Clinical Pharmacokinetics最新文献

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_IDeg,0-24h) for BioIDeg to Tresiba was calculated. Subjects with an AUC_IDeg,0-24h ratio of 0.9 to 1.1 were enrolled and categorized based on the AUC_GIR,0-24h ratio (Group A: AUC_GIR,0-24h ratio < 0.80 or > 1.25; Group B: 0.80 ≤ AUC_GIR,0-24h 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_IDeg,0-12h, AUC_IDeg,0-24h, 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.

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).

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.

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.

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.

Background: The increasing use of the immune checkpoint inhibitor nivolumab places a significant financial burden on healthcare systems, contributes to environmental concerns, and strains hospital capacities. The nivolumab average exposure and exposure variation of a fixed subcutaneous (SC) dosing regimen (1200 mg every 4 weeks) is significantly higher compared with 3-mg/kg every 2 weeks intravenous dosing.

Objectives: We aimed to develop alternative dosing regimens for SC nivolumab to reduce drug expenses and lower the treatment burden for patients while ensuring effective exposure.

Methods: Population pharmacokinetic simulation was conducted using a population pharmacokinetic model developed by the license holder to explore alternative SC regimens. In this process, patients were divided into three weight groups: less than 60 kg, 60-90 kg, and more than 90 kg. Furthermore, two experimental progressive alternative dosing regimens were developed, one based on a minimum effective concentration-driven approach. The second progressive alternative regimen was based on using the 1200-mg SC formulation as an intravenous infusion.

Results: We developed an alternative bodyweight-based regimen consisting of SC 1200 mg every 7 weeks (<60 kg), 1200 mg every 6 weeks (60-90 kg), and 1200 mg every 5 weeks (>90 kg). This new alternative dosing regimen would save an average of €24,345 (35%) per patient per year compared with SC 1200 mg every 4 weeks. The results for the first experimental, progressive, extended-interval dosing regimen for patients with melanoma indicate that 95% of patients exceed a steady-state trough concentration of 2.5 mg/L when administered SC 1200 mg every 10 weeks. This dosing regimen would decrease the yearly cost from €68,870 to €27,548 (60% less) per patient per year. The second experimental progressive regimen using SC 1200 mg as an intravenous administration every 7 weeks leads to a potential saving of €29,516, which is a 43% decrease compared with the SC 1200-mg approved regimen.

Conclusions: The developed dosing regimen with a bodyweight-dependent interval offers a cost-effective and patient-friendly method to optimize SC nivolumab use while ensuring adequate exposure, which can be directly implemented in clinical practice. Moreover, the two experimental progressive proposed regimens provide a rationale for a clinical non-inferiority study in which alternative dose regimens are compared to standard dosing according to the drug label.

Background and objective: Cefuroxime is a widely prescribed beta-lactam antibiotic, particularly in pediatric cardiac and medical-surgical intensive care units. The aim of this study was to describe intravenous cefuroxime disposition in critically ill pediatric patients. Moreover, target attainment of currently applied dosing regimens was evaluated, and suggestions for improving these dosing regimens were provided.

Methods: Two datasets were pooled for population pharmacokinetic (popPK) analysis, using NONMEM version 7.5. To assess the optimal target attainment (> 90% of patients with 100% time [T] > [4×] minimal inhibitory concentration [MIC]_8mg/L), pharmacokinetic (PK) profiles of different dosage regimens (intermittent/continuous) were simulated using the estimated popPK parameters.

Results: The cohort consisted of 45 pediatric patients with a median (interquartile range [IQR]) age of 391 days [31-3505] and body weight of 9.0 kg [5.0-29.8]. A two-compartment popPK model with first-order elimination and allometric scaling best described cefuroxime disposition. Intravenous cefuroxime clearance was estimated at 5.29 L/h/70 kg. Postnatal age and creatinine clearance (mL/min/1.73 m²) were the best descriptive covariates for the maturation of cefuroxime clearance. Simulations evaluating the current cefuroxime dosing regimens stratified for estimated glomerular filtration rate (eGFR) levels illustrated moderate (< 90%) (eGFR < 30 and 30-80 mL/min/1.73 m²) and poor (< 20%) (eGFR 80-120 and > 120 mL/min/1.73 m²) cefuroxime target attainment across the entire age range. Alternative dosing regimens, including four times daily schedules and continuous infusion, improved target attainment, particularly in older children and those with augmented renal clearance.

Conclusions: These findings indicate that underexposure due to augmented renal function is possible when applying the current cefuroxime dosing regimens. Future research should focus on individualized dosing strategies to optimize cefuroxime exposure and efficacy in pediatric populations.

Background: Excessive production of reactive oxygen species (ROS), particularly superoxide anion ( ${\text{O}}_2^{·-}$ ), is a key mechanism in diseases such as cancer, inflammatory disorders, neurodegenerative conditions, and metabolic diseases. Evidence also suggests that microgravity-induced oxidative stress, primarily driven by elevated ${\text{O}}_2^{·-}$ levels, may contribute to the adverse physiological effects observed in astronauts during extended space missions. Superoxide dismutase (SOD) is critical for mitigating oxidative stress, and exogenous SOD supplementation offers a potential therapeutic strategy.

Methods: This randomized, double-blind, placebo-controlled Phase I study evaluated the safety, tolerability, and pharmacokinetics of recombinant human Cu/Zn-SOD (rhSOD, SOD1) following subcutaneous administration of 40 mg every 12 hours in 16 healthy volunteers. Eight subjects were enrolled each in the single-dose (SD) and multiple-dose (MD) cohorts. Study assessments, including pharmacokinetic sampling, were performed for 72 (SD) or 92 hours (MD). Injection site erythema was objectively assessed using the innovative Standardized Erythema Value (SEV*) method, derived from photographs taken with Scarletred®Vision software (SCARLETRED Holding GmbH).

Results: No serious adverse events occurred, and all treatment-related adverse events were mild. Injection site erythema was objectively assessed using the innovative standardized erythema value (SEV*) method, derived from photographs taken with Scarletred^® Vision software (SCARLETRED Holding GmbH). The Visual Analog Scale scores and SEV* assessments were comparable between the rhSOD and placebo groups. Beyond safety and tolerability, pharmacokinetic analysis revealed that the volume of distribution, clearance, and half-life at presumed steady state were 129 ± 66.3 L, 5.97 ± 1.25 L/h, and 15.0 ± 6.69 h, respectively. Compared with the rapid systemic elimination after intravenous administration of SOD, subcutaneous administration resulted in a favorable plasma concentration-time profile.

Conclusions: These findings suggest that subcutaneous rhSOD may be a promising therapeutic candidate for conditions characterized by excessive ${\text{O}}_2^{·-}$ exposure or diminished endogenous SOD activity. Further clinical studies are warranted to assess its anti-inflammatory potential in relevant patient populations. EudraCT Number: 2022-000173-11.

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.