Clinical Pharmacokinetics[JOURNAL]
Sun
200 papers
Pharmacokinetic-Pharmacodynamic Modeling and Simulation of Merigolix, a Nonpeptide Gonadotropin-Releasing Hormone Antagonist.
Bae SH, Kang J, Jeon S … +4 more , Kim SM, Kim HT, Han S, Han S
Clin Pharmacokinet · 2026 Mar · PMID 41420759 · Publisher ↗
Gonadotropin-releasing hormone (GnRH) antagonists inhibit estrogen synthesis and secretion, making them promising treatment options for estrogen-dependent diseases, such as endometriosis. This study developed a populatio...
Gonadotropin-releasing hormone (GnRH) antagonists inhibit estrogen synthesis and secretion, making them promising treatment options for estrogen-dependent diseases, such as endometriosis. This study developed a population pharmacokinetic/pharmacodynamic (PK/PD) model for merigolix, a novel oral GnRH antagonist, to determine its optimal dosing in the treatment of endometriosis. Population PK/PD modeling was performed using NONMEM 7.4, incorporating data from phase I clinical studies involving single and multiple ascending dose (SAD and MAD) trials in healthy premenopausal volunteers. The PK profile was characterized using a two-compartment model incorporating first-order absorption and elimination processes. The temporal delay between merigolix concentration and subsequent estradiol (E2) suppression was described using an indirect response turnover model. The models were evaluated via visual predictive checks, goodness-of-fit plots, and bootstrap analysis. The PK model described merigolix concentrations across various doses (estimated clearance: 549 L/h, central volume of distribution: 1690 L). The PD model demonstrated dose-dependent E2 suppression (estimated maximum inhibitory effect [I]: 1, half-maximal inhibitory concentration [IC]: 0.209 ng/mL). Simulations suggested that, assuming a baseline E2 concentration of 100 pg/mL, daily doses of 120 and 160 mg achieved the clinically meaningful target E2 range of 20-40 pg/mL (partial suppression), while higher doses of 240 and 320 mg resulted in target E2 levels below 20 pg/mL (full suppression), effectively controlling symptoms and minimizing the risk of bone mineral density loss. This PK/PD model provides a quantitative framework for optimizing merigolix dosing and supports the selection of dosing regimens for future clinical trials, potentially offering a novel therapeutic option for endometriosis treatment.
Development and Validation of a Chinese Obesity-Specific Physiological Database for PBPK Modeling.
Yang R, Wen Y, Zhang S … +3 more , Yang G, Zhu L, Pei Q
Clin Pharmacokinet · 2026 Feb · PMID 41390893 · Publisher ↗
OBJECTIVES: To develop and validate a physiologically based pharmacokinetic (PBPK) population model for the Chinese obese population. METHODS: A Chinese adult population database was established in PK-Sim through recalib...
OBJECTIVES: To develop and validate a physiologically based pharmacokinetic (PBPK) population model for the Chinese obese population. METHODS: A Chinese adult population database was established in PK-Sim through recalibration of the East Asian population database, using newly collected anatomical and physiological data from Chinese adults. All three drugs (dexmedetomidine, omeprazole, and propofol) possessing Chinese obese population PK data were selected, with their PBPK models then developed and validated using matched clinical data. These models with the fixed drug-specific parameters were applied to the Chinese adult database to simulate drug concentrations, with results compared with the built-in East Asian database. Then, physiological parameters were adjusted using real-world and literature data from Chinese patients with obesity to establish a Chinese obese adult database. Similarly, drug concentrations in this population were simulated and compared with the simulation results based on the published White obese population database. RESULTS: The predicted C and AUC values were within 0.5-2 fold of the observed values, demonstrating all drug models were validated. The Chinese adult database showed superior accuracy to the East Asian database (90% versus 75% of AUC and 80% versus 70% of C within 0.8-1.25 fold). Similarly, the Chinese obese database outperformed the White obese database (83% versus 33% for AUC and 33% versus 0% for C within 0.8-1.25 fold). CONCLUSIONS: The validated drug models, combined with the Chinese adult and obese adult databases, reliably predicted drug concentrations in Chinese adults and adults with obesity, outperforming the East Asian population database and White obese population database.
Platform Assessment of Concentration-QTc Relationship Across GalNAc-siRNA Molecules.
Badri P, Kolachana K, Duong A … +4 more , Lasko M, Nandi T, Mehrotra N, Robbie GJ
Clin Pharmacokinet · 2026 Feb · PMID 41388232 · Full text
BACKGROUND: GalNAc-conjugated short interfering RNAs (GalNAc-siRNAs) lack a biologically plausible mechanism for QT/QTc prolongation based on their unique physicochemical and absorption, distribution, metabolism, and exc...
BACKGROUND: GalNAc-conjugated short interfering RNAs (GalNAc-siRNAs) lack a biologically plausible mechanism for QT/QTc prolongation based on their unique physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties. Nevertheless, regulatory agencies require characterization of QTc effects via either a thorough QT (TQT) study or a concentration-QTc (C-QTc) analysis using early-phase data. This manuscript summarizes platform-level experience across eight GalNAc-siRNAs to assess QTc prolongation risk via C-QTc analysis. METHODS: Time-matched electrocardiogram (ECG) data and plasma concentration data collected from phase 1/2 studies (N = 686), involving healthy subjects and/or patients receiving single ascending doses of study drug or placebo, were used for C-QTc analysis for eight GalNAc-siRNAs. For each drug, individual and mean change from baseline in placebo-corrected values of Fridericia corrected QT interval (∆ΔQTcF) were assessed over time. Linear regression analysis evaluated the relationship between plasma concentrations of parent/metabolite and ∆ΔQTcF. A concentration-dependent QTc effect was defined as an increase of ≥ 10 ms in the upper bound of the 90% confidence interval (CI) for predicted ∆∆QTcF at the clinically relevant exposures. As per International Council for Harmonisation (ICH) E14 guidance, categorical analyses of QTcF interval data were also performed. RESULTS: GalNAc-siRNAs demonstrated similar pharmacokinetics with rapid absorption and short plasma half-lives, with concentrations typically declining to below quantifiable levels within 24-48 h. Across the eight GalNAc-siRNAs, there were no dose-dependent increases in ∆∆QTcF over time. No subject had a QTcF interval > 500 ms or a change from baseline > 60 ms. Slopes of the linear regression of concentration versus ∆∆QTcF were close to zero, and the upper bound of 90% CI for ∆∆QTcF values at mean C values of the highest doses tested was well below 10 ms. CONCLUSIONS: No concentration-dependent increase in QTcF was observed with multiple GalNAc-siRNA molecules across diverse targets and indications, confirming that GalNAc-siRNAs are highly unlikely to pose a QT prolongation risk. Hence, dedicated TQT studies are not necessary for the molecules in this platform and assessment of C-QTc relationships from early clinical studies up to maximum feasible clinical doses, which might be less than twofold of the likely therapeutic dose, is sufficient to assess the QT liability. CLINICAL TRIAL REGISTRATION NOS: NCT02797847, NCT04565717, NCT02706886, NCT05256810, NCT03338816, NCT03934307, NCT05661916, and NCT05761301.
Antibacterial Pharmacokinetics in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation (ECMO): A Systematic Review of Population Pharmacokinetic Studies.
Ren C, Huang F, Cheng V … +3 more , Xie J, Roberts JA, Abdul-Aziz MH
Clin Pharmacokinet · 2026 Feb · PMID 41385144 · Publisher ↗
BACKGROUND AND OBJECTIVE: Achieving optimal antibacterial dosing in critically ill patients is challenging owing to the pathophysiological changes that alter drug pharmacokinetics. Extracorporeal membrane oxygenation (EC...
BACKGROUND AND OBJECTIVE: Achieving optimal antibacterial dosing in critically ill patients is challenging owing to the pathophysiological changes that alter drug pharmacokinetics. Extracorporeal membrane oxygenation (ECMO) further complicates pharmacokinetics, hypothesized to act as another pharmacokinetic compartment influencing drug concentrations. Ensuring therapeutic antibacterial concentrations is crucial to prevent treatment failure and resistance. This systematic review aimed to identify and evaluate published population pharmacokinetic studies of antibacterials in critically ill adult ECMO patients. METHODS: A systematic search of PubMed, Embase, and Cochrane databases was conducted from database inception to March 2025. Studies were included if they were population pharmacokinetic analyses of antibacterial agents in adult (aged ≥ 18 years) ECMO patients; non-compartmental analyses and non-antibacterial agents were excluded. Data on study characteristics, patient demographics, ECMO parameters, pharmacokinetic models, and covariates were extracted. RESULTS: The search yielded 31 eligible population pharmacokinetic studies. Most studies indicated that ECMO-specific variables (mode, flow rate, oxygenator type) did not significantly influence the pharmacokinetics of the majority of antibacterials. Instead, pharmacokinetic variability was primarily driven by critical illness-related factors, notably renal function and presence of renal replacement therapy. Dosing recommendations frequently highlighted the need for individualized therapy and therapeutic drug monitoring. CONCLUSIONS: Our findings indicate that ECMO itself does not consistently alter the pharmacokinetics of most antibacterials in critically ill adult patients. Observed pharmacokinetic variability and subsequent dosing recommendations are primarily attributable to critical illness factors. Therapeutic drug monitoring is recommended to optimize exposure but minimize toxicity. Further prospective studies with standardized reporting of covariates and clinical endpoints are needed to enhance the evidence base. CLINICAL TRIAL REGISTRATION: PROSPERO Registration and date: CRD420251165914 (15 October, 2025).
Population Pharmacokinetics of Total and Protein-Unbound Prednisolone in Children with Immune-Mediated and Systemic Inflammatory Diseases.
Möhlmann JE, Lindemans CA, Jansen MHA … +6 more , van Luin M, Punt AM, Ezzafzafi S, Nierkens S, Huitema ADR, de Vries Schultink AHM
Clin Pharmacokinet · 2026 Feb · PMID 41379279 · Full text
BACKGROUND AND OBJECTIVE: High-dose systemic prednisolone is the mainstay treatment of children with various (auto)immune diseases. The standard empirical dosing regimen with dosages up to 2 mg/kg/day is generally adequa...
BACKGROUND AND OBJECTIVE: High-dose systemic prednisolone is the mainstay treatment of children with various (auto)immune diseases. The standard empirical dosing regimen with dosages up to 2 mg/kg/day is generally adequate for immune suppression, though often accompanied by substantial adverse effects in the majority of patients. Pharmacokinetic (PK) variability may be an important determinant for both efficacy and toxicity but has only limitedly been investigated in children. This research aimed to characterise the population pharmacokinetics and determinants of variability of protein-bound and unbound prednisolone in children with (auto)immune diseases. METHODS: Patients received ≥ 0.5 mg/kg systemic prednisolone for either an autoimmune disease or as part of allogeneic haematopoietic cell transplantation (HCT). A priori allometric scaling was implemented, normalised to a body weight (BW) of 70 kg. RESULTS: The study population consisted of 60 children with a median (range) age of 10 (0.2-19) years and a BW of 36.5 (5.0-109) kg. A total of 305 serum samples from 68 PK occasions were measured for total and protein-unbound prednisolone concentrations. The PK data were best described by a two-compartment model, accounting for both the linear and saturable binding of prednisolone to albumin and corticosteroid binding globulin (CBG), respectively, and the circadian rhythm of CBG. The population estimates (95% confidence interval [CI]) for the binding affinity of prednisolone to albumin was 200 µM (164-253) and to CBG was 0.048 µM (0.043-0.053). The population estimate for clearance (95% CI) was 155 L/h (137-182). Patients with prednisolone as prophylaxis following HCT had a 10% higher clearance compared with patients treated for graft-versus-host disease or an autoimmune disease. CONCLUSION: This population PK model provides valuable insights into PK variability of prednisolone and can be used to address the clinical implications of BW-based dosing of prednisolone in children with immune-mediated and inflammatory diseases.
Pharmacokinetics and Target Attainment of Fluoroquinolones in Older Adults: A Systematic Review.
De Clercq A, Vervalcke J, De Petter C … +5 more , De Ryck S, Desmet T, De Paepe P, Petrovic M, De Cock PA
Clin Pharmacokinet · 2026 Jan · PMID 41348398 · Publisher ↗
BACKGROUND AND OBJECTIVE: Fluoroquinolones are among the most frequently prescribed antibiotics in older adults. Age-related pharmacokinetic (PK) changes can affect treatment efficacy and increase the risk of adverse dru...
BACKGROUND AND OBJECTIVE: Fluoroquinolones are among the most frequently prescribed antibiotics in older adults. Age-related pharmacokinetic (PK) changes can affect treatment efficacy and increase the risk of adverse drug reactions. This systematic review provides a comprehensive overview of the current knowledge on the PK and PK/pharmacodynamic (PD) target attainment of fluoroquinolones in older adults to inform strategies for personalised fluoroquinolone therapy. METHODS: A comprehensive search of the Medline, Embase, Web of Science and Scopus databases was conducted. Relevant articles published before 1 December 2024 were included when they contained data on the PK of fluoroquinolones in older adults (median age ≥ 65 years). Extracted information included PK parameters, significant covariates influencing PK parameters, PK/PD target attainment rates and dosing recommendations. The ClinPK Statement checklist was used for quality grading. RESULTS: Fifty-five articles were included in this review, encompassing a total of 1542 non-critically ill older adults and 585 younger controls. Eight articles (14.5%) identified covariates with a significant effect on PK parameters. Most of these covariates (66.7%) were indicators of renal function. PK/PD target attainment was assessed in 30.9%, and dosing recommendations were provided in 61.8% of all included PK studies. Studies had an average quality score of 65.9% (standard deviation, SD ± 12.3%). CONCLUSIONS: High-quality PK studies on fluoroquinolones in older adults remain sparse. While a substantial amount of the included articles provided dosing recommendations, only a minority did so on the basis of PK/PD target attainment data. The limited application of advanced PK/PD modeling and simulation approaches hampers the development of evidence-based, individualised fluoroquinolone dosing strategies in older adults. TRIAL REGISTRATION: Prospectively registered in PROSPERO. TRIAL REGISTRATION NUMBER: CRD42023480126. Registration date: 17/11/2023.
Guidance for External Evaluation and Selection of Population Pharmacokinetic Models for Precision Dosing.
El Hassani M, Marsot A
Clin Pharmacokinet · 2026 Jan · PMID 41343019 · Publisher ↗
Model-informed precision dosing relies on population pharmacokinetic models to personalize drug therapy and improve clinical outcomes. While hundreds of models are published, only a small fraction are externally evaluate...
Model-informed precision dosing relies on population pharmacokinetic models to personalize drug therapy and improve clinical outcomes. While hundreds of models are published, only a small fraction are externally evaluated and even fewer are applied in practice. This gap reflects a lack of clear standardized guidance on how to identify, assess, and implement published models in new clinical settings. This guidance provides a structured step-by-step framework for the external evaluation and selection of published population pharmacokinetic models to support their use in model-informed precision dosing. It outlines key considerations for defining the model's intended use, assessing the characteristics of the available dataset, screening for suitable candidate models, and applying prediction- and simulation-based diagnostics. By addressing methodological and practical challenges, this framework supports more reproduceable use of published models in real-world settings to help bridge the gap between model development and clinical application.
Correction: How is Levetiracetam Monotherapy Currently Monitored in Pregnancy? A Systematic Review.
Rademaker T, Goo Y, Soh MC … +4 more , Pasupathy D, Wong C, Bleasel A, Alffenaar JW
Clin Pharmacokinet · 2026 Jan · PMID 41324777 · Full text
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Factors Accounting for Pharmacodynamic Variability of Basal Insulin Preparations in Euglycemic Clamp Settings in Healthy Individuals.
Liu H, Li T, Yu H … +4 more , Chen X, Li J, Tan H, Yu Y
Clin Pharmacokinet · 2026 Feb · PMID 41324776 · Publisher ↗
BACKGROUND: The euglycemic clamp technique is a standard method for assessing the pharmacokinetics (PK) and pharmacodynamics (PD) of insulin biosimilars compared to their reference products. Despite similar pharmacokinet...
BACKGROUND: The euglycemic clamp technique is a standard method for assessing the pharmacokinetics (PK) and pharmacodynamics (PD) of insulin biosimilars compared to their reference products. Despite similar pharmacokinetic profiles, differences in the pharmacodynamic profiles between a basal insulin biosimilar and its reference product are not uncommon. This study aimed to identify potential factors contributing to this phenomenon. METHODS: Data were collected from euglycemic clamp studies comparing the PK/PD profiles of an insulin degludec biosimilar (BioIDeg) and the reference product, Tresiba. The ratio of the area under the curve of IDeg from 0 to 24 h (AUC) for BioIDeg to Tresiba was calculated. Subjects with an AUC ratio of 0.9 to 1.1 were enrolled and categorized based on the AUC ratio (Group A: AUC ratio < 0.80 or > 1.25; Group B: 0.80 ≤ AUC ratio ≤ 1.25). Differences between groups and treatments were analyzed. RESULTS: Fifty-eight healthy subjects were included, with 20 in group A and 38 in group B. Significant differences were found in target blood glucose (BG), basal C-peptide, AUC, AUC, and target BG variations. Logistic regression analysis identified variations in target BG (standardized odds ratio 1.384, P=0.038) as an independent factor. CONCLUSION: Variations in target BG might contribute to PD variability of long-acting insulin preparations in euglycemic clamp settings in healthy individuals.
Design Optimization for Developing Population Pharmacokinetic Models in Critically Ill Children: Application to Teicoplanin, Piperacillin and Meropenem.
García-Orueta G, Butragueño-Laiseca L, Santiago MJ … +2 more , Parra-Guillén ZP, Trocóniz IF
Clin Pharmacokinet · 2026 Feb · PMID 41317276 · Full text
BACKGROUND AND OBJECTIVE: Population pharmacokinetic (popPK) models in pediatric patients are essential to optimize dosing and ensure therapeutic efficacy. However, study designs are often not fully optimized, leaving ro...
BACKGROUND AND OBJECTIVE: Population pharmacokinetic (popPK) models in pediatric patients are essential to optimize dosing and ensure therapeutic efficacy. However, study designs are often not fully optimized, leaving room to improve efficiency, which is an important goal in this population, where patients are limited and resources scarce. The aim of the present work is to optimize study designs for the development of popPK models for teicoplanin, piperacillin and meropenem in pediatric patients, with or without continuous kidney replacement therapy (CKRT), to achieve greater model precision while reducing patient burden and economic cost. METHODS: Methodology based on the optimization of the Fisher information matrix (FIM) was followed, using the $DESIGN option in NONMEM 7.5. A previously developed model was selected for each of the antibiotics. The number of subjects in the optimized designs was fixed to 28 patients (14 with and 14 without CKRT). It was assumed that only plasma samples were extracted from patients without CKRT, while prefilter, postfilter, and effluent samples could be extracted simultaneously from patients undergoing CKRT. Sensitivity to different proportions of patients with and without CKRT was tested. The optimized designs were evaluated through simulation and re-estimation procedures, including the impact of covariates. RESULTS: The number of sampling times per individual needed to achieve precise parameter estimates was 3 in teicoplanin, 4 in piperacillin, and 6 in meropenem. The optimized designs reduced the total number of samples per patient by 25, 51, and 21% for teicoplanin, piperacillin, and meropenem, respectively, compared with the original studies used in the previous studies. The resulting samples were taken during 0-40 h from the beginning of the study in teicoplanin and piperacillin, while in the case of meropenem optimal sampling times went between 0-64 h. The optimized designs remained robust under different proportions of patients with and without CKRT and under different covariate values. CONCLUSIONS: This work emphasizes the importance of optimizing study designs to improve accuracy and precision in the model parameters while reducing the number of samples needed. This is a relevant advantage especially when dealing with critically ill pediatric patients.
Correction: Population Pharmacokinetics Analysis of Infliximab in up to 10‑Year‑Old Patients with Paediatric Inflammatory Bowel Disease: Label‑Recommended Dose Fails to Achieve Therapeutic Target Concentration.
Zhao Q, Jongsma MME, Vuijk SA … +15 more , de Winter BCM, Martinez-Vinson C, Kolho KL, Norsa L, Hussey S, Wine E, Cohen S, Shouval DS, Assa A, Lev-Tzion R, de Meij T, Wolters VM, Huynh HQ, Preijers T, de Ridder L
Clin Pharmacokinet · 2026 Jan · PMID 41313575 · Full text
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Population Pharmacokinetics of Levosimendan and its Metabolites OR-1855 and OR-1896 in Critically Ill Adults, Neonates and Infants on Veno-Arterial ECMO.
Bertin S, Guidi M, Haefliger D … +9 more , Thoueille P, Bardinet C, Decosterd LA, Perez MH, Giraud R, Assouline B, Schneider A, Buclin T, Livio F
Clin Pharmacokinet · 2026 Feb · PMID 41288922 · Full text
BACKGROUND AND OBJECTIVE: Levosimendan is an inotrope and vasodilator agent commonly used in critical care, particularly to facilitate weaning from veno-arterial extracorporeal membrane oxygenation (VA-ECMO). However, cr...
BACKGROUND AND OBJECTIVE: Levosimendan is an inotrope and vasodilator agent commonly used in critical care, particularly to facilitate weaning from veno-arterial extracorporeal membrane oxygenation (VA-ECMO). However, critical illness and ECMO may affect levosimendan and its clinically relevant metabolites' pharmacokinetics, potentially compromising circulating exposure and efficacy. There are limited data on levosimendan pharmacokinetics in critically ill patients, including those on VA-ECMO, thus emphasising the need for further research in this area. The aim of this study was to characterise the pharmacokinetic profile of levosimendan and its metabolites OR-1855 and OR-1896 in both critically ill adults and neonates/infants on VA-ECMO. METHODS: We conducted a bicentric, prospective, observational, pharmacokinetic study in critically ill adults and neonates/infants on VA-ECMO receiving levosimendan. Dosage history, sampling and clinical information were gathered. Samples were analysed by ultra-high-performance liquid chromatography coupled to tandem mass spectrometry using a validated highly sensitive method. A population pharmacokinetic model describing levosimendan and its metabolites OR-1855 (inactive) and OR-1896 (active, long-lasting) was developed using non-linear mixed-effects modelling (NONMEM). Model-based simulations were performed to compare exposures produced by various dosing scenarios. RESULTS: Twenty-one patients, 15 adults, three neonates and three infants, provided 155 blood samples. In adults, levosimendan was started at a rate of 0.05 µg/kg/min for 1-4 h, then increased to maintenance doses reaching 0.1 (n = 9), 0.15 (n = 3) or 0.2 (n = 3) µg/kg/min for a total infusion time of approximately 24 h. The neonates/infants received a continuous infusion of 0.1 µg/kg/min for 48 h. A two-compartment model best characterised levosimendan pharmacokinetics, with a transit compartment adequately describing the metabolites' delayed synthesis. The transformation of OR-1855 into OR-1896 was 3.7-fold slower in neonates/infants than in adults. Model-based simulations using a standard 0.1-µg/kg/min regimen for 24 and 48 h in adults and neonates/infants, respectively, achieved lower levosimendan and metabolite concentrations in neonates/infants. Simulations using a 48-h infusion of 0.2 µg/kg/min in neonates/infants predict levosimendan concentrations comparable to those in adults receiving a 0.1-µg/kg/min maintenance dose. However, in this scenario, OR-1896 concentrations would remain considerably lower than in adults. CONCLUSIONS: Our data indicate that levosimendan and its metabolites exhibit altered the pharmacokinetics in neonates/infants on VA-ECMO. Although some of these changes may be associated with ECMO, definitive conclusions on causality cannot be drawn, as age-dependent specific physiology and critically ill conditions may also contribute. These findings support the consideration of dose optimisation in this population. In adults, levosimendan pharmacokinetics seem unaffected, although metabolite concentrations appear slightly reduced compared with non-critically ill patients with heart failure.
Population Pharmacokinetics of Propofol in Critically Ill Patients with and Without Extracorporeal Membrane Oxygenation.
Bertin S, Haefliger D, Mercier T … +7 more , Decosterd LA, Giraud R, Assouline B, Schneider A, Buclin T, Guidi M, Livio F
Clin Pharmacokinet · 2026 Feb · PMID 41264092 · Full text
BACKGROUND AND OBJECTIVE: Propofol is commonly used in critically ill patients on extracorporeal membrane oxygenation (ECMO). Although ECMO may theoretically affect drug pharmacokinetics (PK) through various mechanisms,...
BACKGROUND AND OBJECTIVE: Propofol is commonly used in critically ill patients on extracorporeal membrane oxygenation (ECMO). Although ECMO may theoretically affect drug pharmacokinetics (PK) through various mechanisms, data on propofol PK in this context remain scarce, with only one small recent study available. Our aim was to assess the impact of ECMO on propofol PK in a larger cohort. METHODS: We conducted a prospective, bicentric observational PK study in critically ill patients with and without ECMO (controls). Critically ill adults receiving a continuous infusion of propofol were eligible for inclusion. Controls were selected to ensure similarity with ECMO patients. We collected a maximum of eight samples per patient over 9 h. We analysed plasma samples using a high-performance liquid chromatography coupled to tandem mass spectrometry validated method. We developed a population pharmacokinetic (popPK) model using a classical stepwise approach with nonlinear mixed effects modelling software. RESULTS: A total of 40 patients, 20 with and 20 without ECMO, contributed 300 samples. A two-compartment model best described the data, with body weight affecting clearance. ECMO had no substantial impact on propofol PK. The final popPK model parameter estimates with between-subject variability were as follows: clearance 68 L/h (34%), intercompartmental clearance 26 L/h, and central and peripheral volumes of distribution 1.2 L/kg (230%) and 1.4 L/kg, respectively. A proportional error model best described the residual unexplained variability (13%). CONCLUSIONS: Our popPK analysis shows that propofol PK does not differ between critically ill patients with and without ECMO and confirms a high PK variability in this population.
TLD-1, a Novel Liposomal Doxorubicin, in Patients with Solid Tumors: Comparative Pharmacokinetics and Final Results of a Multicenter Phase 1 Study (SAKK 65/16).
Klose M, Colombo I, Gobat K … +16 more , Koster KL, Haefliger S, Rabaglio M, Bastian S, Schwitter M, Zürrer-Härdi U, Eckhardt K, Hayoz S, Halbherr S, Sessa C, Michelet R, Mc Laughlin AM, Hess D, Stathis A, Kloft C, Joerger M
Clin Pharmacokinet · 2026 Feb · PMID 41252081 · Publisher ↗
BACKGROUND AND OBJECTIVE: Targeted liposomal doxorubicin (TLD-1) is a novel PEGylated liposomal doxorubicin (PLD) with optimized formulation characteristics, developed to improve the benefit-risk profile of PLD. This ran...
BACKGROUND AND OBJECTIVE: Targeted liposomal doxorubicin (TLD-1) is a novel PEGylated liposomal doxorubicin (PLD) with optimized formulation characteristics, developed to improve the benefit-risk profile of PLD. This randomized intrapatient crossover amendment to the phase 1 SAKK 65/16 trial (NCT03387917) compared the pharmacokinetics (PK) of TLD-1 and Caelyx™ and included a pooled analysis of safety and preliminary antitumor activity at the recommended phase 2 dose (RP2D). METHODS: Patients with advanced breast or platinum-resistant ovarian cancer in the comparative PK part were randomized to receive TLD-1 in cycle 1 and Caelyx™ in cycle 2, or vice versa, followed by TLD-1 thereafter. Both formulations were administered intravenously at 40 mg/m and PK was assessed using non-compartmental analysis. Safety and antitumor activity were analyzed across 23 patients treated with TLD-1 at the RP2D, including 13 from the comparative PK part and 10 from the published dose-escalation part. RESULTS: In 10 evaluable patients from the comparative PK part, TLD-1 showed higher encapsulated doxorubicin exposure (AUC: 3222 vs 2139 mg·h/L) and longer median half-life (118 vs 70 h) than Caelyx™. Severe treatment-related events occurred in 43% of patients (10/23) in the full RP2D cohort, most commonly grade 3 palmar-plantar erythrodysesthesia, oral mucositis, and anemia (2 patients each). The investigator-assessed objective response rate was 8.7% (2/23), with partial responses in patients with breast cancer. CONCLUSIONS: Targeted liposomal doxorubicin demonstrated prolonged systemic circulation and low variability in liposomal drug release, likely due to its formulation characteristics. At 40 mg/m every 3 weeks, TLD-1 was well tolerated and showed modest preliminary antitumor activity in advanced breast cancer. GOV IDENTIFIER: NCT03387917, registered 2017-11-21.
Clinical Pharmacokinetic-Pharmacodynamic Relationships of Pharmacological Strategies for Attenuating p-Cresyl Sulfate in Patients with Kidney Disease.
Dhungana P, Dam A, Kiang TKL
Clin Pharmacokinet · 2025 Dec · PMID 41247431 · Publisher ↗
p-Cresyl sulfate (pCS) is a highly toxic uremic compound that is produced from tyrosine and phenylalanine in the gut and primarily excreted renally. In patients with kidney dysfunction, the accumulation of pCS can lead t...
p-Cresyl sulfate (pCS) is a highly toxic uremic compound that is produced from tyrosine and phenylalanine in the gut and primarily excreted renally. In patients with kidney dysfunction, the accumulation of pCS can lead to the worsening of kidney disease and manifestation of organ toxicities. Various pharmacological strategies have been proposed to reduce pCS in patients with chronic kidney disease (CKD), but systematic pharmacokinetic-pharmacodynamic assessments have not been conducted to our knowledge. The objectives of this scoping review were to comprehensively and critically summarize the available literature using a newly devised, pharmacokinetic-pharmacodynamic assessment method. We searched PubMed, Embase, and Scopus for primary research articles in patients with CKD and devised the following novel approach to systematically evaluate each study: (i) positive reduction or null reduction of pCS; (ii) dose dependency; (iii) time dependency; (iv) effects on free versus total pCS; and (v) relationships to diet regimens (e.g., protein intake), microbiome composition, blood biochemistry, and clinical outcomes (i.e., progression of renal disease measured by initiation of dialysis or renal transplant; cardiovascular outcomes such as incidence of myocardial infarction, heart failure, cardiovascular death; and changes in qualityof- life instruments). Fifty-nine studies were identified with a total of 2593 study participants (pre-dialysis CKD: n = 1060; CKD on dialysis: n = 1499; and post-transplant CKD: n = 34). The studies included AST-120 (n = 3), sevelamer (n = 9), sucroferric Noxyhydroxide (n = 1 [+ 1 overlapping with sevelamer]), prebiotics (n = 15), probiotics (n = 9), synbiotics (n = 13), antibiotics (n = 3), ketoanalogs (n=3), and curcumin (n = 3). Only AST-120 and synbiotics consistently demonstrated significant pCS reductions, and the percentage (%) reductions by AST-120 were 40.9-75.6% for free and 28.8-42.8% for total pCS; whereas the percentage reduction by synbiotics were 6.4-78.1% for total and 16.7% for free pCS, the latter only evident in a subgroup with antibiotic-free regimen. Although sevelamer was also associated with a pCS reduction, the percentage reduction was modest and only based on the total concentration. In contrast, the majority of sucroferric oxyhydroxide, prebiotics, probiotics, ketoanalogs, and curcumin studies did not demonstrate consistent pCS reductions. Furthermore, dose dependency was not established in the majority of studies, and although some temporal relationships were evident, the data were very limited. Only a few of the analyzed studies measured both bound and unbound forms of pCS, and inconsistencies have been reported in a few studies. In Ngeneral, it was also difficult to establish associations with outcomes in most studies because of limitations in experimental design, and in instances where potential pharmacokinetic-pharmacodynamic relationships were observed, they were generally weak and only with surrogate markers of commonly measured biochemistry, oxidative stress, lipid profiles, and inflammatory markers, with only a handful of studies capturing clinical outcomes. In conclusion, we have identified potential pharmacological interventions that may be further developed for the purpose of reducing pCS in patients with CKD.
Population Pharmacokinetic Modeling of Oxcarbazepine and Its Active Metabolite 10-Monohydroxy Derivative to Inform Dosing in Children with Obesity.
Sinha J, Zimmerman K, Balevic SJ … +12 more , Hornik C, Muller WJ, Rathore M, Meyer M, Finkelstein Y, Al-Uzri A, Lakhotia A, Goldstein S, Chen JY, Anand R, Gonzalez D, Best Pharmaceuticals for Children Act–Pediatric Trials Network Steering Committee
Clin Pharmacokinet · 2026 Feb · PMID 41247430 · Full text
BACKGROUND: Oxcarbazepine (OXZ) is an antiepileptic drug whose pharmacological effect is primarily mediated by its active metabolite, 10-monohydroxy derivative (MHD). OXZ is approved for use in adults and children older...
BACKGROUND: Oxcarbazepine (OXZ) is an antiepileptic drug whose pharmacological effect is primarily mediated by its active metabolite, 10-monohydroxy derivative (MHD). OXZ is approved for use in adults and children older than 2 years with an age- and body weight-tiered dosing recommendation, but dosing guidance for children with obesity is lacking. OBJECTIVE: This work aimed to assess the dosing requirements of OXZ in children with obesity to support label extension. METHODS: Two multicenter studies (NCT01431326 and NCT02993861) were conducted in patients receiving standard-of-care OXZ therapy. Participants ≥ 2 years of age with a body mass index ≥ 95th percentile were classified as obese. Plasma concentrations were measured by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) assay. Nonlinear mixed effects modeling was performed using NONMEM 7.4 to characterize the population pharmacokinetics of OXZ and MHD simultaneously. Simulations were performed to compare MHD systemic exposure in children ≥ 2 years of age with and without obesity. RESULTS: One hundred study participants with a median (range) age of 9 years (44 days-20.90 years) contributed 425 plasma concentrations of OXZ (n = 212) and MHD (n = 213). Fifty-two percent of the participants had obesity. A one-compartment joint parent-metabolite model with linear input-output and bi-directional transformation between OXZ and MHD best characterized the pharmacokinetics. Body size was the only covariate affecting pharmacokinetics, and a fat-free mass-based metric termed pharmacokinetic weight (PKWT) best characterized that effect allometrically. Simulation results revealed that the current dosing regimen of OXZ can produce comparable exposure of MHD in children ≥ 2 years of age with and without obesity. CONCLUSION: A model-informed analysis confirms that the current pediatric dosing regimen of OXZ applies to children in general, regardless of their obesity status.
Population Pharmacokinetics of Atogepant for the Prevention of Migraine.
Schlachter L, Stodtmann S, Voelkner A … +3 more , Jonsson F, Lagraauw HM, Boinpally RR
Clin Pharmacokinet · 2026 Jan · PMID 41222899 · Full text
BACKGROUND AND OBJECTIVE: Atogepant is an oral calcitonin gene-related peptide receptor antagonist developed for the preventive treatment of migraine. This work aimed to develop a population pharmacokinetic (popPK) model...
BACKGROUND AND OBJECTIVE: Atogepant is an oral calcitonin gene-related peptide receptor antagonist developed for the preventive treatment of migraine. This work aimed to develop a population pharmacokinetic (popPK) model to support dosage regimen selection during the clinical development of atogepant in patients with episodic migraine (EM) or chronic migraine (CM) and to guide the dosing recommendations for regulatory approval. METHODS: Pharmacokinetic data collected from 12 phase 1 studies, 1 phase 2b/3 study, and 1 phase 3 study in healthy participants and patients with EM were used to develop a popPK model that was externally validated with data from a CM phase 3 study and a phase 3 study in patients with EM for whom two to four classes of conventional oral preventive treatments have failed. The model was built and evaluated using nonlinear mixed-effect modeling and diagnostic assessments. RESULTS: The final model featured three disposition compartments, with linear elimination from the central compartment and a sequential zero-/first-order lagged absorption process. Formulation, dose, food status, liver function, concomitant medication, and body weight were each found to have a statistically significant influence on atogepant's pharmacokinetics. Absorption was affected by dose and formulation, the apparent central volume of distribution (V/F) increased with body weight, relative bioavailability (F) modestly increased with dose, and a high-fat meal lengthened absorption lag time. Severe hepatic impairment and coadministration of itraconazole, quinidine, or a single rifampin dose decreased apparent clearance (CL/F) by ~37% and ~66%, ~29%, and ~13%, respectively, while coadministration of multiple rifampin doses increased CL/F by 1.82-fold. F increased by 1.95 and 2.4 fold with coadministration of itraconazole and a single rifampin dose, respectively, and decreased by ~25% with multiple rifampin doses. Mild/moderate renal impairment, coadministration of breast cancer resistance protein (BCRP) inhibitors, BCRP substrates and statins, age, and sex had no clinically relevant effect on atogepant pharmacokinetics. No statistically significant differences were observed in atogepant's pharmacokinetics between healthy participants and patients with migraine. CONCLUSIONS: The pharmacokinetics of atogepant are similar in healthy participants and patients with CM or EM. Dose adjustments owing to intrinsic factors of age, sex, race, and body weight, or owing to concomitant medications consisting of P-glycoprotein (P-gp) inhibitors, BCRP inhibitors, oral contraceptive components (ethinyl estradiol and levonorgestrel), famotidine, esomeprazole, sumatriptan, acetaminophen, and naproxen are not necessary. Atogepant's popPK model provides a valuable tool for evaluating specific questions for patients, healthcare providers, and regulatory agencies. Integration into other modeling approaches has also aided in model-informed drug development decisions. CLINICAL TRIAL REGISTRATION: NCT03855137 (EudraCT number: 2018-004337-32).
Development of a Semi-Mechanistic Population Pharmacokinetic Model for Predicting Tenofovir Disoproxil Fumarate and Tenofovir Alafenamide Exposure in Plasma and Cellular Matrices During Pregnancy and Postpartum.
Yu Y, Brooks KM, Doncel GF … +13 more , Best BM, Marzinke MA, Mirochnick M, Anderson P, Myer L, Celum C, Heffron R, Coleman J, Davey DJ, Hendrix CW, Momper JD, Bies R, Scott RK
Clin Pharmacokinet · 2026 Jan · PMID 41222898 · Full text
BACKGROUND AND OBJECTIVE: Tenofovir (TFV)-based regimens are backbones of both HIV treatment and pre-exposure prophylaxis during pregnancy. Multiple studies have shown up to one-third decreases in dried blood spot tenofo...
BACKGROUND AND OBJECTIVE: Tenofovir (TFV)-based regimens are backbones of both HIV treatment and pre-exposure prophylaxis during pregnancy. Multiple studies have shown up to one-third decreases in dried blood spot tenofovir-diphosphate concentrations during pregnancy among participants taking tenofovir disoproxil fumarate (TDF). Currently, there are no mechanism-based models describing the pharmacokinetics of tenofovir diphosphate (the active anabolite) in peripheral blood mononuclear cells (PBMCs) of pregnant individuals receiving TDF or tenofovir alafenamide (TAF), and the mechanisms behind observed differences between dried blood spots and PBMCs remain unclear. METHODS: To address this gap, we developed a semi-mechanistic model to simultaneously describe the pharmacokinetics of all clinically relevant TDF and TAF-derived moieties and conducted clinical trial simulations to compare TDF and TAF pharmacokinetics during pregnancy and postpartum. RESULTS: The pharmacokinetics of plasma TAF and TFV were best described by one-compartment and two-compartment models, respectively, with first-order absorption. A transit compartment was included to reflect the slower elimination rate of plasma TFV after receiving TAF. Cellular matrix PBMC and dried blood spots were included using a biophase model. For TDF, plasma TFV apparent clearance increased by 24.9% and 13.1% during the second and third trimesters of pregnancy, respectively, compared with non-pregnant populations. In the postpartum period, plasma TFV apparent clearance in pregnant women was 9.3% lower than in non-pregnant women. The bioavailability for TAF decreased by 17.3% and 5.1% during the second and third trimesters, respectively, and increased by 18% during the postpartum period relative to non-pregnant women. In pregnant women, simulations showed that TAF maintains approximately five times higher tenofovir diphosphate concentrations in PBMCs compared with TDF during the second and third trimesters, despite a decrease in PBMC tenofovir diphosphate concentrations for both drugs. This finding is consistent with the higher PBMC loading effect of TAF observed in non-pregnant populations. CONCLUSIONS: Our semi-mechanistic model provides a framework for understanding pregnancy-associated pharmacokinetic changes and supports future research to refine dosing strategies for HIV treatment and prevention in pregnancy.
A Population Pharmacokinetic and Exposure-Response Analysis for Baricitinib in Pediatric Patients with Atopic Dermatitis.
Decker RL, Ernest CS, Radtke DB … +2 more , Prakash A, Zhang X
Clin Pharmacokinet · 2026 Jan · PMID 41212510 · Full text
BACKGROUND: Baricitinib is approved for the treatment of adults with moderate-to-severe atopic dermatitis (AD) who are candidates for systemic therapy and has received regulatory authorization in Europe for moderate-to-s...
BACKGROUND: Baricitinib is approved for the treatment of adults with moderate-to-severe atopic dermatitis (AD) who are candidates for systemic therapy and has received regulatory authorization in Europe for moderate-to-severe AD in patients 2 to <18 years. OBJECTIVE: This study aims to optimize dosing for baricitinib in pediatric patients with atopic dermatitis using pharmacokinetic/pharmacodynamic modeling leveraging adult data. METHODS: The phase III, randomized, double-blind, placebo-controlled study, BREEZE-AD-PEDS (NCT03952559, registration date: 2019-05-16), enrolled patients (aged 2 to <18 years) with moderate-to-severe AD. During a pharmacokinetic (PK) lead-in period, baricitinib concentration data from age-based dose cohorts (4 mg once daily [QD]: 10 to <18 years; 2 mg QD: 2 to <10 years) were compared with actual and simulated concentration values from adult patients receiving baricitinib 4 mg QD. A population PK model incorporating allometric scaling was developed to determine weight-based dosing in pediatric patients that matches adult exposures. The exposure-response (E-R) relationships were analyzed for the primary endpoint: a validated Investigator Global Assessment (vIGA-AD) score of 0 or 1 (clear to almost clear skin) with ≥2-point improvement from baseline at week 16. Baricitinib pharmacokinetics were characterized from 393 pediatric patients using a 2-compartment model with allometric scaling on clearance and volume of distribution. RESULTS: The age-based and subsequent weight-based dosing (2 mg for patients 10 to <30 kg and 4 mg for patients ≥30 kg) was comparable to the 4-mg adult exposure. A clear E-R relationship was observed for the primary endpoint when sorted for age or weight groups. CONCLUSION: The population PK model developed using baricitinib concentrations from adult patients, with allometric scaling for weight on clearance and volume, adequately predicted exposures in the pediatric population. The PK modeling, with E-R analysis, informed an appropriate weight-based dosing regimen.
Systematic Search of Height and Weight Changes of Exclusively Breastfed Infants Until 1 Year of age: A Contribution from the ConcePTION Project.
Van Neste M, Macente J, Nauwelaerts N … +5 more , Ameye L, Bogaerts A, Smits A, Annaert P, Allegaert K
Clin Pharmacokinet · 2025 Nov · PMID 41201765 · Full text
Physiologically based pharmacokinetic (PBPK) modelling and simulation allows prediction of drug exposure in specific populations, such as infants during lactation. However, the influence of feeding type (e.g., human milk...
Physiologically based pharmacokinetic (PBPK) modelling and simulation allows prediction of drug exposure in specific populations, such as infants during lactation. However, the influence of feeding type (e.g., human milk vs formula) on physiology has not yet been implemented in current PBPK platforms. We conducted a systematic search to compile datasets during the first year of life of infants who were exclusively breastfed for at least 4 months to incorporate in the virtual breastfed infant populations of PBPK platforms. Physiological data in exclusively breastfed infants were extracted from 223 included articles. This article reports the results on sex-specific height and weight data, collected from 35 and 43 articles, respectively, and assesses these data for girls and boys separately. The datasets were converted to pooled means ± standard deviation and subsequently to mathematical equations describing height and weight trajectories for exclusively breastfed infants. For the purpose of external verification, the novel function was compared with Flemish height and weight profiles stratified by maternal origin, revealing the most similarity with breastfed infants from European mothers. Furthermore, to assess the differences in current functions from PBPK software, data from the literature showed that current PBPK height and weight equations often overestimate relative to the novel equations for breastfed infants from 6 months onwards. These overestimations may result in differences in PBPK predictions. Systematic searches to assess maturational processes of other physiological parameters (e.g., body composition) in exclusively breastfed infants is likely warranted. These patterns should be incorporated in PBPK platforms to more adequately represent infant exposure to medicines, specifically for lactation-related medicine systemic exposure.
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