Clinical Pharmacokinetics最新文献

{"title":"Pharmacokinetics of IL-23p19 Inhibitors: A Systematic Review Across Immune-Mediated Inflammatory Diseases.","authors":"Ilse A Pool, Alise D E de Groot, Ron J Keizer, Marla C Dubinsky, Joana Torres, Raja Atreya, Paul Malik, Erwin Dreesen, Gerard Dijkstra, Henkjan J Verkade, Paola Mian, Arno R Bourgonje","doi":"10.1007/s40262-026-01693-7","DOIUrl":"10.1007/s40262-026-01693-7","url":null,"abstract":"<p><strong>Background: </strong>Interleukin (IL)-23p19 inhibitors are increasingly used in immune-mediated inflammatory diseases (IMIDs), particularly inflammatory bowel disease (IBD). Almost half of patients show inadequate response, partly due to pharmacokinetic (PK) variability. However, a comprehensive overview of their PK parameters is lacking, which limits understanding of population variability. This systematic review assessed the PK of IL-23p19 inhibitors in healthy subjects, IBD and other IMIDs.</p><p><strong>Methods: </strong>A systematic literature search was performed in PubMed/MEDLINE and Embase. Studies were screened by two independent researchers. Quality was assessed using the Cochrane risk of bias tool and the Clinical Pharmacokinetic Study Checklist.</p><p><strong>Results: </strong>A total of 21 studies were included (risankizumab n = 9, guselkumab n = 6, tildrakizumab n = 3, mirikizumab n = 3), covering healthy subjects, psoriasis, psoriatic arthritis, Crohn's disease (CD), ulcerative colitis (UC) and pustular/erythrodermic psoriasis. Only one study examined a distinct IBD group, specifically, mirikizumab in pediatric UC. For risankizumab, dose-normalized maximum concentrations and area under the concentration‑time curves over a dosing interval, along with central and peripheral volume of distribution and clearance were generally similar across CD and UC. Patients with CD and UC demonstrated increased risankizumab trough levels over consecutive dosing intervals, while an opposite trend was observed for other IMIDs. Covariate analysis revealed that only albumin in UC and body weight in CD were relevant covariates to risankizumab PK.</p><p><strong>Conclusion: </strong>Limited PK data and lack of subphenotype-specific data on IBD highlight the need for future studies to better define PK parameters. Also, more research is needed to guide personalized dosing strategies for IL-23p19 inhibitor use in IBD, as well as in other IMIDs.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1441-1461"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13623995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148789041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics, Elimination and Dialyzability of HRS-9231 in Patients with Varying Degrees of Renal Impairment.","authors":"Qiwen Han, Rongjun Zhang, Yan He, Rui Yan, Litong Shi, Nan Wu, Luhai Yu, Gulimire Muhetaer, Xiangyun Meng, Li Liu, Tengrui Yin, Yuanyuan Huang, Wei Zhao","doi":"10.1007/s40262-026-01688-4","DOIUrl":"10.1007/s40262-026-01688-4","url":null,"abstract":"<p><strong>Objectives: </strong>This study aimed to characterize the pharmacokinetics (PK), elimination and dialysability of HRS‑9231, a novel macrocyclic gadolinium‑based contrast agent, in individuals with varying degrees of renal impairment, including those requiring hemodialysis.</p><p><strong>Methods: </strong>In this open‑label, non‑randomized, Phase 1 study, 40 participants were stratified into five cohorts based on renal function: normal, mild, moderate, severe impairment, and end‑stage renal disease (ESRD). All received a single intravenous dose of HRS‑9231 (0.05 mmol/kg). Intensive PK sampling was performed over 96-120 h. End‑stage renal disease patients underwent hemodialysis sessions post‑dose, with concurrent plasma and dialysate collection. Long‑term gadolinium elimination and safety were monitored for up to 6 months.</p><p><strong>Results: </strong>Systemic exposure to HRS‑9231 increased with renal impairment severity: geometric mean area under the plasma concentration versus time curve from zero to infinity (AUC_0‑∞) was 35%, 104%, and 333% higher in mild, moderate, and severe impairment cohorts, respectively, versus normal function. Mean terminal half‑life prolonged from 1.7 h (normal) to 7.2 h (severe). Cumulative urinary excretion exceeded 85% across cohorts. In ESRD patients, hemodialysis efficiently removed HRS‑9231, with an 84% reduction in plasma concentration after the first session and concentrations falling below the limit of quantitation after three sessions. Gadolinium levels declined over time, returning to the unexposed reference range within 6 months. During the 6‑month follow‑up, no cases of nephrogenic systemic fibrosis (NSF) or related symptoms were observed. Given the low expected incidence of NSF with macrocyclic GBCAs and the limited sample size per cohort, this study was not statistically powered to definitively assess NSF risk. Nonetheless, the absence of NSF cases in this at‑risk population provides supportive evidence consistent with the established safety profile of macrocyclic GBCAs.</p><p><strong>Conclusions: </strong>HRS‑9231 exhibits a PK profile consistent with renal elimination. Its clearance decreases proportionally with renal impairment, and it is effectively cleared by hemodialysis. HRS‑9231 was generally well tolerated in this small cohort of patients with varying degrees of renal impairment, including those on hemodialysis. No new safety signals or NSF cases were identified. These findings, together with the PK data, support that dose adjustment is unlikely to be necessary for patients with any degree of renal impairment.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov Identifier: NCT06657560.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1527-1540"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788462","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 Rivoceranib 200 mg Once Daily on the Pharmacokinetics of a Cocktail Probe Substrate of Cytochrome P450 Enzymes: A Phase I Trial in Healthy Volunteers.","authors":"David Nguyen, Xiaohui Tracey Wei, Xianzhang Meng, Laura Alexander, Kristin Ryan, Seong Jang","doi":"10.1007/s40262-026-01686-6","DOIUrl":"10.1007/s40262-026-01686-6","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background and objective: &lt;/strong&gt;Rivoceranib, a vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor with antitumor activity, is metabolized in the liver mostly by cytochrome P450 (CYP)3A4/5. In vitro studies suggest that rivoceranib at clinically relevant concentrations may inhibit metabolism of various CYP substrates. This study evaluated the effects of rivoceranib 200 mg once daily (QD) on the pharmacokinetics of various CYP substrates using the Cooperstown 5+1 cocktail. The dosing regimen of rivoceranib used in this study is similar to the proposed rivoceranib regimen (250 mg QD) in combination with camrelizumab for the treatment of patients with hepatocellular carcinoma.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;This open-label, fixed-sequence, crossover, drug-drug interaction phase I study evaluated the impact of multiple oral doses of rivoceranib 200 mg QD on the single oral dose pharmacokinetics of CYP enzyme substrates administered in the modified Cooperstown 5+1 cocktail (caffeine 200 mg [CYP1A2], warfarin 10 mg [S-warfarin as CYP2C9 substrate] + vitamin K 10 mg, omeprazole 40 mg [CYP2C19], dextromethorphan 30 mg [CYP2D6], and midazolam 2 mg [CYP3A4]) in 18 healthy volunteers. After fasting, volunteers received a single dose of the Cooperstown 5+1 cocktail on day 1 and rivoceranib plus Cooperstown 5+1 cocktail on day 11. After completing a meal, volunteers received a single dose of rivoceranib on days 6-10 and 12-15. Blood samples for pharmcokinetic analyses of substrates were collected pre-dose and up to 120 h post-Cooperstown 5+1 cocktail dosing on days 1 and 11. Volunteers returned once between days 21 and 25 for safety follow-up.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Rivoceranib 200 mg QD decreased the cumulative area under the plasma concentration-time curve from time 0 to infinity (AUC&lt;sub&gt;0-inf&lt;/sub&gt;) for caffeine by 20% and maximum observed plasma concentration (C&lt;sub&gt;max&lt;/sub&gt;) by 7%, increased S-warfarin AUC&lt;sub&gt;0-inf&lt;/sub&gt; by 1.35-fold and C&lt;sub&gt;max&lt;/sub&gt; by 1.05-fold, increased omeprazole AUC&lt;sub&gt;0-inf&lt;/sub&gt; by 2.06-fold and C&lt;sub&gt;max&lt;/sub&gt; by 1.64-fold, increased dextromethorphan AUC&lt;sub&gt;0-inf&lt;/sub&gt; by 2.67-fold and C&lt;sub&gt;max&lt;/sub&gt; by 1.9-fold, and increased midazolam AUC&lt;sub&gt;0-inf&lt;/sub&gt; by 1.44-fold and C&lt;sub&gt;max&lt;/sub&gt; by 1.15-fold.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Rivoceranib 200 mg QD may substantially inhibit the metabolism of CYP2D6 substrates. Therefore, concomitant use of CYP2D6 substrate drugs with rivoceranib should be approached with caution, and dose adjustment of substrates of CYP2D6 may be necessary when co-administration cannot be avoided. Rivoceranib 200 mg QD may also exert weak inhibitory effects on the metabolism of CYP3A, CYP2C9, and CYP2C19 substrates. In such cases, close monitoring for substrate-related adverse reactions is recommended, particularly when toxicity is sensitive to increased exposures of these substrate drugs.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Clinical trial registration: &lt;/strong&gt;Clinical","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1565-1574"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148856956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A First-in-Human Study of Ulacamten, a Novel Cardiac Myosin Inhibitor for HFpEF.","authors":"Justin D Lutz, Neha Maharao, Tyrell Simkins, Kathleen Cheplo, Genzhou Liu, Camelia Dumitrescu, Adrienne Griffith, Rajaa Sukhun, Stephen B Heitner, Stuart Kupfer, Polina German","doi":"10.1007/s40262-026-01694-6","DOIUrl":"10.1007/s40262-026-01694-6","url":null,"abstract":"<p><strong>Background and objectives: </strong>Ulacamten (CK-4021586) is a small molecule allosteric inhibitor of cardiac myosin in development for treating heart failure with preserved ejection fraction. This first-in-human study evaluated safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and food effect (FE) of ulacamten in healthy adult participants.</p><p><strong>Methods: </strong>This was a phase I, double-blind, randomized, placebo-controlled, single and multiple ascending dose escalation (SAD, MAD) and FE study. Seven SAD cohorts (n = 10; eight active, two placebo) received oral doses of 10-600 mg, two MAD cohorts received 100 and 200 mg once daily for 7 days, and one FE cohort received a single 150-mg dose. Participants were required to have left ventricular ejection fraction (LVEF) ≥ 60% or ≥ 65% at screening. Intensive PK plasma sampling was conducted (Days 1, 7 [MAD only] for 168 h post dose). Safety was monitored throughout the study. Multiple echocardiographic measurements were collected (for 24 h post dose) for PD assessment.</p><p><strong>Results: </strong>Ulacamten was steadily absorbed, with median plasma half-life of 14-18 h, median t_max of 1.5-5 h, and generally dose-proportional exposure. Following multiple-dose administration, PK was linear with time, steady state was achieved by Day 4, and mean accumulation of exposure at steady state was 37-69%, consistent with the half-life. Ulacamten plasma concentrations demonstrated a modest and predictable PK/PD relationship with change from baseline in systolic function measures. All adverse events were mild or moderate in severity. Stopping criteria were not met in this study.</p><p><strong>Conclusions: </strong>Ulacamten demonstrated dose-proportional exposure, a predictable PK/PD relationship with respect to LVEF, and good tolerability, supporting its further clinical development.</p><p><strong>Clinical trial registration: </strong>ClinicalTrials.gov identifier: NCT05877053, registered May 23, 2023.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1575-1589"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13624000/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863850","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":"Differential Oral Absorption Pharmacokinetics of Tacrolimus in Simultaneous Kidney-Pancreas Transplant Compared to Kidney Transplant Recipients.","authors":"J Kamp, A Gelinck, M Lyousoufi, S Meziyerh, H S Spijker, V A L Huurman, P J M van der Boog, A P J de Vries, D J A R Moes","doi":"10.1007/s40262-026-01689-3","DOIUrl":"10.1007/s40262-026-01689-3","url":null,"abstract":"<p><strong>Background and objectives: </strong>Simultaneous pancreas kidney transplantation (SPK) is a preferred option for type 1 diabetes (T1DM) patients with end-stage renal disease (ESRD). Most transplant centers use kidney transplant (KT) protocols target trough concentrations (C₀) to dose tacrolimus in SPK recipients, due to a lack of evidence for optimal tacrolimus C₀ in SPK recipients. However, tacrolimus pharmacokinetics (PK) might be altered in SPK recipients due to diabetic gastroparesis or complications from intraperitoneal surgery and/or enteric drainage. We therefore aimed to compare oral tacrolimus PK in SPK versus KT recipients as a first step to define the optimal target tacrolimus concentrations in SPK recipients.</p><p><strong>Methods: </strong>A retrospective observational study was performed to describe and compare tacrolimus population PK in SPK and KT recipients. Relevant demographic and PK data were extracted from our local transplantation database for patients transplanted between 2005 and 2020 at our hospital. Pharmacokinetic data were analyzed using nonlinear mixed effect modeling in NONMEM. Furthermore, simulations were performed to assess potential differences in AUC_0-12h to C₀ ratios between SPK and KT recipients.</p><p><strong>Results: </strong>Tacrolimus population PK in SPK and KT recipients were best described by two-compartmental models. The combined SPK and KT model showed a significantly reduced oral absorption rate for SPK recipients, compared to KT recipients (0.231 h^-1 vs 0.336 h^-1 respectively). Simulations indicated a 10% (95% CI 8.8%-11.1%) lower AUC_0-12h to C₀ ratio in SPK recipients compared to KT recipients.</p><p><strong>Conclusions: </strong>We successfully developed two separate population PK models for tacrolimus in SPK and KT recipients together with a combined SPK and KT model, showing a significantly reduced tacrolimus oral absorption rate in SPK recipients. In addition, our data suggested that SPK recipients might need higher C₀ target concentrations to obtain a similar tacrolimus exposure as KT recipients.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1517-1525"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13623778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148763225","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":"Protein Binding Determination of Cefepime, Flucloxacillin, Meropenem, Piperacillin and Tazobactam by Ultrafiltration in Critically Ill Patients: The Choice of Device Matters.","authors":"Matthieu Gregoire, Steven C Wallis, Paul G Williams, Hayoung Won, María Patricia Hernández-Mitre, Mohd H Abdul-Aziz, Jason A Roberts","doi":"10.1007/s40262-026-01659-9","DOIUrl":"10.1007/s40262-026-01659-9","url":null,"abstract":"<p><strong>Background and objective: </strong>Therapeutic drug monitoring (TDM) and pharmacokinetic studies of beta-lactam antibiotics in critically ill patients aim to define optimal dosing and require accurate measurement of unbound drug concentrations. This study compared the performance of two ultrafiltration devices, Centrifree and Amicon, for measuring unbound concentrations of cefepime, meropenem, flucloxacillin, piperacillin and tazobactam.</p><p><strong>Methods: </strong>Non-specific binding (NSB) was specifically assessed in phosphate-buffered saline, and unbound concentrations were measured using a chromatographic method in both spiked plasma and plasma samples from critically ill patients, in order to compare the two ultrafiltration devices.</p><p><strong>Results: </strong>Centrifree exhibited no significant NSB for any antibiotics (≤ 15%), while Amicon displayed significant NSB for meropenem (26-61%), flucloxacillin (18-58%) and piperacillin (15-72%), resulting in lower unbound concentrations in both patient and spiked plasma samples compared to Centrifree. Additionally, piperacillin, and to a lesser extent flucloxacillin, demonstrated concentration-dependent NSB with Amicon. The comparative mean ± standard deviation of unbound fractions in intensive care unit (ICU) patients were as follows: cefepime, 0.85 ± 0.12 (Centrifree) versus 0.90 ± 0.10 (Amicon); meropenem, 0.87 ± 0.07 (Centrifree) versus 0.77 ± 0.05 (Amicon); flucloxacillin, 0.25 ± 0.13 (Centrifree) versus 0.18 ± 0.13 (Amicon); piperacillin, 0.91 ± 0.07 (Centrifree) versus 0.67 ± 0.13 (Amicon); and tazobactam, 0.97 ± 0.08 (Centrifree) versus 0.95 ± 0.08 (Amicon).</p><p><strong>Conclusion: </strong>These findings underscore significant differences in results between ultrafiltration devices, depending on the drug, influenced by NSB. Such factors should be considered when developing methods for determining unbound concentrations of beta-lactam antibiotics.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1553-1564"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13624041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148856968","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":"Structured Evaluation of Model-Informed Precision Dosing of Mycophenolic Acid and Tacrolimus in Pediatric Patients with Kidney Disease.","authors":"Astrid Heida, Elisabeth A M Cornelissen, Rob E Aarnoutse, Brenda C M de Winter, Ron J Keizer, Rob Ter Heine, Nynke G L Jager","doi":"10.1007/s40262-026-01708-3","DOIUrl":"https://doi.org/10.1007/s40262-026-01708-3","url":null,"abstract":"<p><strong>Background and objective: </strong>Mycophenolic acid and tacrolimus are frequently used in kidney transplant recipients and patients with nephrotic syndrome. For both drugs, therapeutic drug monitoring is recommended. Model-informed precision dosing, not only uses population pharmacokinetic data but also increases flexibility. To optimize treatment with mycophenolic acid and tacrolimus using a limited number of samples, we evaluated model-informed precision dosing for both drugs.</p><p><strong>Methods: </strong>We performed the following steps: (1) selection of population pharmacokinetic models; (2) retrospective evaluation using real-world data; and (3) evaluation of limited sampling strategies, (4) prospective evaluation of the predictive performance by predicting an area under the concentration-time curve from time zero to 12 h at a next occasion (3 months later). Acceptable bias and imprecision were defined as a mean prediction error and a normalized root mean square error of less than 25%.</p><p><strong>Results: </strong>A 3‑point sampling schedule (t = 0, t = 1, t = 2 h) provided accurate area under the concentration-time curve from time zero to 12 h estimation for both drugs, with mean prediction error and normalized root mean square error of 0.1% (- 0.3 to 0.6%) and 21.0% (7.1-34.8%) for mycophenolic acid, and 0.2% (0.03-0.4%) and 7.8% (3.0-12.6%) for tacrolimus. Substantial between-occasion variability limited the prediction of future area under the concentration-time curve from time zero to 12 h. For mycophenolic acid, the mean prediction error was 15.4% (14.4-16.4%) and the normalized root mean square error was 48.6% (18.2-79.0%). For tacrolimus, corresponding values were 64.2% (59.7-68.7%) for mean prediction error and 210% (37.1-383%) for normalized root mean square error.</p><p><strong>Conclusions: </strong>Model-informed precision dosing-guided limited sampling strategies are feasible for estimation of current exposure using similar sampling times for mycophenolic acid and tacrolimus. Accurate long-term prediction is not possible, underscoring the need for repeated therapeutic drug monitoring.</p><p><strong>Clinical trial registration: </strong>NCT06095895.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105090","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":"Understanding Pharmacokinetic Variability of Pomalidomide: A Physiologically Based Pharmacokinetic Analysis of Disease-Related Physiology, Ethnicity, Hepatic Impairment, Food Effects, Drug Interactions, and Smoking.","authors":"Jeffry Adiwidjaja, Alan V Boddy, Andrew J McLachlan","doi":"10.1007/s40262-026-01698-2","DOIUrl":"https://doi.org/10.1007/s40262-026-01698-2","url":null,"abstract":"<p><strong>Background and objective: </strong>Understanding interindividual pharmacokinetic variability and potential for drug interactions is of clinical importance for pomalidomide given its long-term use in patients with relapsed and/or refractory multiple myeloma (RRMM). This study aimed to develop a physiologically based pharmacokinetic (PBPK) model of pomalidomide that integrates multiple sources of pharmacokinetic (PK) variability, including RRMM-related physiology, ethnicity, hepatic impairment, food effects, drug interactions, and cigarette smoking.</p><p><strong>Methods: </strong>A PBPK model was developed incorporating in silico-predicted and experimentally measured physicochemical and biopharmaceutical properties, together with physiological parameters representing disease state, liver function, prandial status, and ethnic differences. Changes in PK and systemic exposure associated with multiple sources of variability, evaluated as shifts in central tendency, were predicted by the model.</p><p><strong>Results: </strong>The model provided reliable estimates of observed PK profiles across all evaluated scenarios, with more than 90% of predicted PK metrics falling within 0.80- to 1.25-fold of clinically reported values. Changes in pharmacokinetics associated with RRMM in people of European and Japanese ancestry, as well as severity-graded hepatic impairment, were reasonably predicted, despite slight overestimation of systemic exposure in severe hepatic impairment (prediction-to-reported ratio ≈ 1.55). Physiologically based pharmacokinetic model predictions of the effect of co-administration with high-fat, high-calorie meals (15-30% reduction in C_max) were also consistent with clinical observations in both European and Chinese cohorts. In addition, the PBPK model demonstrated good predictive performance in simulating moderate interactions perpetrated by fluvoxamine (cytochrome P450 1A2 [CYP1A2] inhibition) and tobacco smoking (CYP1A2 induction) and the negligible effect of ketoconazole co-administration (CYP3A4 inhibition), with predicted-to-reported C_max and AUC ratios all within the 0.90-1.05 range.</p><p><strong>Conclusions: </strong>Overall, this work highlights the utility of a PBPK modelling framework in providing mechanistic insights into multiple sources of pomalidomide PK variability, with potential broader applicability to other drugs.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105065","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":"Optimization of Cefotaxime Treatment in Intensive Care Patients: Impact of Inter- and Intra-patient Variability on Pharmacokinetics and Target Attainment.","authors":"Anthéa Deschamps, Florence Gattacceca, Olivier Blin, Lionel Velly, Romain Guilhaumou","doi":"10.1007/s40262-026-01701-w","DOIUrl":"https://doi.org/10.1007/s40262-026-01701-w","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Cefotaxime is a beta-lactam antibiotic commonly used in critically ill patients. In this population, pathophysiological features induce high inter- and intra-individual pharmacokinetic variability that can result in supra or sub-therapeutic concentrations of cefotaxime. However, factors leading to variability during the treatment course remain poorly described.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;The objective of the present study was to characterize the pharmacokinetics of cefotaxime and associated inter- and intra-individual variability in order to optimize individual dosing regimens for adult intensive care patients. Simulations based on the population pharmacokinetic model characterized the impact of these covariates on pharmacokinetic/pharmacodynamic target attainment.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Adult intensive care patients were included in a prospective observational study. Cefotaxime concentrations were measured 30 min after the loading dose, during the continuous infusion at days 1, 4, and 7 after drug initiation, and 4 h after the end of infusion. Pharmacokinetic analyses were performed using a parametric population approach. The impact of covariates was determined by combining a baseline covariate model with a time-varying covariate model. Monte Carlo simulations were performed to evaluate the probability of target attainment for different dosing regimens, with a pharmacokinetic/pharmacodynamic target of 100% of the time with cefotaxime free concentration over the minimal inhibitory concentration.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The study included 76 intensive care patients (251 cefotaxime plasma concentrations). A one-compartment model with linear elimination and proportional residual error best described the data. Serum albumin concentration, age, sex, and time-varying serum creatinine concentration were identified as significant covariates. Simulations based on the final model showed that the recommended dosing regimen (2-g loading dose followed by 6 g per day) only achieves pharmacokinetic/pharmacodynamic targets for a minimal inhibitory concentration ≤1 mg/L. As a consequence of serum creatinine concentration intra-individual variability, observed probability of target attainment decreased with time: 59.3, 56.4, and 50.7%, respectively at days 1, 4, and 7, for patients with a baseline serum creatinine concentration between 100 and 150 µmol/L. For minimum inhibitory concentration values above 1 mg/L, an initial dosing regimen of a 2-g loading dose followed by 10 g per day could be appropriate.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;A population pharmacokinetic model of cefotaxime was developed to determine both inter- and intra-individual variability in intensive care patients and was applied to evaluate the impact of various dosing regimens on pharmacokinetic/pharmacodynamic target attainment. Serum creatinine concentration explained a significant part of the observed inter- and intra-individual pha","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105083","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":"The Effect of Intrinsic Factors on the Pharmacokinetics of Once-Weekly Insulin Icodec in Type 1 and Type 2 Diabetes: A Population Pharmacokinetic Analysis of Phase II and Phase III trials.","authors":"Niels R Kristensen, Mundot P Haridas, Athena Philis-Tsimikas, Rasmus Ribel-Madsen, Chantal Mathieu","doi":"10.1007/s40262-026-01710-9","DOIUrl":"https://doi.org/10.1007/s40262-026-01710-9","url":null,"abstract":"<p><strong>Background and objective: </strong>Insulin icodec is a novel basal insulin with pharmacokinetic and pharmacodynamic properties suitable for once-weekly administration. This study evaluated the effect of several intrinsic factors on icodec exposure using population pharmacokinetic modelling.</p><p><strong>Methods: </strong>Data for the population pharmacokinetic analysis originated from one phase II and four phase III randomised, parallel-group, treat-to-target clinical trials comparing the efficacy and safety of icodec with once-daily comparators in type 1 or type 2 diabetes. A total of 1244 participants each contributed with up to seven pharmacokinetic samples during 26 weeks of icodec treatment. A one-compartment pharmacokinetic model with first-order absorption and elimination was used to estimate potential effects of individual covariates on apparent clearance.</p><p><strong>Results: </strong>There were minor or no effects of age, sex, type of diabetes, race, ethnicity, serum albumin level or anti-insulin icodec antibody level on icodec exposure. For all these covariates, the 90% confidence intervals for the icodec exposure ratio versus a reference individual were within the equivalence limits of 0.80-1.25. Icodec exposure was inversely correlated with body weight. However, the effect of body weight was of a magnitude not considered clinically relevant given that icodec, consistent with any other insulin, should be titrated according to individual needs.</p><p><strong>Conclusions: </strong>Based on the present pharmacokinetic results, no specific dose recommendations are necessary for icodec across age, sex, type of diabetes, race, ethnicity, body weight, serum albumin level and anti-insulin icodec antibody level.</p><p><strong>Clinical trial registration: </strong>ClinicalTrials.gov identifiers: NCT03751657, NCT04770532, NCT04795531, NCT04880850 and NCT04848480.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105105","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}