Clinical Pharmacokinetics最新文献

{"title":"Collecting Metabolite Pharmacokinetics in Drug-Drug Interaction Studies: A Review of Industry Practices and Data Utilization.","authors":"Tatyana Dubich, Thijs van Iersel, Kamelia Mirdamadi, Ewoud-Jan van Hoogdalem","doi":"10.1007/s40262-026-01657-x","DOIUrl":"10.1007/s40262-026-01657-x","url":null,"abstract":"<p><strong>Introduction: </strong>Systemic exposure of a sensitive probe is considered a 'gold standard' for assessment of clinical relevance of a potential cytochrome P450 (CYP)-driven drug-drug interaction (DDI). Typically, the change in systemic exposure is judged by the area under the concentration-time curve [AUC]) of the parent, but sometimes metabolite exposure is used to further elucidate the mechanism of the DDI.</p><p><strong>Methods: </strong>For this review, we retrieved records of clinical DDI studies conducted between September 2014 and September 2024 for commonly used CYP probes (midazolam [CYP3A4], flurbiprofen [CYP2C9], omeprazole [CYP2C19], bupropion [CYP2B6], repaglinide [CYP2C8], and dextromethorphan [CYP2D6]). We reviewed these records for reported systemic or urinary metabolite endpoints, concordance of parent and metabolite results, and utilization of metabolite data in clinical recommendations reflected in the label of the investigational medicinal product (IMP).</p><p><strong>Results: </strong>Although DDI studies with probes primarily metabolized by a single pathway (i.e. midazolam, flurbiprofen, omeprazole) often included metabolite endpoints, metabolite data did not add additional sensitivity in detecting the DDI and often were not used in the label recommendations. In contrast, DDI studies with probes that are metabolized by several pathways (i.e. bupropion, repaglinide) demonstrated a higher sensitivity of metabolite-to-parent ratio to detect a DDI compared with use of the parent AUC alone. Urinary phenotyping indexes (as exemplified by dextromethorphan) are rarely collected.</p><p><strong>Conclusions: </strong>Based on these findings, we formulated criteria for deciding on the relevance of metabolite endpoints in clinical DDI studies.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"995-1011"},"PeriodicalIF":4.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148148836","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":"Advancing Precision Dosing of 5-FU: Population PK Model Development, Limited Sampling Strategies, and Fit-for-Use Application.","authors":"Zhiyuan Tan, Aymara Sancho-Araiz, Swantje Völler, Sofía L J Peeters, Thomas Manten, Maarten J Deenen, Jan Gerard Maring, Pierre M Bet, Ron A A Mathôt, Catherijne A J Knibbe, Dirk Jan A R Moes","doi":"10.1007/s40262-026-01645-1","DOIUrl":"10.1007/s40262-026-01645-1","url":null,"abstract":"<p><strong>Background: </strong>A significant proportion of patients receiving 5-fluorouracil-based chemotherapy have been reported to experience grade ≥ 3 toxicities, which range from 21 to 76% depending on the treatment regimen. This may in part be due to interpatient variability in pharmacokinetics. More recently, only about 20% of the patients were reported to achieve the target area under the concentration-time curve from time zero to infinity of 20-30 mg*h/L.</p><p><strong>Objective: </strong>We aimed to evaluate existing population pharmacokinetic models and develop a final pharmacokinetic model. In addition, we aimed to identify optimal limited sampling strategies to accurately estimate individual area under the concentration-time curve from time zero to infinity, facilitating model-informed precision dosing using a fit-for-use application.</p><p><strong>Methods: </strong>Patient data from four prospective clinical studies were obtained. Published 5-fluorouracil population pharmacokinetic models were evaluated. A final model was developed, and limited sampling strategies were identified. A user-friendly model-informed precision dosing application was created for initial and subsequent dose adjustments.</p><p><strong>Results: </strong>Using the published models, population predictions resulted in underestimation of observed concentrations and misspecification of a 24-h infusion regimen were observed, with the two-compartment Michaelis-Menten model outperforming the other model structures. Of this model, the parameters were re-estimated and covariates analysis was conducted. Body surface area significantly influenced the maximum rate of reaction and was implemented using allometric scaling with an exponent of 1.14 (relative standard error 24%). For a bolus in combination with a 46-h continuous infusion, the best limited sampling strategy was T = 0.1 (end of bolus), 1 and 3 h after treatment initiation; while for the 46-h continuous infusion, the optimal limited sampling strategy was T = 0.8, 2, and 5 h. Model-informed precision dosing algorithms were implemented in an model-informed precision dosing application.</p><p><strong>Conclusions: </strong>The external evaluation of 5-fluorouracil population pharmacokinetic models against a pooled prospective population resulted in a generic two-compartment Michaelis-Menten pharmacokinetic model with body surface area as a covariate on the maximum rate of reaction. The limited sampling strategy and the shiny model-informed precision dosing application demonstrated the potential for accurate dose individualization of 5-fluorouracil.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1027-1042"},"PeriodicalIF":4.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13356066/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147986949","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":"Vutrisiran-Mediated Knockdown of Transthyretin in Patients with ATTR Amyloidosis.","authors":"Marianna Fontana, Vincent Algalarrondo, Pablo Garcia-Pavia, Mathew S Maurer, Julian D Gillmore, Francesco Cappelli, Kiranmai Kolachana, Xiuqing Gao, Satyawan Jadhav, Nitin Mehrotra, Gabriel Robbie, Prajakta Badri","doi":"10.1007/s40262-026-01651-3","DOIUrl":"10.1007/s40262-026-01651-3","url":null,"abstract":"<p><strong>Background and objective: </strong>We assessed the consistency of serum transthyretin (TTR) knockdown with the RNA interference therapeutic vutrisiran across subpopulations of patients with hereditary TTR amyloidosis (ATTR) with polyneuropathy (ATTRv-PN) in HELIOS-A (NCT03759379) and ATTR with cardiomyopathy (ATTR-CM) in HELIOS-B (NCT04153149).</p><p><strong>Methods: </strong>Patients received vutrisiran 25 mg subcutaneously every 3 months (Q3M). Serum TTR was measured during randomized treatment through Month 18 in HELIOS-A (post-dose/peak and pre-dose/trough sampling) and Month 30 in HELIOS-B (trough only, except Week 6). The effects of intrinsic/extrinsic factors on serum TTR knockdown from baseline were assessed. Pharmacokinetic/pharmacodynamic modeling was used to support consistency in TTR knockdown between studies.</p><p><strong>Results: </strong>Observed median (95% confidence interval [CI]) serum TTR knockdown with vutrisiran was 64.2% (61.6-67.8) at Week 3 (n = 114), with steady-state trough knockdown 86.2% (84.1-92.6) (n = 118) in HELIOS-A, and 69.0% (66.0-72.0) at Week 6 (n = 294), with steady-state trough knockdown 82.5% (80.5-84.9) (n = 307) in HELIOS-B. There were no meaningful differences in serum TTR percent knockdown across subgroups defined by baseline characteristics, including age, sex, ethnicity/race, weight, TTR genotype, N-terminal pro-B-type natriuretic peptide, and serum TTR concentration (both studies), and ATTRwt/ATTRv, disease stage/severity, troponin I, and tafamidis use (HELIOS-B), or anti-drug antibodies. Model-predicted peak serum TTR knockdown in HELIOS-B was sustained and consistent with observed knockdown in HELIOS-A; predicted median (95% CI) reduction at Month 30 was 87.1% (84.8-89.4).</p><p><strong>Conclusions: </strong>Vutrisiran led to rapid, sustained, and consistent TTR knockdown in HELIOS-A and HELIOS-B, supporting fixed-dose vutrisiran 25 mg Q3M across patients with ATTRv-PN and ATTR-CM.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1073-1085"},"PeriodicalIF":4.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13356086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148027643","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":"Therapeutic Drug Monitoring of Imatinib in Paediatric Chronic Myeloid Leukaemia: Towards Practical Implementation and Interpretation of Measured Plasma Concentrations.","authors":"Phyllis Lensker, Andrea Gottschalk, Thomas Zerjatke, Ingo Roeder, Martin F Fromm, Frank Dörje, Meinolf Suttorp, Manfred Rauh, Ingmar Glauche, Markus Metzler","doi":"10.1007/s40262-026-01644-2","DOIUrl":"10.1007/s40262-026-01644-2","url":null,"abstract":"<p><strong>Background and introduction: </strong>Imatinib (IMA) revolutionised the treatment of chronic myeloid leukaemia (CML). Therapeutic drug monitoring (TDM) of IMA is recommended to improve treatment outcomes in adults, but guidance for reliable interpretation of plasma concentrations in children is limited. Using real-world paediatric data, we aimed to develop a practical algorithm with recommendations for an IMA TDM procedure in paediatric oncology.</p><p><strong>Methods: </strong>Imatinib plasma concentrations and clinical data were collected from patients enrolled in the multicentre CML-PAED-II study and subsequent registry. We evaluated the method of exponential extrapolation for estimating interpretable IMA trough concentrations and used linear mixed effects models to assess plasma concentration predictors. Associations between IMA trough concentrations and molecular response were analysed, and a paediatric-specific target threshold was evaluated. Findings were integrated into an algorithm for clinical application of IMA TDM.</p><p><strong>Results: </strong>In total, 269 IMA trough concentrations from 72 patients and BCR::ABL1/ABL1 transcript ratios from 50 patients were included. Using a correction tool, we obtained estimates of trough concentration by exponential extrapolation. Administered IMA dose was the main predictor of plasma concentrations. Higher trough concentrations tended to correlate with faster initial molecular response. The adult-derived target threshold of 1000 ng/mL proved applicable in paediatric practice. The developed algorithm outlines clinical decision points and consequences, which are key elements of existing intensified clinical pharmacological/pharmaceutical care programmes during oral antitumour therapy.</p><p><strong>Conclusion: </strong>The algorithm supports the use of TDM during paediatric IMA treatment, enabling early identification of exposure below the targeted concentration and variations in treatment efficacy to further improve treatment outcomes.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1013-1026"},"PeriodicalIF":4.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13356057/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147971177","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":"Development and Clinical Application of a Real-World Population Pharmacokinetic Model of Rivaroxaban in Asian Patients with Atrial Fibrillation.","authors":"Nian-Shiuan Lai, Chun-Jung Lin, Ching-Hua Kuo, Yu-Fong Peng, Sung-Chun Tang, Chih-Fen Huang, Shin-Yi Lin, Shu-Wen Lin","doi":"10.1007/s40262-026-01650-4","DOIUrl":"10.1007/s40262-026-01650-4","url":null,"abstract":"<p><strong>Background: </strong>Rivaroxaban, a factor Xa inhibitor, is used to prevent stroke in patients of atrial fibrillation (AF). This study aimed to establish a population pharmacokinetic (PPK) model for rivaroxaban using real-world data, apply it to concentration prediction, and investigate the association between drug exposure and clinical outcomes.</p><p><strong>Methods: </strong>Patients with AF receiving rivaroxaban were enrolled from an observational cohort (2016-2023) to measure plasma concentrations. An independent cohort was randomly selected to validate the PPK model. Clinical outcomes of interest included stroke or systemic thromboembolism, and major bleeding.</p><p><strong>Results: </strong>A total of 226 patients contributed to 452 rivaroxaban concentration measurements. Rivaroxaban pharmacokinetics were adequately described using a one-compartment model with first-order elimination. The estimated apparent clearance (CL/F) and the volume of distribution (V/F) were 6.13 L/h and 45.57 L, respectively. CL/F was significantly influenced by creatinine clearance and concomitant use of cytochrome 3A4 or P-glycoprotein inhibitors, whereas V/F was associated with lean body weight. External validation demonstrated a good predictive performance at the individual level. Patients with low trough concentrations tended to have an increased risk of systemic thromboembolism, whereas those with high trough concentrations tended to have a higher risk of major bleeding.</p><p><strong>Conclusions: </strong>In an Asian population, rivaroxaban pharmacokinetics are influenced by renal function, lean body weight, and drug interactions. The developed PPK model facilitates the estimation of rivaroxaban concentrations at standardized timepoints from random samples. This provides a practical tool for standardized exposure assessment and the identification of patients at risk for adverse clinical outcomes.</p><p><strong>Registration: </strong>ClinicalTrials.gov identifier no. NCT05333666.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"929-941"},"PeriodicalIF":4.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13272223/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147962401","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":"Precision Dosing of Vancomycin: A Systematic Review of Population Pharmacokinetics Models and Comparative Evaluation of Software Tools.","authors":"Nada Dia, Yannick Hoffert, Angela Elma Edwina, Jos Tournoy, Isabel Spriet, Erwin Dreesen","doi":"10.1007/s40262-026-01638-0","DOIUrl":"10.1007/s40262-026-01638-0","url":null,"abstract":"<p><strong>Background and objectives: </strong>Vancomycin is a widely used antibiotic with a narrow therapeutic window and considerable pharmacokinetic variability, necessitating accurate and precise dosing. Population pharmacokinetics (popPK) models have become essential for facilitating model-informed precision dosing (MIPD) of vancomycin. We aimed to summarise and compare popPK models of vancomycin and evaluate MIPD software modules incorporating these models.</p><p><strong>Methods: </strong>We systematically searched PubMed, EMBASE, and reference lists of relevant articles from inception through 01 January 2026 to identify articles describing the development of compartmental, one-stage parametric popPK models based on data from adult patients (aged ≥ 18 years) receiving intravenous vancomycin. We extracted and summarised key information on study design, patients, vancomycin dosing regimens, sampling strategies, quantification methods, modelling techniques, and covariates. We contacted providers of MIPD software tools and invited them to complete an online questionnaire assessing the features and clinical integration of their vancomycin module. We evaluated the incorporated models and their clinical applicability.</p><p><strong>Results: </strong>We identified 99 adult-applicable vancomycin popPK models across 97 articles: 48 (48.5%) were one-compartment, 47 (47.5%) two-compartment models, and 4 (4.0%) three-compartment models. Kidney function estimators and body weight metrics were the most commonly retained covariates on clearance and volume of distribution, respectively. Of 18 identified MIPD software tool providers, 13 (72.2%) completed the questionnaire, confirming the inclusion of vancomycin modules. These tools incorporated a total of 101 vancomycin models, of which 48 were intended for adults. Three tools had been evaluated in prospective non-interventional studies, and two in a prospective interventional trial. Five tools were certified as conforming to European Union (EU) regulatory standards under the Medical Devices Directive and were in the process of obtaining EU conformity under the Medical Device Regulation. Mapping published models to tool implementations revealed partial overlap, limited transparency on model selection and lack of model‑level external validation, underscoring the need for structured evaluation before routine clinical adoption.</p><p><strong>Conclusion: </strong>This review presents a comprehensive overview of vancomycin popPK models and MIPD software modules for adult patients. Our findings highlight the diversity among popPK models and the need for standardised reporting, transparent model selection, and prospective evaluation to support clinical implementation of MIPD.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"795-809"},"PeriodicalIF":4.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834255","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":"Evaluating Bayesian Vancomycin Dosage Adjustment in Neonates: A Simulation-Based Virtual TDM Study.","authors":"Anne Ravix, Yann Thoma, Annie Cathignol, Paul Thoueille, Catia Marzolini, Eric Giannoni, Thierry Buclin, Chantal Csajka, Kim Dao, Monia Guidi","doi":"10.1007/s40262-026-01642-4","DOIUrl":"10.1007/s40262-026-01642-4","url":null,"abstract":"<p><strong>Background and objectives: </strong>Therapeutic drug monitoring (TDM) of vancomycin, ideally based on the ratio of the daily area under the curve to the minimal inhibitory concentration at steady state (AUC_24,SS/MIC), is hindered by sampling limitations in neonates, so trough concentration (C_trough) is often used as a surrogate. This virtual TDM study aimed to evaluate the performance of Bayesian model-informed precision dosing (MIPD) for vancomycin in neonates.</p><p><strong>Methods: </strong>Reference pharmacokinetic (PK) parameters and drug concentrations were simulated in NONMEM for 1000 virtual neonates using a published population PK model. Four TDM strategies were compared based on the percentage of patients achieving an AUC_24,SS/MIC between 360 and 540 h. Strategy 1 maintained the initial regimen unchanged; strategy 2 adjusted doses using a standard rule of three to target a C_trough of 10-15 mg/L; strategies 3 and 4 used the MIPD software Tucuxi with a steady-state C_trough and two concentrations after the first dose, respectively, for Bayesian dosage optimization. Individual dosages were adjusted following each strategy, recalculating AUC_24,SS to determine the percentage of target attainment. Iterative adjustments were performed by resampling C_trough. A sub-study evaluated optimal sampling time by comparing Tucuxi-estimated AUC_24,SS with the reference value.</p><p><strong>Results: </strong>Less than 49% of patients reached the target with strategy 1, leading to frequent vancomycin overexposure. Strategy 2 enabled over 75% of patients to achieve AUC_24,SS/MIC between 360 and 540 h with every-8-h regimens, but only 31% with longer dosing intervals. Strategies 3 and 4 allowed over 74% of patients to reach the target after one TDM cycle and 100% after four cycles, regardless of the initial dosing regimen. A single sample sufficed for accurate AUC_24,SS prediction.</p><p><strong>Conclusion: </strong>This virtual TDM study indicates that Bayesian MIPD optimizes vancomycin exposure in neonates, while simplifying the sampling strategy. This approach deserves to be integrated and validated in routine neonatal care.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"915-927"},"PeriodicalIF":4.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147811728","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":"Therapeutic Drug Monitoring and Model-Informed Precision Dosing of Oral TKIs and PARP Inhibitors: A Practical Framework for Clinical Implementation.","authors":"Arnau Torrent-Rodríguez, Carla Bastida, Esther Carcelero San Martín, Inés Monge Escartín, Alicja Puszkiel, Benoit Blanchet, Juan Carlos Laguna, Teresa Gorria, Angela Montes, Ismael Macías, Alberto Alvárez, Ana Arance, Francisco Aya Moreno, Aleix B Fabregat-Bolufer, Eva Soler, Dolors Soy Muner","doi":"10.1007/s40262-026-01660-2","DOIUrl":"10.1007/s40262-026-01660-2","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Oral tyrosine kinase inhibitors and poly (adenosine diphosphate-ribose) polymerase inhibitors are widely used across solid tumors and hematologic malignancies and are typically administered at fixed doses. However, substantial interindividual pharmacokinetic variability results in heterogeneous systemic exposure, potentially leading to underexposure with reduced antitumor efficacy or overexposure with preventable toxicity. Therapeutic drug monitoring and model-informed precision dosing have emerged as complementary strategies to individualize dosing and optimize the exposure-response balance in routine oncology practice. This narrative problem-oriented review evaluates the clinical applicability of therapeutic drug monitoring and model-informed precision dosing for selected oral targeted agents, including epidermal growth factor receptor, anaplastic lymphoma kinase, BCR-ABL, vascular endothelial growth factor receptor, mitogen-activated protein kinase kinase, and multi-kinase inhibitors, as well as poly(adenosine diphosphate-ribose) polymerase inhibitors. For each agent, we assessed the presence of clinically meaningful exposure-response or exposure-toxicity relationships, the availability of validated assays, and the existence of actionable concentration thresholds. We also integrated an updated therapeutic drug monitoring usefulness score to contextualize the strength of recommendation. High-level evidence, including prospective interventional studies, supports exposure-guided dosing for imatinib and sunitinib, demonstrating improved molecular or clinical outcomes when predefined trough concentration targets are achieved. For alectinib, cabozantinib, trametinib, and lenvatinib, consistent exposure-response or exposure-toxicity relationships and pragmatic concentration thresholds support selective implementation, although randomized validation remains limited. For agents such as osimertinib, brigatinib, olaparib, and niraparib, monitoring appears most clinically relevant in toxicity-driven scenarios rather than for efficacy optimization. In contrast, lorlatinib currently lacks a clearly defined therapeutic window, limiting routine applicability. Across drugs, steady-state trough concentration remains the default sampling strategy. Clinical scenarios warranting measurement include early or unexpected disease progression, recurrent or severe adverse events, suspected drug-drug interactions, altered absorption, organ dysfunction, or concerns regarding adherence. Model-informed precision dosing extends conventional monitoring by integrating patient-specific covariates with pharmacokinetic models to simulate individualized dosing regimens. In conclusion, therapeutic drug monitoring and model-informed precision dosing are ready for selective clinical adoption in a subset of oral targeted therapies. Future prospective trials integrating pharmacometric tools with patient-centered outcomes are required to refine exposure targets and expand evidence","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"773-793"},"PeriodicalIF":4.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13272284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148223549","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 Pharmacokinetics of Sacubitril/Valsartan in Patients with Heart Failure and End-Stage Renal Disease Undergoing Peritoneal Dialysis.","authors":"Ying Jin, Nuo Xu, Wenyu Yang, Bijue Liu, Runhan Liu, Yufei Shi, Mengyu Zhang, Xiaoqiang Xiang, Zhenlei Wang, Xiao Zhu","doi":"10.1007/s40262-026-01647-z","DOIUrl":"10.1007/s40262-026-01647-z","url":null,"abstract":"<p><strong>Background and objective: </strong>Cardiovascular risk is markedly increased in end-stage renal disease. Although sacubitril/valsartan provides cardiovascular benefits in heart failure, evidence supporting its use in end-stage renal disease, particularly in patients undergoing peritoneal dialysis, remains limited. This study aimed to characterize the pharmacokinetics of sacubitril/valsartan in patients with heart failure and end-stage renal disease undergoing peritoneal dialysis and to determine whether dose adjustment is warranted.</p><p><strong>Methods: </strong>In this prospective study, plasma, urine, and peritoneal dialysate samples were collected from 40 patients with heart failure and end-stage renal disease undergoing peritoneal dialysis, and population pharmacokinetic models were developed to simultaneously characterize valsartan and LBQ657 pharmacokinetic profiles across the three matrices. Covariates' effects were quantitatively evaluated using a forest plot. Renal and peritoneal dialysate excretion fractions of valsartan and LBQ657 were estimated based on population pharmacokinetic models.</p><p><strong>Results: </strong>A one-compartment model with first-order absorption and elimination, incorporating urinary excretion and bidirectional exchange with peritoneal dialysate, was developed to characterize the pharmacokinetics of valsartan and LBQ657 in patients with end-stage renal disease. Fat-free mass was a key determinant of non-renal clearance and exposure for both analytes. A covariate analysis showed that, relative to the median fat-free mass (42.2 kg), a fat-free mass of 58.95 kg was associated with a 54% lower valsartan area under the concentration-time curve during steady state and a 26% lower LBQ657 area under the concentration-time curve during steady state. Urinary and peritoneal dialysate eliminations of valsartan and LBQ657 were minimal, not exceeding 1% and 7%, respectively.</p><p><strong>Conclusions: </strong>The population pharmacokinetic models for valsartan and LBQ657 adequately characterized profiles in plasma, urine, and peritoneal dialysate in patients with heart failure and end-stage renal disease undergoing peritoneal dialysis. In this special population, the impact of peritoneal dialysis was minimal, and no dose adjustment is required based on peritoneal dialysis status.</p><p><strong>Clinical trial registration: </strong>Chinese Clinical Trial Registry identifier no. ChiCTR2200055924.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"883-895"},"PeriodicalIF":4.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764607","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":"Why the Assay Matters in Model-Informed Precision Dosing: An Example of Ustekinumab in Crohn's Disease.","authors":"Wei Zhang, Zhigang Wang, Thierry Dervieux, Nick Geukens, Bram Verstockt, Marc Ferrante, Séverine Vermeire, Erwin Dreesen","doi":"10.1007/s40262-026-01639-z","DOIUrl":"10.1007/s40262-026-01639-z","url":null,"abstract":"<p><strong>Background and objective: </strong>Systematic bias between therapeutic drug monitoring assays may lead to inappropriate treatment decisions in clinical practice. While such bias is well recognized, its impact on model-informed precision dosing remains unexplored. In this study, we evaluate how assay bias affects the predictive performance of population pharmacokinetic models, using ustekinumab in patients with Crohn's disease as an example.</p><p><strong>Methods: </strong>We repurposed data from 83 patients with Crohn's disease. Ustekinumab concentrations were measured using both an homogeneous mobility shift assay and enzyme-linked immunosorbent assay. Two corresponding population pharmacokinetic models were developed. Bayesian forecasting was performed under matched and mismatched combinations of assay data and population pharmacokinetic models. Predictive accuracy and precision were assessed using relative bias and relative root mean square error, with predefined thresholds for clinical acceptability. Agreement between assays and clearance estimates was evaluated using Bland-Altman plots, Deming regression, and concordance correlation coefficients. Model prior flattening strategies were explored to mitigate mismatches between model priors and therapeutic drug monitoring data.</p><p><strong>Results: </strong>Ustekinumab concentrations measured by the homogenous mobility shift assay were overall 8.1 mg/L higher than those measured by an enzyme-linked immunosorbent assay (95% confidence interval -23.6, 39.7). Clearance estimates from the homogenous mobility shift assay-based population pharmacokinetic model were systematically lower (0.107 L/day; relative standard error, 7.6%) compared with those from the enzyme-linked immunosorbent assay-based population pharmacokinetic model (0.235 L/day; relative standard error, 5.4%). When assay data and population pharmacokinetic models were matched, Bayesian forecasting yielded clinically acceptable predictions across all scenarios (relative bias <20%, 95% confidence interval including zero). Mismatched combinations led to reduced accuracy. Precision was highest using the homogenous mobility shift assay data, irrespective of the population pharmacokinetic model. Flattening strategies improved predictive performances in some mismatched scenarios but did not fully recover bias.</p><p><strong>Conclusions: </strong>Assay bias has a clinically relevant impact on the predictive performance of model-informed precision dosing. Our findings underscore the importance of aligning the therapeutic drug monitoring assay format with the assay format used to build the population pharmacokinetic model to ensure accurate and clinically acceptable dosing predictions.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"837-848"},"PeriodicalIF":4.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147637975","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}