Clinical Pharmacokinetics最新文献

{"title":"Population Pharmacokinetic/Pharmacodynamic Modeling of Therapeutic Enzymes in Lysosomal Storage Diseases.","authors":"Ina Barzel, Ans T van der Ploeg, W W M Pim Pijnappel, P Hugo M van der Kuy, Johanna M P van den Hout, Tim Preijers","doi":"10.1007/s40262-026-01636-2","DOIUrl":"https://doi.org/10.1007/s40262-026-01636-2","url":null,"abstract":"<p><strong>Background: </strong>Lysosomal storage diseases (LSDs) are rare genetic disorders treated with enzyme replacement therapy (ERT). However, treatment outcomes are highly variable, reflecting the complexities of therapeutic enzyme pharmacology, patient heterogeneity and therapy response. Population pharmacokinetic/pharmacodynamic (popPK/PD) modeling can help characterize this variability, identify covariates, and optimize dosing strategies.</p><p><strong>Objectives: </strong>This review aimed to provide a comprehensive overview of published popPK and popPD models of therapeutic enzymes in LSDs, summarize modeling strategies and study characteristics, and evaluate the quality of the available models.</p><p><strong>Methods: </strong>A systematic search of Medline, Embase, and Web of Science (inception-March 2025) identified studies reporting popPK and/or popPD models of therapeutic enzymes in patients with LSDs. Data on study characteristics, structural and statistical model choices, covariate analyses, and evaluation methods were extracted and compared.</p><p><strong>Results: </strong>This review included studies describing 6 popPK models and 3 popPD models of therapeutic enzymes in LSD. All models were developed using the nonlinear mixed-effects (NLME) modeling approach. The PK characteristics were adequately described using a two-compartment model in three studies, a three-compartment model in two studies, and a one-compartment model in one study. Three studies additionally assessed PK parameters in monocytes, leukocytes, and cerebrospinal fluid (CSF). Among all tested covariates, total body weight (TBW) was identified as a significant predictor for clearance (CL) and volume of distribution in the central compartment (V<sub>c</sub>) in three studies. In one study evaluating PK parameters in CFS, age-based scaling was applied instead of weight-based allometric scaling to improve model fit. PopPD models were limited, with exposure-response relationships described either by an inhibitory maximal effect (I<sub>max</sub>) model or by a longitudinal logistic regression model with a first-order Markov element.</p><p><strong>Conclusions: </strong>PopPK modeling of therapeutic enzymes in LSDs is relatively well established. However, progress in popPD modeling remains limited. Existing models support the use of indirect response and maximum effect (E<sub>max</sub>) models to describe the delayed and saturable effects of ERT, and innovative approaches such as intracellular PK assessment and Markov modeling illustrate the potential of advanced pharmacometric methods. Nevertheless, there remains a need to further clarify the role of drug concentration measurements in target cells, to characterize CNS distribution in LSDs affecting the brain following intrathecal administration of ERTs and intravenous administration of a novel fusion protein, and to identify robust PD biomarkers in defining exposure-response relationships of therapeutic enzymes in LSD","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834314","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":"Effect of Enzalutamide on Morphine Exposure in Patients with Prostate Cancer.","authors":"Catharina J P Op 't Hoog, Niven Mehra, Benthe van der Weij, Erik Olofsen, Diederik M Somford, Inge M van Oort, Paul Hamberg, Nielka P van Erp, Emmy Boerrigter","doi":"10.1007/s40262-026-01640-6","DOIUrl":"https://doi.org/10.1007/s40262-026-01640-6","url":null,"abstract":"<p><strong>Background and objective: </strong>Pain management in patients with prostate cancer receiving enzalutamide is challenging owing to its high potential for drug-drug interactions. Morphine is generally preferred because of its favorable metabolic profile, but the effect of enzalutamide on the pharmacokinetics of morphine is unclear. The objective of this study was to assess whether a drug-drug interaction exists between enzalutamide and morphine in patients with prostate cancer.</p><p><strong>Methods: </strong>In a multicenter two-arm parallel study, 24 men with prostate cancer received morphine with enzalutamide (n = 12) and without enzalutamide (n = 12). Plasma concentrations of morphine and its active metabolite morphine-6-glucuronide were measured. Pharmacokinetic parameters were calculated using a non-compartmental analysis. Geometric mean ratios (GMR) of the area under the plasma concentration-time curves were calculated. No clinically relevant interaction was defined if 90% of the confidence interval (CI) of the GMR of morphine was within the range of 0.5-2.0.</p><p><strong>Results: </strong>Morphine exposure was similar between both groups, with the 90% CI falling within the range of 0.5-2.0 (GMR 1.01; 90% CI 0.77-1.31). The exposure of morphine-6-glucuronide was increased with enzalutamide (GMR 1.77; 90% CI 1.43-2.17).</p><p><strong>Conclusions: </strong>The exposure of morphine was unaffected by enzalutamide, while morphine-6-glucuronide exposure was increased. Because of the inconclusive potency of morphine-6-glucuronide and its uncertain ability to cross the blood-brain barrier, the increase is likely of modest clinical significance. Therefore, morphine and enzalutamide can be safely combined when starting at a low dose and titrated based on efficacy and tolerability.</p><p><strong>Clinical trial registration: </strong>NCT05339672.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147811768","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":"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":"https://doi.org/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":""},"PeriodicalIF":4.0,"publicationDate":"2026-05-04","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":"https://doi.org/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":""},"PeriodicalIF":4.0,"publicationDate":"2026-05-02","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":"Impacts of Uremic Toxins on the Population Pharmacokinetics of Total Mycophenolic Acid and its Glucuronide Metabolite in Adult Kidney Transplant Recipients.","authors":"Ala'a R Al-Dajani, Yan Rong, Jinal Adhiya, Puja Dhungana, Patrick Mayo, Penny Colbourne, Sita Gourishankar, Tony K L Kiang","doi":"10.1007/s40262-026-01646-0","DOIUrl":"https://doi.org/10.1007/s40262-026-01646-0","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background and objective: &lt;/strong&gt;Mycophenolic acid (MPA) exhibits considerable inter-individual variability in drug exposure, which can result in acute graft rejection as well as hematological or infectious adverse effects. Evidence from our group and others indicates that certain uremic toxins may contribute to this variability through pharmacokinetic (PK) interactions. This study aimed to develop a novel population PK (popPK) model to investigate how conjugated metabolites of p-cresol and indole (i.e., toxicokinetically important uremic toxins) affect total MPA PK, and to conduct model-based simulations to identify potentially relevant dosing recommendations.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;A prospective observational study enrolled adult kidney transplant recipients on steady-state oral mycophenolate mofetil (MMF; prodrug of MPA) with tacrolimus (±prednisone). Total plasma concentrations of p-cresol sulfate (pCS), p-cresol glucuronide (pCG), indoxyl sulfate (IxS), indoxyl glucuronide (IxG), MPA, and its major glucuronide metabolite (MPAG) were quantified with our validated liquid chromatography tandem-mass spectrometry assays. PopPK modelling was conducted with stochastic approximation expectation-maximization, and Monte-Carlo simulation was used to assess the potential impacts of significant covariates on MPA exposure.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Forty-one participants contributed 283 samples across three early post-transplant periods (~1, ~3, and ~6 months). The final popPK model was described by first-order absorption (K&lt;sub&gt;a&lt;/sub&gt; = 0.672 [0.47-0.99] h&lt;sup&gt;-1&lt;/sup&gt;, estimate [95% confidence interval]) with lag time (T&lt;sub&gt;lag&lt;/sub&gt; = 0.403 [0.39-0.42] h), two compartments for MPA (central volume, V&lt;sub&gt;c&lt;/sub&gt; = 1.09 [0.75-1.53] L; peripheral volume, V&lt;sub&gt;p&lt;/sub&gt; = 113.9 [76.33-197.33] L; intercompartmental clearance, Q = 15.9 [10.11-25.61] L/h; and clearance = fixed at 1.4 L/h), and a single compartment for MPAG (clearance, CL&lt;sub&gt;MPAG&lt;/sub&gt; = 0.296 [0.23-0.35] L/h; MPA-to-MPAG metabolic conversion, K&lt;sub&gt;pm&lt;/sub&gt; = 3.21 [2.46-4.18] h&lt;sup&gt;-1&lt;/sup&gt;). A proportional error model with inter-individual and inter-occasional variability best described the random effects. Potentially significant covariates were \"pCS exposure\" on MPA T&lt;sub&gt;lag&lt;/sub&gt;, K&lt;sub&gt;pm&lt;/sub&gt;, and Q (covariate coefficients, β = - 0.226 [-0.53 to 0.079], -0.133 [-0.25 to -0.033], and -0.162 [-0.39 to 0.13], respectively); \"IxS exposure\" and \"estimated glomerular filtration rate (eGFR)\" on CL&lt;sub&gt;MPAG&lt;/sub&gt; (β = -0.181 [-0.28 to -0.035] and 0.407 [0.085-0.73], respectively); and \"IxG exposure\" on MPA T&lt;sub&gt;lag&lt;/sub&gt; (β = 0.295 [-0.0057 to 0.59]). The model was validated by goodness-of-fit plots, residual plots, visual-predictive checks, and non-parametric bootstrapping. Model simulations identified pCS as a covariate positively influencing total MPA exposure; that pCS and eGFR had negative effects on MPAG exposure, potentially opposing the effects of IxS; wh","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147811761","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 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":"https://doi.org/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":""},"PeriodicalIF":4.0,"publicationDate":"2026-04-29","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":"Clinical Validation of Venetoclax Volumetric Microsampling in Patients with Leukemia with Assessment of Whole-Blood-to-Plasma Conversion Strategies and Self-Microsampling Feasibility.","authors":"A D Levens, J Rijstenbil, E Metscher, P von dem Borne, A Albersen, J J Swen, D J A R Moes","doi":"10.1007/s40262-026-01635-3","DOIUrl":"https://doi.org/10.1007/s40262-026-01635-3","url":null,"abstract":"<p><strong>Background and objective: </strong>Venetoclax shows substantial pharmacokinetic (PK) variability and frequent toxicity, making it an archetypal candidate for PK monitoring. Capillary microsampling may facilitate decentralized PK monitoring of venetoclax. However, clinical validation is lacking. This study aimed to clinically validate capillary microsampling for venetoclax and to assess the feasibility of home-based self-microsampling.</p><p><strong>Methods: </strong>Adult patients with acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) receiving oral venetoclax therapy provided paired venous plasma and capillary samples using dried blood spot (DBS) and volumetric absorptive microsampling (VAMS) devices. We evaluated individualized hematocrit-based microsample-to-plasma correction models and previously published whole-blood-to-plasma conversion strategies. Agreement and predictive performance were assessed according to international microsampling validation criteria. The feasibility of home-based self-microsampling was evaluated by examining patients' ability to collect samples independently, the proportion of usable returned samples, and device usability.</p><p><strong>Results: </strong>A total of 25 patients contributed 64 sets of paired venous plasma, DBS, and VAMS samples. Uncorrected DBS and VAMS venetoclax concentrations underestimated plasma concentrations (mean bias - 21% and - 14%, respectively) and showed clear hematocrit dependence. Individualized hematocrit-plasma/microsample ratio models showed excellent performance, with 95% of DBS and 91% of VAMS concentrations within ± 20% of plasma and low bias and imprecision across all validation metrics. Literature-based correction strategies showed lower acceptance rates and wider limits of agreement. Among patients attempting self-microsampling, 18 of 21 sampled independently, 76% of returned DBS/VAMS samples were suitable for analysis, and usability ratings were higher for VAMS than DBS.</p><p><strong>Conclusions: </strong>Capillary microsampling enables accurate venetoclax quantification in patients with AML and CLL when individualized hematocrit-based microsample-to-plasma conversion is applied. Both DBS and VAMS met international validation criteria, and home-based self-microsampling proved feasible. Venetoclax home-based self-microsampling warrants further study as a tool for decentralized PK monitoring.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764558","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 for Pediatric Extrapolation of GenSci006: A 3.75-mg Triptorelin Acetate Microsphere Formulation for Central Precocious Puberty.","authors":"Kun Wang, Zhongyi Sun, Fengyan Xu, Lu Liu, Tianhong Luo, Weiwei Gao, Tangping Zhao, Guangli Ma, Xiaoyan Zhu","doi":"10.1007/s40262-026-01634-4","DOIUrl":"https://doi.org/10.1007/s40262-026-01634-4","url":null,"abstract":"<p><strong>Background and objectives: </strong>Triptorelin acetate microspheres are long-acting gonadotropin-releasing hormone (GnRH) agonist used for treating central precocious puberty (CPP). GenSci006 is a newly developed 3.75-mg formulation intended as a local alternative to Diphereline^®. This study aimed to characterize the pharmacokinetics (PK) of GenSci006 using population pharmacokinetic (PopPK) modeling with pediatric extrapolation, to evaluate pharmacodynamic (PD) comparability, and to support a fixed-dose regimen for CPP.</p><p><strong>Methods: </strong>This study comprised two components: (1) PopPK modeling and model-based simulation to characterize exposure and support pediatric extrapolation; and (2) a comparative pharmacodynamic assessment based on serum luteinizing hormone (LH) responses.</p><p><strong>Results: </strong>The final PopPK model employed a three-compartment structure with mixed sequential absorption phases (two first-order and a zero-order absorption), capturing triptorelin's multiphasic release. Covariates, including weight, age, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), serum creatinine, total bilirubin, and creatinine clearance, showed no significant effect on PK. Allometric scaling (exponents 0.75 for clearance [CL] and 1 for central volume distribution [V₃]) was applied to simulate pediatric exposure. Simulations indicated that at a fixed 3.75-mg dose, exposure decreased with increasing weight, with an approximately 1.7-fold difference between the 20-30 kg and 40-50 kg groups. In the comparative PD analysis, serum LH exposure profiles were comparable between GenSci006 and the reference product over the 0-672-h assessment period.</p><p><strong>Conclusion: </strong>Model-based simulations predicted approximately two-fold higher exposure in lighter children (20-30 kg) compared with adults. This difference was not clinically meaningful given the plateau PD effect and wide therapeutic range of triptorelin.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147643885","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":"https://doi.org/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":""},"PeriodicalIF":4.0,"publicationDate":"2026-04-08","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}

{"title":"Leveraging Model-Informed Drug Development to Predict Asciminib Efficacy in Second-Line Treatment of Chronic Myeloid Leukemia in Chronic Phase.","authors":"Sherwin K B Sy, Deok Yong Yoon, Yiqun Yang, Christelle Darstein, Kohinoor Dasgupta, Shruti Kapoor, Shengyuan Wu, Yasunori Kawakita, Matthias Hoch, Kai Grosch","doi":"10.1007/s40262-025-01616-y","DOIUrl":"10.1007/s40262-025-01616-y","url":null,"abstract":"<p><strong>Background and objectives: </strong>The efficacy of asciminib was proven in newly diagnosed (first-line, 1L) patients with Philadelphia-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) and in patients treated with at least two prior tyrosine kinase inhibitors (third-line, 3L+). Given that no randomized controlled trial has been conducted for second-line (2L) patients with CML, this analysis aims to infer the efficacy of asciminib in the 2L setting using the 80 mg once-daily dosing regimen and to support the use of asciminib in patients with CML-CP irrespective of line of therapy.</p><p><strong>Methods: </strong>Data (n = 430) were used from three studies, including first-in-human and ASCEMBL in 3L+ and ASC4FIRST in 1L trials, to evaluate the effect of line of therapy on efficacy on the basis of the time-course of BCR::ABL1 mRNA transcripts. Previously adapted to characterize the effect of nilotinib as a 1L and 2L therapy on a CML surrogate marker, the model has three compartments representing quiescent leukemic stem cells and proliferating drug-susceptible and resistant bone marrow cells, wherein the effect of asciminib was modeled as an enhancement of the elimination of susceptible cells.</p><p><strong>Results: </strong>Asciminib efficacy in 2L was inferred from 1L by borrowing information from nilotinib data. A credibility assessment showed robust prediction accuracy and precision of the model with external 2L data from the ASC2ESCALATE study (n = 36). Major molecular response (MMR) rates in 2L were predicted to be 61-67% at week 48 and 70-76% at week 96, with the 80 mg total daily dose.</p><p><strong>Conclusions: </strong>A model-informed drug development (MIDD) approach was applied to predict 2L efficacy and supported global regulatory approval of asciminib across treatment lines, despite limited clinical data in 2L.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"595-608"},"PeriodicalIF":4.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146156409","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}