Clinical Pharmacokinetics最新文献

{"title":"Pharmacokinetic/Pharmacodynamic Modelling and Monte Carlo Simulations to Predict Cytomegalovirus Viral Load in Pediatric Transplant Recipients Treated with (val)Ganciclovir.","authors":"Kévin Koloskoff, Bénédicte Franck, Sylvain Benito, Julien Welzel, Julie Autmizguine, Yves Theoret, Annabelle Briand, Philippe Ovetchkine, Jean-Baptiste Woillard","doi":"10.1007/s40262-025-01526-z","DOIUrl":"10.1007/s40262-025-01526-z","url":null,"abstract":"<p><strong>Background and objectives: </strong>Cytomegalovirus (CMV) infection poses significant challenges in pediatric transplant recipients. Ganciclovir and its prodrug valganciclovir are primary treatments because of their potent antiviral effects. Balancing efficacy and toxicity is particularly critical in children. This study aimed to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for (val)ganciclovir and assess the relationship between area under the concentration-time curve (AUC) and CMV viral loads via Monte Carlo simulations.</p><p><strong>Methods: </strong>We conducted a retrospective analysis including 184 viral load samples from 36 transplanted children treated with ganciclovir/valganciclovir. We developed a population pharmacodynamic model using Monolix and performed Monte Carlo simulations to assess viral load decline with varying AUCs. Internal validation was performed using goodness-of-fit plots and bootstraps.</p><p><strong>Results: </strong>We used a viral turnover model with stimulated degradation to model the pharmacodynamic data. Model validation showed no bias or misspecification. Simulations indicated that maintaining an AUC_0-24 ≥ 40 mg·h/L achieved an 85.4% probability of undetectable viral load after 28 days of therapy. An AUC_0-24 > 30 mg·h/L provided 80.9% probability of reducing viral loads by - 1 log after 2 weeks. AUC_0-24 values > 60 mg·h/L offered minimal incremental benefits.</p><p><strong>Conclusion: </strong>The pharmacodynamic model accurately predicted observed data. Simulations indicated that maintaining a ganciclovir plasma AUC_0-24 around 40-60 mg·h/L maximized antiviral efficacy. An AUC_0-24 > 60 mg·h/L might increase the risk of adverse events without providing additional efficacy.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1061-1069"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12185614/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Pharmacokinetics of Inhaled Drugs for Pulmonary Hypertension.","authors":"Yu Lin, Yuanqi Su, Zhongjie Cheng, Bing Zhu, Qi Pei","doi":"10.1007/s40262-025-01525-0","DOIUrl":"10.1007/s40262-025-01525-0","url":null,"abstract":"<p><p>Pulmonary hypertension (PH) is a serious condition characterized by elevated blood pressure in the pulmonary arteries. Current treatment approaches mainly focus on using vasodilator agents to reduce pulmonary blood pressure and improve blood flow. Inhalation treatments offer targeted delivery to the lungs, improving efficacy and reducing systemic side effects. Understanding the pharmacokinetics (PK) of the molecules used in the inhalation treatment is crucial for dose optimization and drug product development. This review examines the clinical PK characteristics of key inhaled PH drugs (approved and investigational agents), including epoprostenol, iloprost, treprostinil, vardenafil, imatinib, seralutinib, MK-5475, milrinone, and sodium nitrite. We provide detailed analyses of their PK parameters and explore how disease conditions, inter-subject variability, and inhaled formulations and devices impact clinical PK characteristics. Future research would focus on how disease-specific factors affect drug behavior and the prediction of pulmonary drug concentrations. This will support more precise drug delivery and personalized treatment strategies for PH.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"973-986"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144173068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Cellular Kinetics of Idecabtagene Vicleucel in Patients with Triple-Class-Exposed Relapsed/Refractory Multiple Myeloma.","authors":"Fan Wu, Jian Zhou, Xirong Zheng, Madhan Masilamani, Yiming Cheng, Andrea Caia, Mark Cook, Julia Piasecki, Manisha Lamba","doi":"10.1007/s40262-025-01531-2","DOIUrl":"10.1007/s40262-025-01531-2","url":null,"abstract":"<p><strong>Background: </strong>Idecabtagene vicleucel (ide-cel, ABECMA) is an autologous, B-cell maturation antigen (BCMA)-directed, chimeric antigen receptor (CAR) T-cell therapy. The current modeling analyses aim to characterize the cellular kinetics (CK) of ide-cel and to assess the covariate effects impacting ide-cel cellular kinetics in patients with relapsed/refractory multiple myeloma.</p><p><strong>Methods: </strong>A modified piecewise model was developed to characterize ide-cel CK through the nonlinear mixed effects method. The model parameterization was conducted using the ide-cel whole-blood transgene data in CK-evaluable subjects (N = 225) from the ide-cel arm of the study KarMMa-3 (NCT03651128). The structural model consists of an initial lag phase and then saturable cell expansion, followed by conversion from effector cells to memory cells and their elimination. Model simulations were performed to evaluate covariate effects on ide-cel exposure parameters.</p><p><strong>Results: </strong>The piecewise CK model with saturable expansion sufficiently captured the clinically observed ide-cel transgene data. The simulations using the final population CK model suggested that the magnitude of covariate effects on ide-cel exposure parameters was considerably smaller than the intersubject variability in the population. Additional analyses revealed a negative effect of treatment-emergent immunogenicity on the ide-cel persistence. Apparent associations were identified between cellular kinetic parameters and clinical responses.</p><p><strong>Conclusions: </strong>The cellular kinetics of ide-cel can be adequately described by the modified piecewise model. No clinically meaningful covariate effects on cellular kinetics were identified from this modeling study. The population CK model suggests that higher cell expansion rate and lower elimination rates of effector and memory cells were observed in patients with longer progression-free survival.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1119-1132"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12185632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetic Analysis of Enalapril and Enalaprilat in Newly Treated Children with Heart Failure: Implications for Safe Dosing of Enalapril (LENA Studies).","authors":"Melina Steichert, Willi Cawello, Stephanie Laeer","doi":"10.1007/s40262-025-01520-5","DOIUrl":"10.1007/s40262-025-01520-5","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Enalapril orodispersible minitablets (ODMT) have been authorised by the European Medicines Agency for the treatment of heart failure in children from birth to 17 years of age in 2023. Consequently, the use of enalapril in very young and angiotensin-converting enzyme inhibitor (ACEi) naïve patients is expected to increase.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objectives: &lt;/strong&gt;Simultaneous characterisation of the pharmacokinetics (PK) of enalapril and the active metabolite enalaprilat in ACEi naïve children with heart failure using a combined population pharmacokinetic (PopPK) model and identification of clinically relevant covariates for the dosing of enalapril in this population.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Data of ACEi naïve subjects from the European project 'Labeling of Enalapril from Neonates up to Adolescents' (LENA) were analysed using nonlinear mixed effects modelling. In the prospective, open-label, multicentre phase II/III PK bridging studies, children with heart failure due to dilated cardiomyopathy (DCM) and congenital heart disease (CHD) received enalapril ODMT according to an age- and weight-dependent dosing regimen. Allometric scaling was implemented for the disposition parameters of enalapril and enalaprilat. Stepwise covariate modelling was used to test the covariates age, sex, serum creatinine and Ross score. The final model was validated using nonparametric bootstrap analysis. Simulations were performed to assess the impact of the covariates after the first dose and at steady state.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The analysed dataset comprised 173 enalapril and 268 enalaprilat serum concentrations from 34 subjects aged 25 days to 2.1 years (median age = 0.3 years). A combined model consisting of a one-compartment model for enalapril coupled with a one-compartment model for enalaprilat with absorption lag was selected as the structural model. Covariate analysis revealed that the weight-adjusted apparent clearance of enalaprilat increases with increasing age and decreases with increasing serum creatinine. In addition, the weight-adjusted apparent volume of distribution of enalaprilat decreases with increasing Ross score. The simulations indicated that serum creatinine levels above the normal reference range, age and weight were clinically relevant covariates for both the first dose and the steady state dose of enalapril. Furthermore, the simulations indicated that the Ross score is a clinically relevant covariate for the first dose of enalapril.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;The results of the PopPK analysis and simulations indicated that, in addition to the currently considered parameters of weight and renal function, the parameters of age and severity of heart failure should also be considered when dosing enalapril in children with heart failure.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Trial registration: &lt;/strong&gt;Trial registration number (date of registration): EudraCT 2015-002335-17 (30 November 2015), EudraCT 2015-002396-18 (3","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1103-1118"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12185616/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comment on \"Ticagrelor is Associated with Increased Rosuvastatin Blood Concentrations in Patients Who Have Had a Myocardial Infarction\".","authors":"Ziteng Wang, Koo Hui Chan, Eric Chun Yong Chan","doi":"10.1007/s40262-025-01518-z","DOIUrl":"10.1007/s40262-025-01518-z","url":null,"abstract":"","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1133-1135"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the Influence of Obesity and CYP2 C19 Genotype on Lansoprazole Pharmacokinetics in Pediatric Patients: A Population Modeling Approach.","authors":"Victória E Helfer, Daniel Gonzalez, Kathryn E Kyler, Tyler C Dunlap, Veronica Williams, Jansynn Radford, Rangaraj Selvarangan, Anjana Sasidharan, Sherwin Chan, Nathan Artz, Brandon Retke, Paul Toren, Kim Gibson, Valentina Shakhnovich","doi":"10.1007/s40262-025-01517-0","DOIUrl":"10.1007/s40262-025-01517-0","url":null,"abstract":"<p><strong>Background and objective: </strong>Pediatric pharmacokinetics pose unique challenges, particularly concerning drug dosing in the presence of obesity and genetic variability in drug-metabolizing enzymes such as cytochrome P450 (CYP) 2C19. This study aimed to develop a lansoprazole pediatric population pharmacokinetic (popPK) model considering obesity, obesity-associated changes in inflammatory cytokines and the liver, and CYP2C19 genotype, and to assess implications for dosing strategies.</p><p><strong>Methods: </strong>Pediatric subjects with and without obesity (6-21 years, n = 47) received one oral dose of 1.2 mg/kg fat-free mass (FFM), not exceeding 60 mg. Plasma concentrations were measured at multiple time points, and a popPK analysis using NONMEM with stepwise covariate modeling was performed. Simulations compared exposures between children without and with obesity (BMI percentile ≥ 95th) after two dosing strategies: U.S. Food and Drug Administration (FDA)-approved total body weight-tiered and FFM-based dosing.</p><p><strong>Results: </strong>A total of 537 lansoprazole concentrations were modeled using a two-compartment model with Weibull absorption and linear elimination. Parameters were allometrically scaled to FFM with fixed exponents of 0.75 for clearances and 1 for volumes. CYP2C19 was identified as a significant covariate for CL/F. No significant differences in lansoprazole exposure were observed between children with and without obesity, with both dosing approaches. Higher exposure was noted in poor/intermediate metabolizers of CYP2C19. FFM-based dosing led to similar levels of exposure between children (aged 6-11 years) and adolescents (aged 12-17 years).</p><p><strong>Conclusions: </strong>Obesity was not associated with differences in lansoprazole pharmacokinetics in children. A FFM-based dosing approach could result in comparable exposure between children and adolescents. Dose adjustments are supported for poor/intermediate metabolizers of CYP2C19.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1047-1059"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12187529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Utilizing Opportunistic Computed Tomography Imaging to Refine Lean Body Weight Estimates in Patients with Obesity.","authors":"Radin Alikhani, Steven Horbal, Amy E Rothberg, Manjunath P Pai","doi":"10.1007/s40262-025-01530-3","DOIUrl":"10.1007/s40262-025-01530-3","url":null,"abstract":"<p><strong>Introduction: </strong>While dual-energy X-ray absorptiometry (DEXA) is the gold standard for measuring lean body weight (LBW), computed tomography (CT) provides muscle composition and distribution metrics that can refine LBW for better weight-based dosing. We explored how existing computed tomography (CT) images could be utilized to better estimate LBW.</p><p><strong>Methods: </strong>Sixty-three adult patients (71.4% female) with a median age of 53.4 years and mean BMI of 36.84 having both DEXA and CT scans were retrospectively analyzed to assess the relationship between CT-based skeletal muscle variables and DEXA-derived LBW.</p><p><strong>Results: </strong>Linear regression results revealed significant correlations. CT-derived skeletal muscle area (SMA) strongly predicted DEXA-derived LBW (p value < 0.05 and R² between 0.67 and 0.80) at four different vertebra levels. DEXA-derived LBW showed a strong correlation with a height, weight, and sex-based estimate of LBW using an equation developed in 2005 (LBW₂₀₀₅). A final model incorporating SMA with the LBW₂₀₀₅ equation improved the coefficient of determination at all four vertebra levels (R² 0.82-0.86).</p><p><strong>Discussions/conclusion: </strong>This study demonstrates opportunistic CT scan data may improve an existing equation for LBW that has been predictive of select drug pharmacokinetic parameters. Improving LBW estimation may enable improved personalized drug dosing strategies in patients with obesity and other populations that benefit from using LBW over total body weight.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1093-1102"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12185603/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Efsubaglutide Alfa on the Pharmacokinetics of Metformin and Digoxin in Healthy Participants.","authors":"Xiaojie Wu, Jinjie He, Junzhen Wu, Wei Liu, Yulong Xu, Yiming Li, Jing Zhang, Qinghua Wang","doi":"10.1007/s40262-025-01541-0","DOIUrl":"https://doi.org/10.1007/s40262-025-01541-0","url":null,"abstract":"<p><strong>Background: </strong>Efsubaglutide alfa, as a novel glucagon-like peptide-1 receptor agonist, was developed for the treatment of type 2 diabetes mellitus. Its effect on the rate and extent of absorption of concomitant oral medications (digoxin and metformin) was evaluated in healthy participants.</p><p><strong>Methods: </strong>We conducted a single-center, open-label, fixed-sequence clinical trial involving 32 healthy participants who were assigned to either digoxin (N = 16) or metformin (N = 16) groups. The participants received oral doses of digoxin (0.25 mg, single dose) or metformin (1000 mg at first dose, 500 mg twice daily for 2 days) before and after subcutaneous injections of 3 mg efsubaglutide alfa at steady state. Pharmacokinetic parameters of digoxin and metformin before and after the administration of efsubaglutide alfa injections were measured, and safety assessments were conducted throughout the study.</p><p><strong>Results: </strong>Efsubaglutide alfa slightly delayed the time to reach peak plasma concentration (T_max) of digoxin but had no substantial effect on its elimination. While the maximum concentration (C_max) of digoxin decreased by approximately 24% (from 1.75 ± 0.673 to 1.37 ± 0.545 ng/mL), and AUC_0-inf increased by about 15% (from 20.2 ± 3.53 to 23.2 ± 4.04 ng/h/mL). In the metformin group, efsubaglutide alfa did not noticeably affect T_max, C_max,ss, or the overall pharmacokinetics, as demonstrated by a consistent AUC_0-tau (from 7557 ± 2155 to 8737 ± 2852 ng/h/mL). Adverse events with efsubaglutide alfa and co-administered medication were comparable to those reported during treatment with efsubaglutide alfa alone and were mostly gastrointestinal-related.</p><p><strong>Conclusions: </strong>No clinically significant pharmacokinetic change of digoxin and metformin was identified, and no new safety issues were observed with the co-administration of efsubaglutide alfa injection. These findings suggest that no dose adjustments are required for digoxin and metformin when co-administration with efsubaglutide alfa.</p><p><strong>Clinicaltrials: </strong></p><p><strong>Gov identifier: </strong>NCT05694221.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 Pharmacodynamics Modeling for the Use of Recaticimab in Healthy Volunteers and Patients with Hypercholesterolemia.","authors":"Chang Shu, Ying Wang, Sheng Feng, Shengxian Yang, Kai Shen","doi":"10.1007/s40262-025-01512-5","DOIUrl":"https://doi.org/10.1007/s40262-025-01512-5","url":null,"abstract":"<p><strong>Introduction: </strong>Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein secreted by the liver that binds to low-density lipoprotein (LDL) receptors, which leads to a decreased ability of the liver to clear LDL-C from circulation. By inhibiting PCSK9, it is possible to provide early intervention to achieve clinical benefits.</p><p><strong>Methods: </strong>The database was built using data derived from seven clinical studies, population pharmacokinetic/pharmacodynamic (PopPK/PD) and PK/PD analyses were conducted via nonlinear mixed effects analysis with NONMEM software. The parameter estimation of the model was performed using the first-order conditional estimation with interaction (FOCE-I) method. The stepwise covariate method (SCM) was used to develop and evaluate the final model.</p><p><strong>Results: </strong>A target-mediated drug disposition model (TMDD) model and an indirect response model were developed to illustrated the PopPK profile and PK/PD profile of recaticimab. The PopPK final model was described as a one-compartment TMDD model with a combined residual error model. The PopPK/PD final model was described as an indirect response model with an additive residual error model. Body weight, body mass index, age, statin therapy, and sex were introduced on the model as significant covariates.</p><p><strong>Discussion: </strong>No adjustment of clinical dosage is required based on the PopPK and PopPK/PD covariates. Estimated glomerular filtration rate and anti-drug antibodies are not significant covariates for any PopPK parameter. After achieving a steady state, switching the dosing regimen and prolonging the dosing interval should not cause concerns about drug efficacy.</p><p><strong>Trial registration: </strong>NCT03634436, NCT03944109, NCT05370950, NCT04455581, NCT04849000, NCT04885218, NCT04844125.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 Model and Dosing Algorithm to Guide the Tacrolimus Starting and Follow-Up Dose in Living and Deceased Donor Kidney Transplant Recipients.","authors":"Marith I Francke, Sebastiaan D T Sassen, Nuria Lloberas, Helena Colom, Laure Elens, Serge Moudio, Aiko P J de Vries, Dirk Jan A R Moes, Ron H N van Schaik, Dennis A Hesselink, Brenda C M de Winter","doi":"10.1007/s40262-025-01533-0","DOIUrl":"https://doi.org/10.1007/s40262-025-01533-0","url":null,"abstract":"<p><strong>Introduction: </strong>Tacrolimus treatment is complicated by its narrow therapeutic range and large inter- and intra-patient variability. This study aimed to develop a population pharmacokinetic model and dosing algorithm to predict an individual's dose requirement following living and deceased donor kidney transplantation.</p><p><strong>Methods: </strong>In this international, multicenter, retrospective study, data was collected from patients who had received a living or a deceased donor kidney and received tacrolimus twice daily. A population pharmacokinetic model was developed using nonlinear mixed-effects modeling (NONMEM).</p><p><strong>Results: </strong>This study included 13,427 tacrolimus concentrations from 1180 kidney transplant recipients. A two-compartment model with first-order absorption best described the data. The mean absorption rate was 6.59/h, apparent clearance 20.7 L/h, central volume of distribution 705 L, and peripheral volume of distribution 7670 L. Higher age, creatinine, and hematocrit, as well as lower height, were associated with lower tacrolimus clearance. Tacrolimus clearance was higher for cytochrome P450 (CYP) 3A5*1 carriers compared with CYP3A5*3/*3 individuals, and lower for CYP3A4*22 carriers compared with CYP3A4*1/*1 patients. Together, these covariates explained 19.3% of the inter-individual variability in clearance. From the full model, a starting dose algorithm was developed with age, height, and the CYP3A4 and CYP3A5 genotypes as covariates. Both the full model and the starting dose algorithm were successfully internally validated.</p><p><strong>Conclusions: </strong>In this international, multicenter study, age, CYP3A4 and CYP3A5 genotype, creatinine, height, and hematocrit were identified as significant covariates associated with tacrolimus pharmacokinetics, and can be used to predict the optimal individual's dose requirement for both living and deceased donor kidney transplant recipients.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}