Clinical Pharmacokinetics最新文献

{"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":"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":"863-882"},"PeriodicalIF":4.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13272211/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetics and Pharmacodynamics of Immunoglobulins: A Systematic Review.","authors":"S L van der Zeeuw, S J van Tilburg, B C Jacobs, B C P Koch, V A S H Dalm, M B S Crombag, T Preijers","doi":"10.1007/s40262-026-01641-5","DOIUrl":"10.1007/s40262-026-01641-5","url":null,"abstract":"<p><strong>Background and objective: </strong>Intravenous and/or subcutaneous immunoglobulins (IVIg/SCIg) are used as immunoglobulin replacement therapy (IgRT) in primary and secondary immunodeficiencies (PID/SID) and as immunomodulatory therapy in immune-mediated diseases. Despite empiric immunoglobulin G (IgG) target concentrations in PID, dosing remains variable and suboptimal, particularly in immune-mediated diseases lacking clear IgG target concentrations. Population pharmacokinetic (popPK) and pharmacodynamic (PD) modelling may clarify interindividual variability and support individualised dosing. Recent developments extend beyond PID, emphasising the importance of integrated PK-PD approaches to optimise IgG therapy. This review aimed to provide a comprehensive overview of popPK(-PD) models describing polyclonal IgG therapy, and to emphasise the added value of PK-PD in understanding drug behaviour.</p><p><strong>Methods: </strong>A systematic literature search was conducted in Embase, MEDLINE, and Web of Science from inception to August 2025. Studies describing popPK(-PD) models for exogenous polyclonal IVIg and/or SCIg administration in humans were included.</p><p><strong>Results: </strong>In total, 14 studies were included. While most popPK models focus on PID (N = 10), an increasing number address immune-mediated diseases. Immunoglobulin G pharmacokinetics are typically described using two-compartment models with first-order kinetics, using body weight (BW) as a common covariate for clearance and volume of distribution. Endogenous IgG is often incorporated as a fixed PK parameter; however, this may not adequately capture interindividual variability and potential effects of Ig treatment on IgG concentrations. Two popPK-PD models link IgG concentrations to clinical outcomes in immune-mediated diseases. In contrast, such models are currently lacking for PID. Simulations showed consistent predicted IgG concentrations following SCIg in PID, while IVIg models in PID showed more variability.</p><p><strong>Conclusions: </strong>PopPK models have advanced understanding of IgG PK and its variability between patients and treatment regimens. These models provide a powerful framework to support individualised dosing strategies, thereby potentially reducing reliance on empirical, trial-and-error dosing approaches. However, clear target concentrations are lacking and must be established for individual patients. Models may be further optimised by incorporating essential Neonatal Fc receptor (FcRn) mechanisms using physiology-based pharmacokinetic (PBPK) or semi-mechanistic models. In conclusion, current models are useful to predict IgG concentrations across diseases during Ig treatment; however, a clearer relationship with PD is required. Hence, these findings can guide clinical trial design for tailored dosing regimens.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"811-836"},"PeriodicalIF":4.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13272613/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148027593","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":"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":"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":"897-914"},"PeriodicalIF":4.0,"publicationDate":"2026-06-01","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 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":"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":"849-861"},"PeriodicalIF":4.0,"publicationDate":"2026-06-01","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":"Model-Informed Precision Dosing of Protein Kinase Inhibitors: Evaluation of Model-Averaging and Flattened Priors Methods.","authors":"Félicien Le Louedec, Laura Morvan, Loïc Mourey, Maud Maillard, Christelle Vachoux, Malika Yakoubi, Diego Tosi, Gwenaelle Gravis, Guilhem Roubaud, Frédéric Thuillier, Helen Boyle, Fabienne Thomas, Mélanie White-Koning, Florent Puisset, Étienne Chatelut","doi":"10.1007/s40262-026-01628-2","DOIUrl":"10.1007/s40262-026-01628-2","url":null,"abstract":"<p><strong>Background and objectives: </strong>Therapeutic drug monitoring of protein kinase inhibitors (PKIs) usually relies on the measure of a single trough concentration at steady-state (C_min,ss). When the sampling time differs from the trough, it is theoretically possible to predict C_min,ss from maximum a posteriori (MAP) Bayesian estimates of PK parameters. However, several questions remain with regards to model-informed precision dosing (MIPD) of PKIs, such as choosing which model to use when several are available in the literature. Alternative techniques, such as flattened priors and model averaging may outperform standard analyses. The aim of this work is to report a comprehensive fit-for-purpose validation of MIPD for sunitinib and pazopanib.</p><p><strong>Methods: </strong>Concentration data from 41 renal cancer patients included in the SUP-R trial (NCT02555748) measured 2 and 6 hours after an intake were analyzed (MAP-Bayesian estimation of PK parameters) in order to predict C_min,ss at the current cycle and at the next cycle. Different models from the literature were tested, as well as the model-averaging and flattened priors features available in the R package 'mapbayr'.</p><p><strong>Results: </strong>The quality of C_min,ss predictions depended on the model used. Flattening priors rarely improved or worsened the predictions. Model averaging was robust across the different scenarios tested and should be preferred to using a single model. Overall, a precision of 20% to 25% was achieved, with a minimal bias (< 5%).</p><p><strong>Conclusion: </strong>The benefit of the model-averaging method for the model-informed precision dosing of sunitinib and pazopanib is likely applicable to other protein kinase inhibitors. Thanks to 'mapbayr', this framework was implemented as a standalone shiny application to be used in clinical settings.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"681-692"},"PeriodicalIF":4.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13183724/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147389471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of 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":"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":"763-772"},"PeriodicalIF":4.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13183711/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetic Modelling of Unbound Mycophenolic Acid and its Glucuronide in Adult Kidney Transplant Recipients in Early Post-Transplant.","authors":"Yan Rong, Ala'A Al-Dajani, Jinal Adhiya, Puja Dhungana, Patrick Mayo, Penny Colbourne, Sita Gourishankar, Tony K L Kiang","doi":"10.1007/s40262-026-01632-6","DOIUrl":"10.1007/s40262-026-01632-6","url":null,"abstract":"<p><strong>Background and objective: </strong>The first-line immunosuppressant mycophenolic acid (MPA) is characterised by complex, variable pharmacokinetics (PK) with high protein binding, where the relationship between total and unbound drug can be difficult to predict early post-transplant. We developed a novel population pharmacokinetic (popPK) model for unbound MPA and its major glucuronide (MPAG) in adult kidney transplant recipients to characterise the pharmacologically relevant unbound drug.</p><p><strong>Methods: </strong>This prospective, observational study included de novo adult kidney transplant recipients on steady-state oral mycophenolate mofetil with tacrolimus (±prednisone). The PopPK modelling was performed using stochastic approximation expectation-maximisation, and simulations evaluated the impact of significant covariates on unbound MPA area-under the concentration-time curves (AUC)_0-12h.</p><p><strong>Results: </strong>Forty-one participants (aged 48.3±12.1 years, mean±SD) from 63 occasions representing three study visits (~1, ~3, and ~6 months post-transplant) were enrolled. A structural model based on first-order absorption (k_a=4 h^-1, fixed) with lag time (T_lag=0.38 [0.11-0.56] h; estimate [95% confidence interval]), two-compartments for unbound MPA (volume V₁=4213.41 [2675.47-8337.53] L; V₂=23321.08 [4334.80-54459.85] L; clearance=4.87 L h^-1, fixed), one-compartment for unbound MPAG (transfer rate=0.18 [0.15-0.21] h^-1; V₃=18.23 [12.40-32.77] L; clearance=5.64 [4.14-10.70] L h^-1), and constant error with between-subject and between-occasion effects best described the data. Of 19 covariates, \"age\" and \"alkaline phosphatase\" influenced unbound MPA V₂ (β=3.62 [-0.61-8.13]) and unbound MPAG clearance (β=-0.98 [-1.51-(-)0.21]), respectively. Simulations showed age-dependent reductions in unbound MPA AUC_0-12h and age/dose-dependent shifts in the proportions of patients within the theoretical unbound MPA target range.</p><p><strong>Conclusions: </strong>A popPK model simultaneously characterising unbound MPA and MPAG was developed and evaluated. Simulations indicated that age-dependent MPA dosing may be warranted to optimise unbound therapeutic exposures.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"731-746"},"PeriodicalIF":4.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147510012","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":"Pharmacokinetics of Asciminib 200 mg in the Presence of a Strong CYP3A4 Inducer, Phenytoin, in Healthy Participants.","authors":"Matthias Hoch, Amanda J Taylor, Felix Huth, Seshulatha Jamalapuram, Ioannis Loisios-Konstantinidis, Michelle Quinlan, Athina Kranidi, David Coleman, Noemi Espurz, Suleyman Eralp Bellibas, Annie St Pierre","doi":"10.1007/s40262-026-01629-1","DOIUrl":"10.1007/s40262-026-01629-1","url":null,"abstract":"<p><strong>Background and objectives: </strong>Asciminib is indicated for the treatment of adult patients with newly diagnosed or previously treated Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) at a total daily dose of 80 mg, as well as adult patients with Ph+ CML with the T315I mutation at 200 mg twice daily. In patients with the T315I mutation, responses have been observed at doses of ≥150 mg twice daily and dose reduction to 160 mg twice daily is permitted for management of adverse reactions. The objective of this study was to assess the effect of strong CYP3A4 induction, through phenytoin, on the pharmacokinetics (PK) of single dose asciminib 200 mg. Coproporphyrin-1 (CP-1) was also measured to evaluate the effect of asciminib 200 mg on organic anion transporting polypeptide 1B (OATP1B).</p><p><strong>Methods: </strong>This Phase 1 open-label fixed-sequence study evaluated the PK of a single oral dose of asciminib in healthy participants when administered alone and in combination with phenytoin. A single dose of 200 mg asciminib was administered on Day 1, followed by the administration of phenytoin 100 mg three times daily from Day 6 to Day 23, taken 8 h apart to ensure full induction. On Day 20, the morning doses of phenytoin and asciminib were co-administered. Serial blood samples were collected for the assessment of asciminib PK and CP-1 plasma concentrations.</p><p><strong>Results: </strong>All 15 participants who enrolled were male and 14 received study treatment per protocol. Following co-administration with phenytoin, asciminib-adjusted geometric mean maximum plasma concentration (C_max), area under the curve to the last plasma concentration (AUC_last) and AUC to infinity (AUC_0-inf) were reduced by 22%, 34%, and 34%, with test/reference ratios of 0.780 (90% CI: 0.718-0.847), 0.662 (90% CI: 0.624-0.703), and 0.664 (90% CI: 0.626-0.705), respectively. A single oral dose of asciminib 200 mg did not have a relevant effect on CP-1 plasma exposure.</p><p><strong>Conclusions: </strong>These data support that, considering its large therapeutic window, asciminib 200 mg twice daily can be used without any dose adjustment when co-administered with a strong CYP3A4 inducer drug. Furthermore, asciminib is not an OATP1B inhibitor up to this dose.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"709-718"},"PeriodicalIF":4.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13183751/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147472768","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":"Exposure-Response Relationships of Antibody Drug Conjugates in Solid Tumours.","authors":"Merel J J Lucassen, Pauline L M Buitelaar, Bart A W Jacobs, Tim Schutte, Neeltje Steeghs, Alwin D R Huitema","doi":"10.1007/s40262-026-01633-5","DOIUrl":"10.1007/s40262-026-01633-5","url":null,"abstract":"<p><p>Over the last decade, there has been an increase in development of antibody drug conjugates (ADCs), a drug class designed to bring chemotherapeutic agents to tumour sites. The pharmacokinetics of ADCs are complex, due to their multifaceted structure consisting of an antibody linked to a (chemotherapeutic) payload. This review provides an overview of the pharmacokinetics of approved ADCs for patients with solid tumours in relation to toxicity and/or efficacy outcomes. Due to the complex nature and in vivo modifications of an ADC, the pharmacokinetic exposure is measured partially or with surrogate entities. These entities include the calculated drug-to-antibody ratio (DAR)-corrected ADC, measured conjugated antibody, total antibody and/or free payload concentration. A clear exposure-efficacy and exposure-toxicity relation was evident for the majority of ADCs. A higher exposure of almost all ADCs approved for patients with solid tumours, specifically the conjugated antibody entity, was related to higher objective response rates. A higher exposure of the free circulating cytotoxic payload and of the surrogate entities of ADC exposure, of ADCs with cleavable linkers, was related to toxicity. This is unsurprising as a higher circulating payload may induce toxicities associated with the related chemotherapeutic compound. Non-cleavable linkers increase the plasma stability compared to cleavable linkers, resulting in the absence of an (systemic) exposure-toxicity relation. The exposure-response relations for efficacy and toxicity seem apparent based on current literature, but quantification of all ADC components should be considered to fully elucidate the exposure-response relations. This is a crucial next step for dose optimisation and development of a new generation of this important new therapeutic class.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"635-645"},"PeriodicalIF":4.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13183693/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147590424","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":"Predicting Cumulative Neonatal Sodium Benzoate Exposures During Breastfeeding with Physiologically Based Pharmacokinetic Modelling.","authors":"Shirley Wang, Abdullah Hamadeh, Paola Mian, Andrea N Edginton","doi":"10.1007/s40262-026-01624-6","DOIUrl":"10.1007/s40262-026-01624-6","url":null,"abstract":"<p><strong>Background and objective: </strong>Sodium benzoate (SB) is used as a second-line therapy to treat rare urea cycle disorders (UCDs) in paediatric and adult patients. However, lactation data for SB do not exist, leading to uncertainties regarding the extent of infant drug exposure due to breastfeeding while taking this medication. These uncertainties may lead to cessation of breastfeeding, unnecessarily depriving both mother and infant of its numerous benefits. Thus, this study aims to develop and apply a paediatric physiologically based pharmacokinetic (PBPK) model to predict the compounded neonatal SB exposure from both in utero and from breastfeeding.</p><p><strong>Methods: </strong>An adult whole-body PBPK model for SB was first developed and validated with literature-based plasma concentrations after oral or intravenous doses. To account for age-related changes in SB pharmacokinetics, the adult model was scaled to paediatric populations using age-dependent algorithms to capture physiological and anatomical changes, while ontogeny functions were developed to capture maturation of enzymes and transporters where possible. A published cord-coupled PBPK modelling workflow was followed to simulate the cumulative pre- and post-natal drug exposure levels in breastfed infants, accounting for variability in milk ingestion volumes and assuming a conservative milk-to-plasma ratio of 1:1. The upper area under the curve (AUC) ratio (UAR) was used for risk assessment, taking the ratio between the AUC for the highest risk (95^th percentile simulated AUC) infants and the median maternal AUC following a therapeutic SB dose and multiplying by 100% to report as a percentage.</p><p><strong>Results: </strong>The paediatric PBPK model captured observed SB plasma concentrations in both neonates and children with acceptable bias and precision, supported by the average-fold error (AFE: 1.17) and the absolute AFE (AAFE: 1.24) evaluation metrics, respectively. Neonatal SB exposure levels were the highest on the first day of life (UAR: 14.2%) due to the presence of residual prenatal drug levels. Subsequent UAR values were low (1.5-3.3%) on postnatal days 1-31, suggesting rapid neonatal clearance and negligible contribution of prenatal exposure relative to breastfeeding exposure for the infant's total drug burden.</p><p><strong>Conclusion: </strong>This study is the first to report a paediatric PBPK model of SB pharmaceutical use, incorporating prenatal and lactational exposure to assess the cumulative risk of exposure for the breastfed infant. Model predictions suggest that SB exposure through breastfeeding is minimal and unlikely to cause adverse outcomes when compared with clinical studies. These findings may support clinical decision making in the absence of clinical lactation data; however, empirical studies are needed to validate the predictions given the limited information on milk transfer, enzyme ontogeny, and neonatal concentrations.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"665-680"},"PeriodicalIF":4.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147303188","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}