Clinical Pharmacokinetics最新文献

{"title":"The Effect of Food and the Proton Pump Inhibitor Rabeprazole on Binimetinib Pharmacokinetics in Healthy Participants.","authors":"Erik Hahn, Joseph Piscitelli, Dustin Huynh, Renae Chavira, Lance Wollenberg, Micaela B Reddy","doi":"10.1007/s40262-026-01676-8","DOIUrl":"10.1007/s40262-026-01676-8","url":null,"abstract":"<p><strong>Background: </strong>Binimetinib is a selective and potent MEK1/MEK2 inhibitor approved in combination with encorafenib for patients with BRAF-mutant melanoma and non-small cell lung cancer. Binimetinib is a basic amine with pH-dependent solubility in vitro, indicating that binimetinib may be susceptible to drug-drug interactions when coadministered with a proton pump inhibitor.</p><p><strong>Objective: </strong>The primary objective of this study was to evaluate the effect of a low-fat meal and high-fat meal and, separately, of multiple doses of rabeprazole 20 mg, a proton pump inhibitor, on the pharmacokinetics of a single oral dose of binimetinib 45 mg in healthy subjects.</p><p><strong>Methods: </strong>The food effect study was an open-label, randomized, three-treatment, three-period, six sequence, crossover study, and the proton pump inhibitor effect study was an open-label, two-period, two-treatment, fixed-sequence study. Both studies were conducted in healthy subjects.</p><p><strong>Results: </strong>A total of 12 participants were enrolled in the study evaluating the effect of food on binimetinib pharmacokinetics and 15 participants were enrolled in the study evaluating the effect of concomitant proton pump inhibitor use on binimetinib pharmacokinetics. The area under the plasma concentration-time curve from 0 extrapolated to infinity for binimetinib did not change in the presence of either a low-fat meal or high-fat meal compared to in the fasted state. The geometric mean ratio peak plasma concentration increased 29% with a low-fat meal and decreased by 17.2% with a high-fat meal. The area under the plasma concentration-time curve from 0 extrapolated to infinity and maximum concentration geometric mean ratio values for binimetinib in the presence of oral rabeprazole versus binimetinib alone increased by 4% and decreased by 17.4%, respectively. There were no serious adverse events or patient discontinuations in either study.</p><p><strong>Conclusions: </strong>The results indicate that there were no clinically significant changes in pharmacokinetics or tolerability resulting from meals or proton pump inhibitor use during concomitant administration with binimetinib.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1367-1376"},"PeriodicalIF":4.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13545144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148590872","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 Analyses to Inform the Optimal Epcoritamab Monotherapy Dosing Regimen in Relapsed or Refractory Follicular Lymphoma.","authors":"Mahipal Sinnollareddy, Kinjal Sanghavi, Leonid Gibiansky, Tommy Li, Matthew Putnins, Mohamed-Eslam F Mohamed, Poliana Patah, Elena Favaro, Manish Gupta, Apurvasena Parikh, Steven Xu","doi":"10.1007/s40262-026-01661-1","DOIUrl":"10.1007/s40262-026-01661-1","url":null,"abstract":"<p><strong>Background: </strong>Epcoritamab is approved for treating various relapsed/refractory (R/R) lymphomas. In a phase I/II study in R/R follicular lymphoma (FL) patients, epcoritamab demonstrated high response rates (EPCORE NHL-1: objective response rate [ORR]: 82.0%, complete response [CR] rate: 62.5% [N = 128]; EPCORE NHL-3: ORR: 95.2%, CR rate: 76.2% [N = 21]) with durable responses and a manageable safety profile with a 2-step step-up dosing (SUD) regimen (0.16/0.8/48 mg [full dose]; Cycles 1-3: once-weekly dosing [QW], Cycles 4-9: every 2-week dosing [Q2W], Cycles 10+: every 4-week dosing [Q4W]).</p><p><strong>Methods: </strong>A prior population pharmacokinetic model was updated and exposure-response analyses performed to support the selected dosing regimen (0.76-48 mg full doses evaluated).</p><p><strong>Results: </strong>Higher epcoritamab exposure was associated with higher efficacy (ORR, CR rate, progression-free survival, overall survival; p < 0.05) with potential response rate plateau at 48-mg exposures. Initial response occurred in 96.2% of responders during QW with most maintaining/improving response during Q2W and Q4W, independent of Cycle 4+ exposure. No meaningful trends between epcoritamab exposure and treatment-emergent adverse events were identified, including cytokine release syndrome (CRS). Further optimization using a 3-step SUD regimen (0.16/0.8/3/48 mg), with adequate hydration and dexamethasone prophylaxis in Cycle 1, lowered CRS frequency and severity compared with the 2-step SUD regimen. Similar pharmacokinetics and B-cell depletion occurred with 3-step and 2-step SUD regimens. Median IL-6 levels remained consistently low after each Cycle-1 dose and beyond with the 3-step but not 2-step SUD regimen.</p><p><strong>Conclusion: </strong>These analyses support and confirm the recommended 3-step SUD regimen with 48 mg full epcoritamab dose administered QW-Q2W-Q4W in patients with R/R FL.</p><p><strong>Clinical trial registration: </strong>ClinicalTrials.gov: NCT03625037, NCT04542824.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1415-1428"},"PeriodicalIF":4.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13545055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148653184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetics of Bosutinib in Children with Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia Based on a Phase I Dose-Finding Trial (ITCC-054/COG AAML1921) and Pediatric Recommended Phase II Dosage Evaluation.","authors":"Jen-Hao Wu, Francisco Bautista, Erica Brivio, Marieke Willemse, Karey Kowalski, Brian Jermain, May Garrett, Andrew Bukowinski, Carmelo Rizzari, Jessica Pollard, Laura Murillo-Sanjuán, Matthew Kutny, Sara Zarnegar-Lumley, Michele Redell, Stacy Cooper, Yves Bertrand, Arnaud Petit, Julie Krystal, Markus Metzler, Donna Lancaster, Jean-Pierre Bourquin, Jayashree Motwani, Inge M van der Sluis, Franco Locatelli, Michael E Roth, Nobuko Hijiya, C Michel Zwaan, Alwin D R Huitema","doi":"10.1007/s40262-026-01672-y","DOIUrl":"10.1007/s40262-026-01672-y","url":null,"abstract":"<p><strong>Background and objectives: </strong>Bosutinib, an orally administered dual Src and Bcr-Abl tyrosine kinase inhibitor (TKI), is approved for the treatment of chronic phase Philadelphia chromosome-positive chronic myelogenous leukemia, newly diagnosed or resistant/intolerant to previous treatment of one or more TKIs in adults and children ≥ 1 years (by the US Food and Drug Administration) and ≥ 6 years (by the European Medicines Agency). Owing to the limitations of non-compartmental analysis in pharmacokinetic (PK) characterization, this study applies a prior population PK modeling approach to describe the pediatric PK of bosutinib on the basis of its phase I dose-finding trial and the available bosutinib adult PK knowledge.</p><p><strong>Methods: </strong>From 26 pediatric patients in the phase I part of the ITCC-054/COG AAML1921 trial, 235 plasma bosutinib concentration samples were analyzed. A published adult bosutinib population PK (popPK) model was used as the reference model; the frequentist prior modeling approach was used during model development to integrate adult PK information, especially for parameters with poor identifiability.</p><p><strong>Results: </strong>Bosutinib pediatric PK was well characterized by a two-compartment model with first-order absorption, an absorption lag time of 0.467 h, and allometric scaling with fixed exponents. The typical clearance was 74.9 L/h (normalized to 70 kg), higher than the reported adult value (56.3 L/h). Model-based simulations validated that the bosutinib recommended phase II dose (RP2D) could achieve the target exposure observed in adults and demonstrated the influence of higher clearance in pediatric patients.</p><p><strong>Conclusions: </strong>This study presents the first pediatric bosutinib popPK model, integrating prior adult PK knowledge to enable robust PK characterization using a small pediatric dataset from an early trial stage. In addition, the model confirms a higher clearance in children and supports the RP2D concluded in the phase I dose-finding part of the ITCC-054/COG AAML1921 trial.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1389-1403"},"PeriodicalIF":4.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13545124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148599648","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":"Low Tacrolimus C₀/Dose Ratio is Associated with Higher C_max and AUC Despite Similar Pre-dose Concentrations.","authors":"Amar D Levens, Teun van Gelder, Armin Gelinck, Soufian Meziyerh, Aiko P J de Vries, Danny van der Helm, Jesse J Swen, Dirk Jan A R Moes","doi":"10.1007/s40262-026-01683-9","DOIUrl":"10.1007/s40262-026-01683-9","url":null,"abstract":"<p><strong>Background and objective: </strong>Tacrolimus therapeutic drug monitoring after kidney transplantation is primarily guided by the pre-dose concentration (C₀), assuming it reflects overall drug exposure. At the same time, the tacrolimus concentration-to-dose ratio (C₀/dose) has emerged as a marker associated with clinical outcomes after transplantation, suggesting that differences in peak (maximum concentration [C_max]) and total tacrolimus exposure (area under the concentration-time curve from 0 to 24 h [AUC_0-24h]) may not be fully captured by C₀ alone.</p><p><strong>Methods: </strong>In 534 kidney transplant recipients followed for up to 13 months post-transplantation, 635 tacrolimus pharmacokinetic profiles with corresponding C₀ values were analyzed. The C₀/dose category was defined using the C₀/dose ratio and classified as fast (<1.05 ng·mL⁻¹·mg⁻¹, n = 344), intermediate (1.05-1.53, n = 127), or slow (≥1.54, n = 164). Analyses were restricted to measurements with C₀ between 5.0 and 6.0 ng/mL to compare C_max and AUC_0-24h across C₀/dose categories and tacrolimus formulations (immediate release vs extended release) using linear mixed-effects models. Sensitivity analyses evaluated C₀-adjusted C_max and AUC_0-24h in the full cohort (4271 pharmacokinetic profiles) and assessed consistency when C_max was predicted using population pharmacokinetic models.</p><p><strong>Results: </strong>Despite comparable C₀ levels, the fast C₀/dose category was associated with substantially higher tacrolimus doses and had higher peak concentration and total exposure. Under immediate-release tacrolimus, C_max and AUC_0-24h were 30 and 18% higher, respectively, compared with the slow category. Under extended-release tacrolimus, differences were more pronounced, with 86% higher C_max (estimate: 1.86, 95% confidence interval 1.61-2.13) and 46% higher AUC_0-24h (estimate: 1.45, 95% confidence interval 1.35-1.55). The intermediate category showed a smaller but consistent increase in exposure. Higher C_max and AUC_0-24h relative to C₀ in fast metabolizers remained consistent in the full cohort and when C_max was model predicted.</p><p><strong>Conclusions: </strong>Tacrolimus C₀ alone incompletely reflects the full pharmacokinetic profile and may miss clinically relevant peak-related toxicity. The C₀/dose ratio may help identify patients with disproportionate exposure, in whom more individualized therapeutic drug monitoring beyond C₀ monitoring is recommended.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1339-1351"},"PeriodicalIF":4.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13545023/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148560968","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":"Physiologically Based Pharmacokinetic Modeling of Vedolizumab in Healthy Adults and Patients with Inflammatory Bowel Disease.","authors":"Sanjana Parikh, Kei Irie, Ryota Tanaka, Takanobu Nadai, Phillip Minar, Tomoyuki Mizuno","doi":"10.1007/s40262-026-01682-w","DOIUrl":"10.1007/s40262-026-01682-w","url":null,"abstract":"<p><strong>Background and objective: </strong>Vedolizumab is a gut-selective, humanized monoclonal antibody that binds to α4β7 integrin, preventing lymphocyte trafficking to the intestinal mucosa. While approved for adults with moderate-to-severe ulcerative colitis (UC) or Crohn's disease (CD), drug exposure may vary significantly with disease activity. Physiologically based pharmacokinetic (PBPK) modeling provides a mechanistic framework to integrate drug properties with system physiology, enabling the prediction of pharmacokinetics (PK) under these various pathophysiological conditions. In this study, we developed a minimal mechanistic PBPK model incorporating target-mediated drug disposition (TMDD) to characterize the PK of healthy adults and patients with varying inflammatory bowel disease severity.</p><p><strong>Methods: </strong>A minimal PBPK model incorporating TMDD was developed for vedolizumab using the Simcyp Simulator. The model was parameterized with literature values for healthy adults, verified against clinical PK data from healthy volunteers, and adapted for patients with varying disease severity by estimating target abundance (R_max) to reflect α4β7 upregulation in active inflammation. Model performance was assessed by comparing simulated and observed concentration-time profiles and predicted-to-observed (P/O) ratios for peak concentration (C_max), area under the curve from time 0 to time of the last concentration (AUC_0-tlast), and trough concentration (C_trough).</p><p><strong>Results: </strong>The PBPK model demonstrated robust predictive performance across varying disease states and ethnicities, compared with reported PK parameters in clinical studies. In healthy adults, mean P/O ratios for C_max and AUC_0-tlast ranged from 0.81 to 1.11 and 0.80 to 1.02, respectively, across single doses of 0.2-10 mg/kg. For patients with mild-to-moderate UC, the estimated R_max yielded mean P/O ratios for C_max and AUC_0-tlast of 0.88-1.02 and 0.78-0.99, respectively. Additionally, for moderate-to-severe UC and CD, mean P/O ratios for C_trough fell within 0.67-1.49. Simulations indicated that higher R_max values increased clearance and reduced systemic exposure, with mean predicted C_trough in high target-expression groups frequently falling below the efficacy thresholds of 12 μg/mL and 14 μg/mL.</p><p><strong>Conclusions: </strong>This study presents the first PBPK model for vedolizumab that quantitatively captures disease-related α4β7 upregulation and its impact on PK in adults. The model provides a mechanistic basis for simulating exposure across disease states and supports model-informed precision dosing strategies to optimize treatment outcomes in UC and CD.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1377-1388"},"PeriodicalIF":4.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13545043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148590893","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":"Transitioning Therapeutic Antibodies in Oncology from Intravenous to Hyaluronidase-Facilitated Subcutaneous Administration.","authors":"Xu Steven Xu","doi":"10.1007/s40262-026-01669-7","DOIUrl":"10.1007/s40262-026-01669-7","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Intravenous (IV) infusion remains the predominant delivery route for oncology monoclonal antibodies, but it requires prolonged chair time and substantial infusion-unit resources. Hyaluronidase-facilitated subcutaneous (SC) formulations aim to shorten administration (minutes vs hours), improve convenience, and potentially expand outpatient or home-based delivery, while preserving exposure, efficacy, and safety. We conducted a narrative review of published clinical studies, major congress presentations, trial registries, and Food and Drug Administration (FDA)/European Medicines Agency (EMA) regulatory documents describing development of hyaluronidase-facilitated SC formulations for seven oncology antibodies (trastuzumab, rituximab, daratumumab, atezolizumab, nivolumab, pembrolizumab, and amivantamab). We extracted evidence on formulation strategy, pharmacokinetic (PK) bridging, efficacy comparability, safety/immunogenicity, and regulatory pathways supporting IV→SC approval. Across programs, PH20-based recombinant hyaluronidases, including human hyaluronidase PH20 (rHuPH20) and berahyaluronidase alfa, transiently depolymerize SC hyaluronan, enabling delivery of multi-milliliter injections and high fixed doses. Development strategies converged on PK-anchored bridging, typically targeting non-inferior SC/IV geometric-mean ratios for both initiation and maintenance exposure (e.g., cycle-1 area under the curve [AUC]/average plasma concentration [C&lt;sub&gt;avg&lt;/sub&gt;] and minimum plasma concentration [C&lt;sub&gt;min&lt;/sub&gt;]/trough concentration [C&lt;sub&gt;trough&lt;/sub&gt;]), supported by population PK to ensure covariate coverage. We highlight a pragmatic evolution in trial design: earlier conversions often paired PK with direct clinical activity confirmation in sensitive settings, whereas more recent programs increasingly use prespecified PK non-inferiority as the confirmatory backbone with efficacy as supportive reassurance-enabling use of an approved SC formulation across multiple indications. In pivotal bridging trials, SC regimens generally met or exceeded exposure targets and demonstrated efficacy consistent with IV comparators (treatment effects clustering around unity; Δ ≈ 0; hazard ratio/relative risk ≈ 1). Safety profiles were broadly similar; SC administration was associated with fewer administration-related reactions for several agents, while injection-site reactions were usually mild. Immunogenicity, including anti-hyaluronidase antibodies, did not show consistent clinically meaningful effects on PK or outcomes. Hyaluronidase-facilitated IV→SC conversion has become a reproducible, model-informed, PK-driven development paradigm. By synthesizing study-design choices, formulation pathways, and extrapolation logic across seven approved antibodies-including the recent IO and targeted-therapy wave-this review builds upon a previously described clinical bridging concept and provides a comprehensive updated overview including the most recently approved products,","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1277-1294"},"PeriodicalIF":4.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469413","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 Intravenous Vitamin C in Adults with Sepsis: A Sub-study of the LOVIT Trial.","authors":"Salmaan Kanji, María Patricia Hernández-Mitre, Hugues Blain, Neill K J Adhikari, Francois Lamontagne, Marie-Claude Battista, Julie Ménard, Sheila Sprague, Marie-Hélène Masse, Jason A Roberts","doi":"10.1007/s40262-026-01648-y","DOIUrl":"10.1007/s40262-026-01648-y","url":null,"abstract":"<p><strong>Background and objectives: </strong>High-dose intravenous vitamin C was associated with increased harm in adults with sepsis requiring vasopressors in the large international LOVIT trial. This population pharmacokinetic sub-study of LOVIT aimed to characterise the pharmacokinetics of vitamin C and explore associations with patient characteristics and outcomes.</p><p><strong>Methods: </strong>Patients who enrolled in the LOVIT trial were randomized to receive 50 mg/kg vitamin C every 6 hours for 96 hours or placebo. Blood samples were collected on study Days 1, 3, and 7 for plasma vitamin C quantification. Population pharmacokinetic modeling was performed, with relevant patient and treatment-related factors tested as covariates. Internal validation was conducted using bootstrap resampling (n = 1000). Univariable and multivariable analyses explored associations between 28-day mortality and patient characteristics, as well as the relationship between vitamin C exposure and severity of illness.</p><p><strong>Results: </strong>A total of 464 samples from 161 patients who were randomized to vitamin C were analysed. The median age was 64 (interquartile range [IQR] 56-72) years, weight 82 (IQR, 70-94) kg, and APACHE II score 24 (IQR, 18-29); 65.2% were male. A one-compartment model best described the data, with clearance (CL) significantly influenced by CKD-EPI eGFR and APACHE II score. Population mean estimates for clearance and volume of distribution were 3.37 L/h and 45.06 L, respectively. The model was internally validated and demonstrated to be robust and stable. Although greater vitamin C exposure was observed among non-survivors versus survivors (median 1900.5 [IQR 1191.8-2548.2] vs 1017.8 [IQR 630-1836.7] mg·h/L; p < 0.001), only age (odds ratio [OR] 1.063; 95% confidence interval [CI] 1.024-1.104, p = 0.001) and APACHE II score (OR 1.079; 95% CI 1.005-1.158, p = 0.036) were independently associated with 28-day mortality. Severity of illness was also predictive of vitamin C exposure.</p><p><strong>Conclusions: </strong>Vitamin C pharmacokinetics are highly variable between individuals. Some of this variability can be explained by changes in glomerular filtration and APACHE II score as a measure of illness severity. Although non-survivors had greater vitamin C exposure than survivors, exposure was not independently associated with mortality.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1205-1216"},"PeriodicalIF":4.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148292985","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":"How Feasible is the Use of Saliva for Antiviral Therapeutic Drug Monitoring? A Systematic Review and Analysis.","authors":"Cassandra Weng-Yan Lai, Suzanne A M Wenker, Paul W Groundwater, Justin Beardsley, Gaurav Sutrave, Ricky Hao Chen, Anne-Grete Märtson, Jan-Willem C Alffenaar","doi":"10.1007/s40262-026-01675-9","DOIUrl":"10.1007/s40262-026-01675-9","url":null,"abstract":"<p><strong>Background and objective: </strong>Immunosuppressed patients are susceptible to serious viral infections, often necessitating antiviral prophylaxis and/or treatment. Therapeutic drug monitoring (TDM) has been proposed to optimise drug exposure and clinical outcomes and is typically performed on full blood/plasma samples. Saliva offers a less invasive, patient-friendly approach, and this systematic review aims to assess the feasibility of saliva-based assays for antiviral TDM.</p><p><strong>Methods: </strong>We conducted a search on MEDLINE, EMBASE and ClinicalTrials.gov databases, governmental regulatory websites and conference abstracts. Primary studies reporting both saliva and plasma concentrations of antivirals used forprophylaxis or treatment of opportunistic viral infections were included. Physicochemical properties of eachantiviral were compiled from PubChem and DrugBank to predict salivary excretion. Feasibility classifications were defined as follows: (1) likely, (2) possible, (3) unlikely, (4) unclear but possible, (5) unclear but unlikely.</p><p><strong>Results: </strong>We included nine studies in our review. (Val)acyclovir and favipiravir were considered possibly feasible for saliva-based TDM, whereas molnupiravir and oseltamivir were unclear but possible. Nirmatrelvir was deemed unclear but unlikely. For other included antivirals, no primary studies were available, however, physicochemical profiles suggest that salivary penetration may be feasible for some agents but limited for others.</p><p><strong>Conclusion: </strong>Studies documenting both saliva and plasma concentrations were scarce, and data was inconsistent. Findings from clinical studies sometimes contradicted predictions of penetration based on drug properties, suggesting that other factors, such as drug transporters, may significantly influence the salivary excretion of antivirals. Future robust, standardised investigations are required to confirm the clinical utility of saliva-based TDM. Feasibility is therefore currently inconclusive, but preliminary evidence is promising.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1155-1172"},"PeriodicalIF":4.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13461875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148677258","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":"Correction: Population Pharmacokinetic-Pharmacodynamic Relationships of Sarilumab Using Disease Activity Score 28‑Joint C‑Reactive Protein and Absolute Neutrophil Counts in Patients with Rheumatoid Arthritis.","authors":"Lei Ma, Christine Xu, Anne Paccaly, Vanaja Kanamaluru","doi":"10.1007/s40262-026-01656-y","DOIUrl":"10.1007/s40262-026-01656-y","url":null,"abstract":"","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1273-1274"},"PeriodicalIF":4.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13461850/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419335","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":"Blood Never Lies: The PopPK-Based Lie Detector.","authors":"Sahira Chaiben, Peggy Gandia, Béatrice Duly-Bouhanick, Lauriane Goldwirt, Didier Concordet","doi":"10.1007/s40262-026-01652-2","DOIUrl":"10.1007/s40262-026-01652-2","url":null,"abstract":"<p><strong>Background and objective: </strong>Accurate assessment of drug adherence is essential for long-term oral therapies, where self-administration is unsupervised. Conventional tools such as self-reports, electronic monitors, and even therapeutic drug monitoring often fail to detect non-adherence. Population pharmacokinetic modeling improves objectivity but typically relies on a single analyte, which may still miss hidden non-adherence. We propose a bi-analyte population pharmacokinetic-based approach that uses both the parent drug and a metabolite with distinct pharmacokinetics to enhance adherence detection and reconstruct likely dosing histories.</p><p><strong>Methods: </strong>A literature review identified spironolactone and its metabolite canrenone as suitable candidates, based on long-term use and an available population pharmacokinetic model capturing distinct elimination profiles. Virtual patients were simulated under steady-state assumptions, then exposed to various adherence scenarios. A modified Metropolis-Hastings algorithm jointly estimated individual pharmacokinetic parameters and dosing patterns by analyzing simulated drug and metabolite concentrations. The probability of taking 0, 1, or 2 tablets per day was inferred, and a posterior adherence probability was derived from the posterior distribution to quantify adherence likelihood. A receiver operating characteristic analysis was used to evaluate diagnostic performance.</p><p><strong>Results: </strong>The combined use of parent and metabolite improved non-adherence detection compared with either alone, particularly for recent missed doses. Trough concentrations outperformed peak concentrations, especially when patients did not compensate with extra doses.</p><p><strong>Conclusions: </strong>This probabilistic bi-analyte approach enhances non-adherence detection and is adaptable to other pharmacokinetic settings where distinct profiles and low model variability are present.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1193-1204"},"PeriodicalIF":4.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13461949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148257478","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}