PRIOR subroutine ($PRIOR) in NONMEM and a pooled analysis with historical nivolumab pharmacokinetic data-were used to analyze the simulated data. Results were compared to NCA using intensive and conventional sampling schemes. Analyses showed that model-based analysis provided more accurate area under the curve estimates than NCA. Model-predicted exposure measures, including C_avgd28, maximum serum concentration after the first dose, and minimum serum concentration at day 28, were also consistent across both population pharmacokinetic approaches, with minimal differences in geometric means. In conclusion, both the $PRIOR and pooled population pharmacokinetic methods yielded more accurate results compared to conventional NCA. The MIDD approach was validated as a robust and feasible method to support non-inferiority assessment based on clinical trial simulations.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145129873","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}

{"title":"An Open-Source Framework for Virtual Bioequivalence Modeling and Clinical Trial Design.","authors":"Abdullah Hamadeh, Moriah Pellowe, Pierre Chelle, Cindy Hoi Ting Yeung, Julian Otalvaro, Walter Yamada, Jay Bartroff, Alona Kryshchenko, André Dallmann, Juri Solodenko, Jörg Lippert, Eleftheria Tsakalozou, Michael Neely, Andrea Edginton","doi":"10.1002/psp4.70115","DOIUrl":"https://doi.org/10.1002/psp4.70115","url":null,"abstract":"<p><p>To establish bioequivalence (BE) of a generic test formulation with respect to a reference listed drug, it is necessary to demonstrate a comparable rate and extent to which active ingredients reach the site of action. To decrease unnecessary human testing and simulate scenarios involving specific populations or challenges with recruitment or study design, industry and regulators are increasingly considering in silico virtual bioequivalence (VBE) approaches. This tutorial introduces the VBEToolbox R package: a toolbox within the Open Systems Pharmacology framework to streamline and standardize computational VBE workflows. The package integrates in vitro and in vivo data to train pharmacokinetic models through inference of inter-individual variability from clinical data and establishment of in vitro to in vivo extrapolations. A nonparametric approach is adopted to account for uncertainties from parameter non-identifiability. The trained model is then applied to determine the study size with statistical power needed to demonstrate BE virtually. The use of the VBE tool is illustrated with two case studies. The first evaluates the VBE of petrolatum and ethylene glycol dermal formulations of testosterone by integrating in vitro skin permeation tests, vehicle/skin partitioning data, testosterone solubility data, and in vivo absorption data in a mechanistic in vitro/in vivo dermal absorption model. The second assesses the VBE of two oral bupropion formulations by integrating in vitro dissolution data in a physiologically based pharmacokinetic model. These case studies highlight essential considerations for model development, training, and extrapolation toward application for VBE assessment.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145129890","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}

{"title":"A Population Pharmacokinetic Approach to Understand the Effect of Efavirenz on CYP3A Activity in Healthy Volunteers Using Midazolam as a Probe.","authors":"Kimberly S Collins, Blessed W Aruldhas, Ingrid F Metzger, Jessica B L Lu, Michael A Heathman, Sara K Quinney, Zeruesenay Desta","doi":"10.1002/psp4.70116","DOIUrl":"https://doi.org/10.1002/psp4.70116","url":null,"abstract":"<p><p>Efavirenz induces and inhibits multiple drug-metabolizing enzymes, contributing to significant drug-drug interactions. This study quantified the impact of multiple doses of efavirenz on CYP3A activity via midazolam metabolism using a population pharmacokinetic approach. Healthy volunteers received 1 mg midazolam orally in two sessions: first with a single 600 mg efavirenz dose and then after chronic efavirenz dosing (600 mg/day for 17 days). Midazolam and 1'-hydroxymidazolam were quantified via LC-MS/MS, and CYP2B6, CYP3A4, and CYP3A5 genotypes were assessed using TaqMan assays. Seventy-two volunteers (n = 72) completed sampling after the initial dose, and 58 completed both occasions. Non-linear mixed effects modeling was performed using the stochastic approximation expectation maximization estimation method in NONMEM. The base pharmacokinetic model employed was a two-compartment model with first-order absorption and first-order elimination, incorporating proportional error terms for midazolam and 1'-hydroxymidazolam. Covariate analysis utilized a full model approach to assess the impact of CYP3A4 and CYP3A5 genotypes, self-reported sex, and multiple doses of efavirenz as covariates affecting the formation clearance of 1-OH midazolam. CYP3A5 expressors exhibited a 1.27-fold increase in midazolam clearance compared to non-expressors, while CYP3A4 intermediate metabolizers showed a 0.94-fold decrease relative to normal metabolizers. Clearance was also 1.30-fold higher in females compared to males. Multiple doses of efavirenz increased midazolam clearance by 1.92-fold (95% CI 1.65-2.28) after accounting for inter-individual variability caused by other covariates. Furthermore, K_a and bioavailability (F) increased with repeated efavirenz exposure. In conclusion, this population pharmacokinetic analysis effectively quantified the specific induction effect of multiple doses of efavirenz on CYP3A compared to a single dose of efavirenz. Trial Registration: ClinicalTrials.gov identifier: NCT00668395.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136610","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}