Clinical Pharmacokinetics最新文献

{"title":"Metformin Pharmacogenetics in Heart Failure Patients with Reduced Ejection Fraction: Impact on Metformin and Growth Differentiation Factor-15 Plasma Levels.","authors":"Anders Hostrup Larsen, Tore Bjerregaard Stage, Mette Marie Hougaard Christensen, Søren Feddersen, Flemming Nielsen, Helene Nørrelund, Jørgen Frøkiær, Niels Jessen, Kim Brøsen, Henrik Wiggers","doi":"10.1007/s40262-026-01699-1","DOIUrl":"https://doi.org/10.1007/s40262-026-01699-1","url":null,"abstract":"<p><strong>Background: </strong>This study assessed plasma metformin trough steady-state concentrations and plasma growth differentiation factor-15 (GDF-15) in patients with heart failure with reduced ejection fraction (HFrEF), and evaluated the effect of genetic variations in OCT1, OCT2, MATE1, and MATE2-K on metformin trough levels and GDF-15 levels.</p><p><strong>Methods: </strong>The study population comprised 109 HFrEF patients with type 2 diabetes on stable metformin treatment (median 1700 mg, range 500-3000) in an open-label design. Patients were genotyped for seven selected variants in OCT1, OCT2, MATE1 and MATE2-K. Plasma metformin trough measurements (288 samples) were obtained in triplicates with a median 7-day interval (interquartile range, 6-10 days). Plasma GDF-15 concentrations were measured once per patient.</p><p><strong>Results: </strong>Mean dose-normalised metformin trough concentrations were 508 ng/L/g (range 68-3515) with substantial interpatient variation (intraclass correlation coefficient 0.79). Metformin trough levels were independent of genetic variants in OCT1 (p = 0.12), OCT2 (p = 0.10) and MATE1 (p = 0.95), after adjustment for estimated glomerular filtration rate (eGFR) and time since last tablet intake. MATE2-K was excluded due to insufficient variant frequency. Metformin dose correlated with trough concentrations (R² = 0.36, p < 0.001), and metformin trough concentrations correlated with NT-proBNP levels (R² = 0.31, p < 0.001) and with GDF-15 levels (R² = 0.51, p < 0.001). GDF-15 levels were independent of genetic variants in OCT1, OCT2, and MATE1, after adjustment for eGFR and time since last tablet intake.</p><p><strong>Conclusions: </strong>In HFrEF patients, transporter genetic variants in OCT1, OCT2, and MATE1 did not influence metformin trough steady-state concentrations or circulating GDF-15 levels. Metformin trough levels display large (50-fold) interpatient variability and a dose-dependent relationship.</p><p><strong>Clinical trial registration: </strong>URL: https://clinicaltrials.gov . Unique identifier: NCT02797340.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149073709","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":"Comparing the Predictive Performance of Machine Learning Models with a Newly Developed Population Pharmacokinetic Model for Busulfan in Paediatric Patients.","authors":"Tianwu Yang, Maria Thastrup, Tania Nicole Masmas, Hilde Hylland Uhlving, Jacob Nersting, Malene Johanne Petersen, Anna Sofie Buhl Rasmussen, Kjeld Schmiegelow, Trine Meldgaard Lund","doi":"10.1007/s40262-026-01702-9","DOIUrl":"https://doi.org/10.1007/s40262-026-01702-9","url":null,"abstract":"<p><strong>Background and objectives: </strong>Busulfan, used in conditioning regimens prior to haematopoietic stem cell transplantation, has a narrow therapeutic index; therefore, due to pharmacokinetic variability, therapeutic drug monitoring (TDM) is employed to ensure drug exposure levels associated with optimal clinical outcomes. This study aimed to facilitate dose adjustment and potentially reduce the number of samples required for TDM in clinical practice.</p><p><strong>Methods: </strong>Population pharmacokinetic (popPK) and machine learning (ML) models (Random Forest and XGBoost) were developed using a local, retrospective, extensive-sampling dataset of 67 children (637 observations, Denmark) and externally evaluated using prediction error (PE) on a TDM dataset from another centre with 171 children (1871 observations, Netherlands). Limited sampling schedules were evaluated for both methods.</p><p><strong>Results: </strong>A one-compartment model was the best data fit, showing time-varying clearance decreases of 10.4% and 13% on Days 2 and 3, respectively, compared to Day 1. The popPK, Random Forest, and XGBoost models performed well on the external dataset for concentration prediction, with median PE ranging from -4.82 to -7.44%, median absolute PE of approximately 15%, and approximately 80% of data predicted within ±30% of the PE. Sampling strategies at 0, 0.5, 1, 4 h or 0, 1, 2, 4 h post-infusion adequately predicted busulfan plasma concentration and exposure using the popPK model.</p><p><strong>Conclusions: </strong>A new popPK model was developed to support individualised dose adjustments in children using fewer blood samples. Both Random Forest and XGBoost could predict busulfan's plasma concentration with performance like that of the popPK model (population prediction). However, a larger dataset is needed for ML methods to describe a complete pharmacokinetic profile.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149024272","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":"PBPK Modeling of Coproporphyrin I Reveals Frailty-Associated Changes in Hepatic OATP1B1 Function in Chinese Adults.","authors":"Longjie Li, Mengfan Ye, Wenhang Xu, Xinyan Zhu, Like Xie, Haiping Xu, Qingfeng He, Xiao Zhu, Xiaoqiang Xiang, Juan Xie","doi":"10.1007/s40262-026-01704-7","DOIUrl":"https://doi.org/10.1007/s40262-026-01704-7","url":null,"abstract":"<p><strong>Objectives: </strong>Understanding variability in hepatic organic anion transporting polypeptide 1B1 (OATP1B1) activity is essential for optimizing drug therapy and predicting drug-drug interactions. Coproporphyrin I (CPI) is an endogenous OATP1B1 substrate and a noninvasive biomarker of transporter function. However, CPI disposition in Chinese adults remains insufficiently characterized. This study aimed to characterize CPI variability in Chinese adults and apply physiologically based pharmacokinetic (PBPK) modeling to quantify OATP1B1 variability and explore clinical implications.</p><p><strong>Methods: </strong>Serum CPI concentrations were measured in 122 Chinese inpatients. Variability across age, sex, and frailty status was evaluated. Coproporphyrin I-specific disposition processes were implemented and parameterized within the standard whole-body PBPK structure of PK-Sim^®. External PBPK models for Caucasian, Indian, and Japanese populations were constructed using reported CPI synthesis rates. Model-based simulations were performed to evaluate frailty-associated changes in OATP1B1 function and rosuvastatin exposure under different dosing scenarios.</p><p><strong>Results: </strong>Coproporphyrin I concentrations increased with age and frailty severity. PBPK analyses suggested that hepatic OATP1B1 functional abundance in frail Chinese older adults may be reduced by approximately 40.9% relative to non-frail individuals. The PBPK model reproduced CPI disposition across demographic subgroups and external populations. Simulations indicated that rosuvastatin exposure increased from adults to non-frail elderly and further to frail elderly individuals, with exposure at 5 mg in frail elderly individuals comparable to that at 10 mg in adults.</p><p><strong>Conclusions: </strong>This study provides a PBPK framework for interpreting CPI variability and quantifying frailty-associated changes in OATP1B1 function in Chinese adults, supporting biomarker-informed precision dosing of OATP1B1 substrate drugs.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016054","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":"Towards Model-Informed Precision Dosing of High-Dose Rifampicin: A Parsimonious Population Pharmacokinetic Model Capturing Saturation and Autoinduction in Tanzanian and South African Patients with Tuberculosis.","authors":"Yuan J Petermann, Bibie Said, Margaretha L Sariko, Yann Thoma, Stellah G Mpagama, Chantal Csajka, Monia Guidi","doi":"10.1007/s40262-026-01674-w","DOIUrl":"https://doi.org/10.1007/s40262-026-01674-w","url":null,"abstract":"<p><strong>Background: </strong>Rifampicin, a cornerstone of tuberculosis treatment, exhibits complex pharmacokinetics with variable absorption, saturable elimination and time-dependent autoinduction, together with marked inter- and intra-individual variability in drug exposure. These properties challenge standard weight-based dosing and underscore the need for individualized strategies, particularly in high-burden settings like Tanzania. While therapeutic drug monitoring (TDM) supported by model-informed precision dosing (MIPD) is being implemented, few of the existing population pharmacokinetic (popPK) models includes Tanzanians and are parsimonious.</p><p><strong>Objective: </strong>This study aimed to develop a parsimonious popPK model of rifampicin that successfully captures both its autoinductive and saturable elimination components, achieving predictive performance comparable to more complex reference models described in the literature.</p><p><strong>Methods: </strong>Rifampicin concentrations data from 42 Tanzanian and 92 South African patients, covering doses up to 50 mg/kg over 2 weeks were used to develop the model, which was further benchmarked against literature reference models.</p><p><strong>Results: </strong>The chosen model employed a one-compartment structure with Michaelis-Menten elimination and a time-dependant E_max-based autoinduction function. The final model demonstrated individual Bayesian predictive performance comparable to two complex reference popPK models, and confirmed substantial inter-individual variability in exposure, with exposures differing by up to fivefold within the same weight-based dosing cohort.</p><p><strong>Conclusion: </strong>These findings support the implementation of MIPD and TDM to improve efficacy and safety in TB treatment rather than relying on a uniform dosing approach based on bodyweight. This model provides a robust foundation for individualized dosing and the deployment of clinical decision support tools in high TB burden settings.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148975753","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":"From Clinical Trials to Real-World Patients: Population Pharmacokinetics and Precision Dosing Simulations of Lorlatinib.","authors":"Laura H Bukkems, Benoit Blanchet, Jennifer Arrondeau, Marie Wislez, Yan Wang, Henk-Jan Guchelaar, Egbert Smit, Dirk Jan A R Moes, Alicja Puszkiel","doi":"10.1007/s40262-026-01697-3","DOIUrl":"https://doi.org/10.1007/s40262-026-01697-3","url":null,"abstract":"<p><strong>Background and objective: </strong>The pharmacokinetics of lorlatinib have been characterized in a population pharmacokinetic (PK) model by the license holder, but external validation with real-world data is lacking. As higher trough concentrations are linked to increased toxicity, there may be a role for model-informed precision dosing (MIPD).</p><p><strong>Methods: </strong>The published lorlatinib population PK model was externally validated using data from 150 patients with non-small cell lung cancer (NSCLC) treated in France and the Netherlands. Model performance was assessed using mean percentage error (MPE) and mean absolute percentage error (MAPE). Suboptimal validation results led to development of a refined population PK model, which was subsequently used to simulate lorlatinib exposure across different doses. A MIPD strategy targeting trough concentrations of 75-125 ng/mL was assessed.</p><p><strong>Results: </strong>External validation revealed significant bias (MPE: -6.1%, 95% CI -11.1 to -0.5%), with the original population PK model systematically underestimating trough concentrations. The refined model included a lower clearance (13.7 versus 14.5 L/h). Simulations with the refined model predicted a median steady state trough level of 127.0 ng/mL (IQR: 96.1-162.0 ng/mL) versus 106.0 ng/mL with the original model for standard 100 mg once-daily (QD) regimen. MIPD increased the proportion of patients within target range from 35 to 62% after one cycle of dose adjustment.</p><p><strong>Conclusions: </strong>The published population PK model underestimates real-world trough concentrations, underscoring the importance of external validation of clinical trial-derived models. The refined model reflects lorlatinib pharmacokinetics in clinical practice better. Simulations suggest that lower lorlatinib doses may be feasible and MIPD may reduce toxicity.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148900205","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":"Target Attainment and Clinical and Biochemical Parameters Associated with the Pharmacokinetics of 12 Tyrosine Kinase Inhibitors.","authors":"Zaid N Al Shirity, Paola Mian, Anouk Dontje, Anthonie J van der Wekken, Esther Broekman, Saskia K Klein, Daan J Touw, Thijs H Oude Munnink, Marjolijn N Lub-de Hooge, Bahez Gareb","doi":"10.1007/s40262-026-01684-8","DOIUrl":"https://doi.org/10.1007/s40262-026-01684-8","url":null,"abstract":"<p><strong>Background and objective: </strong>Tyrosine kinase inhibitors (TKIs) are targeted cancer therapies. However, TKIs are still limited due to their high inter-individual variability. This study evaluated target attainment using therapeutic drug monitoring (TDM) data from 12 TKIs, and investigated biochemical and patient-related characteristics influencing TKI pharmacokinetics (PK) METHODS: This single-centre retrospective study included cancer patients treated with TKIs between January 2020 and August 2024. Demographic, clinical, and biochemical data were extracted from electronic health records. Univariate and multivariate linear mixed models were used to identify factors associated with TKI PK.</p><p><strong>Results: </strong>A total of 1237 TKI concentrations from 309 patients were included. Target attainment percentages were: 74.6% for alectinib; 70% for bosutinib; 49.9-61.9% for imatinib depending on the indication; 88.9% for nilotinib; 50% for pazopanib; 50% for ponatinib; 89.5% for regorafenib; 26.6% for sunitinib; ibrutinib, lenvatinib and trametinib had too few data for formal assessment; 40-87.5% for dasatinib, depending on indication and parameter (C_max or C_min). A mixed linear model analysis identified key parameters correlated with TKI concentrations. Glomerular filtration rate was correlated with alectinib, imatinib, and sunitinib. Alkaline phosphatase (ALP), bilirubin, and Gamma-GT correlated with alectinib and ALP with imatinib. Albumin and thrombocytes correlated with imatinib, thrombocytes with pazopanib, absolute neutrophiles count (ANC) with ponatinib, and haematocrit with regorafenib.</p><p><strong>Conclusion: </strong>Target attainment was suboptimal for most TKIs, supporting the need for TDM-guided optimisation and individualised dosing. Associations between TKI exposure and renal, hepatic, and haematological parameters further support personalised treatment strategies.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891045","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":"Simulation-Based Predictions to Support the Development of a Pediatric Fixed-Dose Combination of Dolutegravir/Emtricitabine/Tenofovir Alafenamide Fumarate.","authors":"Hylke Waalewijn, Lisanne A H Bevers, Linda L Lewis, Margaret D Louey, Sonoko Kawakatsu, Yanan Zheng, Carlo Giaquinto, Alessandra Nardone, David M Burger, Rob Ter Heine, Angela Colbers, Elin M Svensson","doi":"10.1007/s40262-026-01671-z","DOIUrl":"10.1007/s40262-026-01671-z","url":null,"abstract":"<p><strong>Background and objective: </strong>Approximately 1.4 million children (aged 0-14 years) are living with human immunodeficiency virus, most infected through mother-to-child transmission. Despite the availability of combination antiretroviral treatment, only 57% of children had access to combination antiretroviral treatment in 2023, with suboptimal formulations contributing to high mortality. Limited access to age-appropriate formulations is a key barrier, particularly in low- and middle-income countries. This study presents stochastic simulations with previously published population pharmacokinetic models to determine an optimal fixed-dose combination (FDC) ratio of dolutegravir (DTG), emtricitabine (FTC), and tenofovir alafenamide (TAF) for children weighing 3-20 kg. For children weighing more than 20 kg, the use of the adult FDC formulation is proposed.</p><p><strong>Methods: </strong>Population pharmacokinetic models were used for exposure simulation of DTG, TAF, and its metabolite tenofovir. The adequacy of the proposed FDC was based on whether the simulated drug exposures met predefined efficacy and safety targets. For DTG, the minimum trough concentration target of 0.32 mg/L; for TAF, the area under the curve (AUC) target of 55 ng*h/mL; and for tenofovir, the maximum AUC of 2586 ng*h/mL were used. Simulated exposures were also compared to adult reference values: geometric mean trough concentration for DTG (0.83 mg/L), median AUC for TAF (185 h*ng/mL), and median AUC for tenofovir (256 h*ng/mL). The US Food and Drug Administration-recognized dosing range for FTC was used to verify appropriate dosing in each weight band.</p><p><strong>Results: </strong>The modeling approach identified a practical FDC dosing ratio for children across weight bands (3-20 kg). Simulated DTG exposure exceeded the minimum target in over 98% of cases, while TAF exposure met the efficacy threshold in more than 90% of children. Tenofovir exposure remained below toxic concentrations in all weight bands, ensuring safety. In a small subset of children aged under 3 months, FTC doses exceeded the approved maximum, though overall dosing remained within safe limits.</p><p><strong>Conclusions: </strong>This paper presents a modeling approach to determine an optimal FDC ratio for pediatric DTG/FTC/TAF. The strategy predicted effective drug exposure and safety across age and weight bands, supporting the development of a child-friendly FDC that could accelerate access to human immunodeficiency virus treatment in low- and middle-income countries. This dosing regimen is being further evaluated in the UNIVERSAL-1 clinical trial.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1405-1414"},"PeriodicalIF":4.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13545028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618522","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":"Pharmacokinetics, Safety, and Dosing of Antiseizure Medications in Patients with Renal or Hepatic Impairment.","authors":"Jingheng Wu, Miaomiao Li, Shuai Wang","doi":"10.1007/s40262-026-01691-9","DOIUrl":"10.1007/s40262-026-01691-9","url":null,"abstract":"<p><p>Ten newer antiseizure medications (ASMs) approved since 2000 and selected for this review (cenobamate, brivaracetam, eslicarbazepine acetate, lacosamide, perampanel, fenfluramine, ganaxolone, cannabidiol, stiripentol, and rufinamide) have broadened treatment options for drug-resistant epilepsy. However, concurrent renal or hepatic impairment alters drug disposition through diminished clearance, shifted protein binding equilibria, accumulation of active metabolites, and variable dialytic removal that standard dosing fails to accommodate. Despite the rising clinical overlap of epilepsy with chronic kidney and liver diseases, consolidated prescribing guidance for these agents in organ-impaired populations remains limited. This narrative review synthesizes pharmacokinetic data from pivotal development programs together with current regulatory labeling issued by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) through 2025 for all ten agents across graded severities of renal and hepatic impairment. Brivaracetam, rufinamide, and cannabidiol proved minimally susceptible to renal decline, whereas eslicarbazepine acetate required no hepatic dose adjustment in mild-to-moderate disease. Conversely, cenobamate and perampanel necessitate strict dose caps or avoidance in severe organ dysfunction, and stiripentol is precluded in any degree of organ impairment owing to unpredictable nonlinear Michaelis-Menten kinetics. Regulatory discrepancies between FDA and EMA labeling were identified for all ten agents, notably divergent hepatic dose caps for perampanel and cenobamate, conflicting renal recommendations for fenfluramine, and discordant guidance for eslicarbazepine acetate in severe renal impairment. These agents exhibit no uniform class effect in organ impairment; prescribing must be governed by agent-specific disposition profiles, organ-function severity, and free-drug monitoring for highly protein-bound agents like perampanel and ganaxolone.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1317-1337"},"PeriodicalIF":4.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788504","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 Review of Population Pharmacokinetic Models and Dosing Algorithms Assessing the Influence of CYP3A5 Genotype and Other Clinical Covariates on Tacrolimus Pharmacokinetics.","authors":"Riley M Randolph, Sara Jubas, Li Gong, Raman Venkataramanan, Dhrita Khatri, Pamala A Jacobson, David Metz, Daniel J Crona","doi":"10.1007/s40262-026-01673-x","DOIUrl":"10.1007/s40262-026-01673-x","url":null,"abstract":"<p><p>Tacrolimus is a narrow therapeutic index drug with wide intrapatient and interpatient pharmacokinetic variability and cytochrome P450 3A5 (CYP3A5) genotype-guided dosing recommendations. This review aimed to evaluate population pharmacokinetic models and dosing algorithms across all treatment settings that analyzed the influence of CYP3A5 genotypic variation plus additional clinical covariates on tacrolimus pharmacokinetics. These effects were mathematically translated and summarized to provide a comparison between models. Changes in apparent clearance warranting tacrolimus dose adjustments were assessed and summarized by relative magnitude and direction. Sixty-eight tacrolimus population pharmacokinetic models were included in this review, including 55 developed for adults and 38 for kidney transplant recipients. The most frequently retained covariates on tacrolimus clearance were CYP3A5 genotype (88%), body size (29%), hematocrit (29%), and days since transplant (28%). The median fold increase in apparent clearance, across all treatments, was 1.64 for CYP3A5 normal and intermediate metabolizer patients compared to poor metabolizer patients. As days since transplant increased, median tacrolimus apparent clearance increased in liver (n = 6) and lung transplant (n = 2) models but decreased early post-transplant and then subsequently increased in kidney transplant models (n = 11). Concomitant administration of tacrolimus with -azole antifungals or Wuzhi capsules was associated with reduced tacrolimus apparent clearance (38% and 31%, respectively), while corticosteroids were associated with a 23% increase in apparent clearance. Based on our analysis, a substantial tacrolimus dose increase (≥ 75%) is required for CYP3A5 normal and intermediate metabolizer patients compared with poor metabolizer patients. Ultimately, these findings can be used to determine optimal personalized tacrolimus doses across a variety of disease states and treatment types.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1295-1315"},"PeriodicalIF":4.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148535462","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":"Pharmacometric Targets During Anti-TNF Induction and Their Association with Deep Remission in Pediatric Crohn's Disease.","authors":"Alexander Nasr, Tomoyuki Mizuno, Kei Irie, Jonathan R Dillman, Kimberly Jackson, Kimberly Lynch, Alexa Horrell, Thomas Aviles, Kelly Chun, Jane Yang, Brendan Boyle, Jeffrey S Hyams, Joshua Noe, Lee A Denson, Phillip Minar","doi":"10.1007/s40262-026-01685-7","DOIUrl":"10.1007/s40262-026-01685-7","url":null,"abstract":"<p><strong>Background and objective: </strong>Personalizing anti-tumor necrosis factor (TNF) therapy in pediatric Crohn's disease (CD) remains challenging due to variable drug clearance and response. Identifying pharmacokinetic (PK) and pharmacodynamic (PD) predictors of deep remission could enable precision dosing strategies. The primary aim was to define PK metrics and PD biomarkers associated with deep remission.</p><p><strong>Methods: </strong>Patients initiating infliximab or adalimumab were prospectively enrolled from four pediatric centers with longitudinal blood and stool biospecimens collected for one year. Deep remission was defined as a combination of weighted pediatric CD activity index (wPCDAI) < 12.5 and Simple Endoscopic Score-CD < 3. Trough concentrations (cTrough) were measured throughout the study. Drug exposure (area under the curve, AUC) and clearance were estimated using drug-specific population PK models and Bayesian estimation using nonlinear mixed-effects modeling (NONMEM).</p><p><strong>Results: </strong>Deep remission was achieved in 34/70 (48.6%) with no difference in outcomes between biologics. Infliximab cTrough thresholds associated with deep remission were 33 µg/mL (Week 2), 15 µg/mL (Week 6), and 4.7 µg/mL (Month 3) with Week 6 cTrough targets ranging 15-26 µg/mL depending on the outcome of interest. Higher AUC during induction for both infliximab and adalimumab was associated with deep remission, whereas rapid infliximab clearance at various timepoints was inversely associated with deep remission. Baseline predictors of rapid infliximab clearance included older age, low albumin, and elevations in body mass index, C-reactive protein, soluble CD64, and wPCDAI.</p><p><strong>Conclusions: </strong>We identified PK/PD cut-points associated with deep remission and rapid infliximab clearance, providing actionable metrics to individualize induction dosing and optimize maintenance therapy for children starting anti-TNF therapy.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1353-1365"},"PeriodicalIF":4.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13545114/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148590862","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}