CPT: Pharmacometrics & Systems Pharmacology最新文献

{"title":"Pharmacokinetic Model-Informed Precision Dosing of Natalizumab in Multiple Sclerosis.","authors":"Stefan P H van den Berg, Alyssa A Toorop, Femke Hooijberg, Gertjan Wolbink, Nivea M F Voelkner, Liza M Y Gelissen, Joep Killestein, Zoé L E van Kempen, Thomas P C Dorlo, Theo Rispens","doi":"10.1002/psp4.70014","DOIUrl":"https://doi.org/10.1002/psp4.70014","url":null,"abstract":"<p><p>Intravenous natalizumab is an effective treatment for relapsing-remitting multiple sclerosis. However, the standard treatment interval of 4 weeks may be excessive for many patients. Personalized interval extension using therapeutic drug monitoring (TDM) can result in adequate drug exposure while reducing hospital visits and healthcare costs. Here, we investigate to which extent TDM-guided personalized dosing can benefit from model-informed precision dosing (MIPD). Individual posterior PK estimates were derived using patient weight and two trough concentrations at the standard dose interval by Bayesian estimation using a newly developed population PK model. MIPD was compared to a previously deployed TDM-guided stratified personalized dosing protocol (SPD) using a decision tree to personalize dosing intervals. Accuracy (mean prediction error) of the predicted dosing intervals was 4.8% versus 24% for model-informed estimates versus decision tree, respectively, when aiming for a 10 μg/mL trough concentration, and 4.8% versus 86% when aiming for 5 μg/mL. Corresponding precision (root mean square error) was 2.3 versus 4.0, and 1.5 versus 5 μg/mL. Finally, we evaluated the feasibility of a MIPD approach to attain a therapeutic trough of 2 μg/mL. Simulating MIPD showed a reduction in the average infusions versus the standard interval by 40%, with an average dose interval of 7 weeks, while maintaining adequate drug exposure. MIPD was concluded to be superior to the conventional TDM-guided personalized dosing approach in terms of enhanced precision in individual dose interval selection, enabling more efficient interval extensions. Simulations supported the clinical deployment of natalizumab MIPD.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662980","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 Approach to Evaluate Anti-Drug Antibody Impact on Drug Exposure With Biologics: A Case Example With the CD3 T-Cell Bispecific Cibisatamab.","authors":"Javier Sanchez, Philippe B Pierrillas, Nicolas Frey, Gregor P Lotz, Siv Jönsson, Lena E Friberg, Nicolas Frances","doi":"10.1002/psp4.70019","DOIUrl":"https://doi.org/10.1002/psp4.70019","url":null,"abstract":"<p><p>The administration of biologics can lead to immunogenic responses that trigger anti-drug antibody (ADA) formation. ADAs can decrease drug exposure. A population pharmacokinetic (popPK) model was developed to describe clinical PK data with and without ADA-driven exposure loss with CEA-directed T-cell bispecific antibody cibisatamab. The PK of cibisatamab was evaluated in two clinical studies (as a single agent and in combination with the checkpoint inhibitor atezolizumab) in patients. The popPK model was developed on cibisatamab clinical PK data using the Stochastic Approximation -Expectation Maximization (SAEM) algorithm implemented in Monolix. Cibisatamab's PK followed a two-compartment model with linear clearance decreasing over time and ADA-associated exposure loss. ADA-driven exposure loss was implemented in the model by accounting for ADA formation, reversible binding to cibisatamab, and elimination of both free ADA and the ADA-cibisatamab complex from the central compartment. The impact of ADAs on PK exposure was time-dependent in the model, with the ADA formation described as a function of time (increasing from zero, reaching its estimated maximum value, and possibly decreasing down to 94% of this maximum value in some patients). The final model included a mixture component differentiating patients with and without exposure loss due to ADA formation (75% and 25% of patients, respectively). The investigated patient demographics, dose or dosing schedule, or atezolizumab coadministration were not identified as factors influencing exposure loss due to ADAs. The developed model can be used to differentiate patients with and without ADA-driven exposure loss, as well as for a precise PK characterization in patients even with ADA formation.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662960","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":"Less Is More: Design Considerations for Interactive Pharmacometrics Tools-A Case Study Using the Model Visualization Platform (MVP) App.","authors":"Steve Choy, Jin Gyu Kim, Julia Korell","doi":"10.1002/psp4.70023","DOIUrl":"https://doi.org/10.1002/psp4.70023","url":null,"abstract":"<p><p>The shiny R package has enabled pharmacometrics (PMX) scientists to create and share interactive R-based tools, or \"shiny apps\". Initially, shiny apps are developed ad hoc (i.e. project specific) to provide simulations, and their complexity have evolved to be more general-purpose and \"platform-like\" in recent years. Despite their complexity and increased amount of features, an unexplored aspect is the design considerations for user interface and user experience (UI/UX) to optimize end-user interactivity and enjoyment.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662979","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 Pharmacokinetics and Exposure-Response Modeling for Evinacumab in Children, Adolescents, and Adults With Homozygous Familial Hypercholesterolemia.","authors":"Sébastien Bihorel, Robert Dingman, Jeanne Mendell, Yuhuan Wang, Poulabi Banerjee, Robert Pordy, John D Davis, A Thomas DiCioccio, Lutz Harnisch","doi":"10.1002/psp4.70016","DOIUrl":"https://doi.org/10.1002/psp4.70016","url":null,"abstract":"<p><p>Evinacumab, an angiopoietin-like 3 (ANGPTL3) inhibitor, significantly reduces low-density lipoprotein cholesterol (LDL-C), independent of low-density lipoprotein receptor, in patients with homozygous familial hypercholesterolemia (HoFH). A population pharmacokinetic (PK)/pharmacodynamic (PD) model was previously developed to characterize evinacumab exposure and LDL-C response in adolescents and adults. In this analysis, the PK/PD model was refined to include children aged 5 to < 12 years and to characterize the lipoprotein apheresis effect on LDL-C reduction. The PK of evinacumab was characterized by a two-compartment model with parallel linear and non-linear elimination. Linear disposition parameters were allometrically scaled by body weight. Baseline ANGPTL3 concentrations and disease status (non-HoFH vs. HoFH) influenced the maximum target-mediated rate of elimination but had a minimal effect on evinacumab exposures at 15 mg/kg intravenous doses every 4 weeks across weight/age groups. In patients with HoFH, the LDL-C reduction was adequately described by an indirect response model in which evinacumab inhibits the formation of LDL-C and that includes a secondary elimination process quantifying the lipoprotein apheresis effect. Older age was associated with a decrease in baseline LDL-C. An increase in body weight was associated with a reduction in the maximum inhibitory effect of evinacumab. Model-based simulations showed that while evinacumab exposure is reduced with decreasing age/body weight, younger patients are predicted to have a comparable or greater magnitude of LDL-C reduction than older patients at a dose of 15 mg/kg. Overall, the model adequately predicted the evinacumab exposure and LDL-C reduction in children, adolescents, and adults with HoFH, aligning with clinically relevant observations.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647549","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":"Comparison of Model-Predicted and Observed Evinacumab Pharmacokinetics and Efficacy in Children Aged < 5 Years With Homozygous Familial Hypercholesterolemia.","authors":"Sébastien Bihorel, Robert Dingman, Jeanne Mendell, Katy C Norman, Richard T George, Xue-Qiao Zhao, Robert Pordy, Daniel Garcia, Wendy S Putnam, Geetha Raghuveer, Brian W McCrindle, Elena Fornari, Ivo Baric, Shubha Srinivasan, Melissa Diamond, Eliot A Brinton, John D Davis, A Thomas DiCioccio, Lutz Harnisch","doi":"10.1002/psp4.70017","DOIUrl":"https://doi.org/10.1002/psp4.70017","url":null,"abstract":"<p><p>Evinacumab, an angiopoietin-like 3 inhibitor, significantly reduces low-density lipoprotein cholesterol (LDL-C) in patients with homozygous familial hypercholesterolemia (HoFH). Herein, we report pharmacokinetic and efficacy analyses of evinacumab in < 5-year-old patients with HoFH. Population pharmacometric models characterizing evinacumab exposure and LDL-C response accounting for lipoprotein apheresis effect in ≥ 5-year-old patients were adapted for growth and maturation to predict and compare evinacumab and LDL-C concentrations across age/weight groups in virtual ≥ 6-month-old patients receiving 15 mg/kg evinacumab intravenous (iv) infusions every 4 weeks (q4w). As expected from allometric theory, weight-based dosing resulted in decreasing evinacumab exposures with declining body weight. Consistent with trends observed in > 5-year-old patients, the predicted percent change from LDL-C baseline (%∆LDL-C) was generally comparable or even higher in < 5-year-old patients (63.0%-68.5%) than in 5- to < 18-year-old patients (61.3%-67.8%) or adults (51.7%), with the predicted percentages of patients achieving %∆LDL-C > 50% also higher in < 5-year-old patients (82.0%-86.9%) versus 5- to < 18-year-old patients (72.0%-84.5%) and adults (54.8%). Through a managed access program, six 1- to < 5-year-old patients received between 5 and 23 iv infusions of 15 mg/kg evinacumab q4w. Rapid and clinically meaningful LDL-C reductions were observed, with %∆LDL-C at the last reported dose ranging from 41.3% to 77.3%. Based on the actual patient dosing and plasmapheresis history, model-predicted evinacumab and LDL-C concentrations were comparable to the observed data collected in the managed access program. Overall, this analysis provides evidence for the use of evinacumab 15 mg/kg iv q4w dosing regimen in 6-month-old to 5-year-old patients.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647548","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":"Translational Physiologically Based Pharmacokinetic Modeling to Predict Human Pulmonary Kinetics After Lung Delivery.","authors":"Haini Wen, Muhammad Waqas Sadiq, Lena E Friberg, Elin M Svensson","doi":"10.1002/psp4.13316","DOIUrl":"https://doi.org/10.1002/psp4.13316","url":null,"abstract":"<p><p>Predicting human lung exposure with reasonable certainty of orally inhaled drugs based on preclinical studies remains a challenge for drug development. We have developed a comprehensive physiologically based pharmacokinetic (PBPK) framework tailored for the pulmonary pharmacokinetic (PK) behavior in both humans and rats, aiming to bridge the translational gap. In this study, we present a mechanistic pulmonary PBPK model for rats that integrates the pulmonary disposition processes, including drug deposition, dissolution, mucociliary clearance, and mass transfer in lung tissues. Apparent permeabilities were translated to effective permeabilities (P_eff) with in vivo-in vitro correlation methods. Unbound tissue-plasma partition coefficients for lung (K_p,u,lung) and P_eff were estimated with plasma and lung PK profiles of salbutamol and fluticasone propionate in rats. The developed PBPK model was translated by keeping the estimated parameters and switching physiological and anatomical parameters from rats to humans. Based on PK observations in rats, the estimated typical P_eff and K_p,u,lung for salbutamol were 1.18 × 10^-5 cm/s and 8.83 and for fluticasone propionate 1.26 × 10^-4 cm/s and 1086, respectively. After interspecies translation, the model framework well predicted the mean epithelial lining fluid concentrations following oral inhalation of salbutamol and fluticasone propionate in human subjects, with fold-errors of lung-to-plasma ratios < 2. Thus, the proposed general pulmonary PBPK framework exhibits the potential to facilitate interspecies translation and can be used to predict safety and efficacy of lung-delivered therapeutics in human.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633818","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 Pharmacokinetic and Pharmacodynamic Analysis to Optimize the Dosing Regimens of Fanastomig (EMB-02) in Patients With Advanced Solid Tumors.","authors":"Chengjun Jiang, Fang Ren, Mingfei Zhang, Qiaoyang Lu, Shuqi Zeng, Guang Yang, Yonghong Zhu","doi":"10.1002/psp4.70011","DOIUrl":"https://doi.org/10.1002/psp4.70011","url":null,"abstract":"<p><p>Fanastomig (also known as EMB-02) is a bispecific antibody targeting programmed cell death protein-1(PD-1) and lymphocyte activation gene-3 (LAG-3), developed for the treatment of advanced solid tumors. A first-in-human (FIH) Phase I study (NCT04618393) evaluated safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and clinical efficacy of Fanastomig in patients with advanced solid tumors. To determine the recommended Phase II dose (RP2D), population pharmacokinetics (PopPK), and exposure and response analysis (E-R) were conducted. The PopPK model, demonstrating good performance, showed no clinically meaningful relationship between areas under the concentration-time curve (AUC) or maximum concentration (C_max) of Fanastomig and selected covariates of interest. A nonlinear E_max model was fitted to Fanastomig PD-1 receptor occupancy (RO) in the peripheral blood compartment. The estimated half-maximal effective concentration (EC₅₀) was 0.084 μg/mL (95% confidence interval [CI]: 0.0369-0.131). Assuming a threefold lower exposure in tumor tissue compared to that in serum, a target trough concentration of Fanastomig at ~2.27 μg/mL would be needed for 90% PD-1 RO in the tumor. Modeling and simulation indicated that a weekly dosing (QW) of 360 mg would achieve full peripheral blood RO in approximately 90% of patients. The incidence of anti-drug antibodies (ADAs) for Fanastomig was high (95.7%, 44/46), with a negative correlation between the ADA titer and dose levels; meanwhile, ADA minimally impacted PK exposure and efficacy. An inverse trend was observed between anaphylaxis and PK exposure. Fanastomig was well tolerated and had acceptable safety profiles up to 900 mg QW. Based on these findings, two dosing regimens have been selected for further clinical development. Trial Registration: ClinicalTrials.gov identifier: NCT04618393.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603816","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 Pragmatic Approach to Handling Censored Data Below the Lower Limit of Quantification in Pharmacokinetic Modeling.","authors":"Marie Wijk, Roeland E Wasmann, Karen R Jacobson, Elin M Svensson, Paolo Denti","doi":"10.1002/psp4.70015","DOIUrl":"https://doi.org/10.1002/psp4.70015","url":null,"abstract":"<p><p>Proper handling of data below the lower limit of quantification (BLQ) is crucial for accurate pharmacokinetic parameter estimation. The M3 method proposed by Beal uses a likelihood-based approach that is precise but has been reported to suffer from numerical issues in converging. Common alternatives include ignoring the BLQs (M1), imputing half of the lower limit of quantification and ignoring trailing BLQs (M6) or imputing zero (M7). The imputation methods fail to account for the additional uncertainty affecting imputed observations. We used NONMEM with FOCE-I/Laplace to compare the stability, bias, and precision of methods M1, M3, M6, M7, and modified versions M6+ and M7+ that inflate the additive residual error for BLQs. Real and simulated datasets with a two-compartment model were used to assess stability through parallel retries with perturbed initial estimates. The resulting differences in objective function values (OFV) were compared. Bias and precision were evaluated on simulated data using stochastic simulations and estimations. M3 yielded different OFV across retries (±14.7), though the parameter estimates were similar. All other methods, except M7 (±130), were stable. M3 demonstrated the best bias and precision (average rRMSE 18.7%), but M6+ and M7+ performed comparably (26.0% and 23.3%, respectively). The unstable OFV produced by M3 represents a challenge when used to guide model development. Imputation methods showed superior stability, and including inflated additive error improved bias and precision to levels comparable with M3. For these reasons, M7+ (of simpler implementation than M6+) is an attractive alternative to M3, especially during model development.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603630","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":"Genotype, Ethnicity, and Drug-Drug Interaction Modeling as Means of Verifying Transporter Biomarker PBPK Model: The Coproporphyrin-I Story.","authors":"Yuki Ujihira, Shawn Pei Feng Tan, Daniel Scotcher, Aleksandra Galetin","doi":"10.1002/psp4.70008","DOIUrl":"https://doi.org/10.1002/psp4.70008","url":null,"abstract":"<p><p>Coproporphyrin-I (CP-I) is a selective endogenous biomarker of organic anion-transporting polypeptide (OATP)1B. Multiple CP-I PBPK models with differing input parameters have been reported so far. This study proposed a harmonized CP-I PBPK model and evaluated its ability to predict the effect of ethnicity, SLCO1B1 genotype c.521T>C, and sex on CP-I baseline and CP-I-drug interactions using the largest clinical dataset to date. The CP-I PBPK model successfully predicted CP-I plasma baseline from 731 subjects, with 97% of predictions within 1.5-fold of the observed data. Prediction of weak, moderate, and strong OATP1B-mediated interactions with probenecid, low-dose cyclosporine, and rifampicin, respectively, was evaluated with 21 datasets. Overall, > 76% of CP-I C_maxR and AUCR were predicted within the Guest criterion. In vivo OATP1B K_i estimated by the biomarker model was up to ninefold lower compared to in vitro values. Sensitivity analyses showed differences in estimated in vivo K_i depending on the assumed contribution of non-inhibited/parallel pathway (renal) for CP-I (0%-15%), highlighting the need to consider this factor when using biomarker PBPK models for such purposes. Finally, the appropriate metric for monitoring CP-I was evaluated for inhibitors with different potency and PK relative to CP-I. In the case of strong/moderate OATP1B inhibitors with short t_1/2, C_maxR was the most sensitive metric for monitoring CP-I OATP1B interactions, whereas both C_maxR and AUCR were applicable for inhibitors with long t_1/2. The current study provides a harmonized CP-I PBPK model, together with recommendations to support the optimal design of prospective clinical trials for the assessment of OATP1B-mediated DDIs using this biomarker.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596567","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/Pharmacodynamic and Exposure-Response Modeling of Garadacimab in Healthy Volunteers and Patients With Hereditary Angioedema.","authors":"Ramon Garcia, Shen Cheng, Fiona Glassman, Ankur Sharma, Bernardo De Miguel-Lillo, Matthew Wiens, Curtis Johnston, John-Philip Lawo, Ingo Pragst, Jonathan French, Dan Polhamus, Partha Nandy","doi":"10.1002/psp4.70009","DOIUrl":"https://doi.org/10.1002/psp4.70009","url":null,"abstract":"<p><p>Hereditary angioedema (HAE) is a rare genetic disease that manifests as recurrent, unpredictable, and potentially life-threatening attacks of angioedema. Garadacimab is a first-in-class, fully human, monoclonal antibody targeting activated factor XII (FXIIa) that is under clinical development for the long-term prophylaxis of HAE attacks. We developed population pharmacokinetic (PK)/pharmacodynamic (PD)/exposure-response (ER) models using pooled data across clinical studies to quantify the relationship between garadacimab concentration and the relative risk of HAE attacks and to support the rationale for 200 mg once-monthly dosing. The PK of garadacimab was adequately characterized by a two-compartment model with first-order absorption and elimination. The PD, as analyzed by FXIIa-mediated kallikrein activity, was adequately characterized by a direct inhibitory response model. PK/PD parameters were generally consistent across multiple covariates. ER analysis based on a repeated-time-to-event model showed that administration of garadacimab 200 mg subcutaneously (SC) once monthly results in 75% of patients reaching the target therapeutic threshold (90% reduction in relative risk of attack vs. run-in). Use of a loading dose (two 200 mg SC injections) as the first administration achieved steady-state PK exposures and PD response, with 85% of patients having exposures surpassing the therapeutic threshold. The models support the use of garadacimab 200 mg SC once-monthly dosing in patients aged ≥ 12 years, with no need for dose adjustments, and indicate that, due to the achievement of garadacimab steady-state exposures after the first administration, the use of a loading dose may facilitate the early onset of protection against HAE attacks, as observed in clinical studies.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556188","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}