Clinical Pharmacokinetics最新文献

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 and objective: Accurate assessment of the glomerular filtration rate (GFR) is crucial in critically ill children, yet standard estimation formulas (eGFR) perform poorly, especially in the youngest. Iohexol plasma clearance is the reference standard for measured GFR; however, its routine use is limited by logistical constraints. This study aims to develop and internally validate a population pharmacokinetic model of iohexol in critically ill children, to derive a practical model-based GFR estimation formula (eGFR_iohexol), and to compare its predictive performance against established eGFR formulas (eGFR_Schwartz, eGFR_{Smeets/Pierce}).

Methods: After administration of iohexol, up to six blood samples were drawn from 107 patients over a 6-hour interval. Data from 93 patients were used for model building, and from 31 patients for internal validation. Reference clearances were obtained using the post hoc Bayesian clearance estimates. Predictive performances of eGFR_iohexol, eGFR_Schwartz, and eGFR_{Smeets/Pierce} were compared with reference clearances using bias, imprecision, Total Deviation Index, concordance correlation coefficient, and the percentage of predictions within 10 and 30% error (P10, P30) around reference clearances.

Results: The final model identified body surface area, serum creatinine, cystatin C, postoperative status, and clonidine treatment as significant predictors of iohexol clearance. eGFR_iohexol demonstrated minimal bias (-0.8%) and imprecision (21%) and high accuracy (P30 = 87%), particularly in patients under 2 years of age (P30 = 90 vs 40% for eGFR_Schwartz). Furthermore, eGFR_iohexol also demonstrated superiority over eGFR_{Smeets/Pierce}, which exhibited moderate bias (-5.4%) and reduced accuracy (P30 = 68%).

Conclusions: A model-derived GFR estimation formula based on iohexol population pharmacokinetic modeling might allow for an accurate bedside assessment of kidney function in critically ill children, outperforming the Schwartz and Smeets/Pierce formulas, particularly in infants. External validation in larger pediatric intensive care unit populations, across the full age and GFR range, is warranted to confirm the generalizability of this equation and its potential for broader clinical application.

Clinical trial registration: ClinicalTrials.gov NCT05179564, registered retrospectively on 5 January, 2022.

Aim: Brensocatib is an oral, competitive, and reversible dipeptidyl peptidase 1 (DPP1) inhibitor in development for the treatment of neutrophil-mediated diseases. Brensocatib is a substrate of CYP3A, P-glycoprotein, and breast cancer resistance protein (BCRP). Its absorption, distribution, metabolism, and elimination could be potentially affected by a decrease in hepatic function. This study evaluated the pharmacokinetics (PK), safety, and tolerability of brensocatib in participants with varying degrees of hepatic impairment and matched participants with normal hepatic function.

Methods: In this phase 1, multicenter, open-label study, 27 participants with normal hepatic function or mild, moderate, and severe hepatic impairment, based on numerical Child-Pugh classifications, received a single, oral 25-mg dose of brensocatib. Blood and urine samples were collected to evaluate brensocatib PK, urinary excretion, and plasma protein binding.

Results: Demographic and baseline characteristics were generally similar across hepatic impairment groups and matched healthy participants. The systemic exposure (area under the curve, AUC) and renal clearance (CL_r) of brensocatib were generally comparable across all groups (≤ 20% difference in AUC compared with healthy participants and CL_r 1.34-1.84 L/h versus 1.66 L/h in healthy participants). The mean elimination half-life was also similar across all hepatic function groups (27.9-31.4 h). Regression analyses indicated no significant relationships between brensocatib systemic exposure and Child-Pugh scores. Unbound brensocatib in plasma slightly increased by the severity of hepatic impairment. The fraction of unbound brensocatib (F_unb) was correlated with serum albumin, suggesting that brensocatib is mainly bound to albumin in plasma. Treatment-emergent adverse events (TEAEs) occurred in 14.8% (4/27) of participants; most TEAEs were mild, and two TEAEs occurring in one participant were considered severe. No new safety findings were observed.

Conclusions: No new safety signals were identified in participants with or without hepatic impairment treated with a single dose of 25 mg brensocatib. The oral absorption and elimination of brensocatib were not significantly altered in participants with mild, moderate, or severe hepatic impairment, suggesting that dose adjustment for brensocatib treatment in patients with hepatic impairment is not necessary.

Trial registry: Clinical Trial Registration Number: NCT05517525.

Background and objective: Cabozantinib is a tyrosine kinase inhibitor approved for the treatment of metastatic renal cell carcinoma. The current patient-unfriendly advice to ingest cabozantinib in a fasted state is based on an increase of 57% in the area under the concentration-time curve after ingestion with a high-fat meal. Taking cabozantinib with a meal that is suitable for daily practice to increase bioavailability could aid in developing alternative dosing strategies. In this study, we aim to investigate the impact of taking cabozantinib with a light breakfast on exposure and toxicity.

Methods: An open-label, randomized, cross-over, pharmacokinetic evaluation study was performed. In the standard regimen, patients took cabozantinib in a fasted state. In the experimental regimen, patients took cabozantinib with a light breakfast. After 4 weeks, pharmacokinetic samples were obtained for area under the concentration-time curve from 0 to 24 h estimation and patients thereafter switched to the other regimen. Patients were monitored for serious adverse events.

Results: Twelve patients completed study procedures. The area under the concentration-time curve for taking cabozantinib in a fasted state and with a light breakfast showed a mean difference of + 8.3% (geometric mean ratio, 90% confidence interval 101-117). Similar results were obtained for trough concentration (mean difference 2.5%, geometric mean ratio, 90% confidence interval 90.7-116.0) and maximum concentration (mean difference 14%, geometric mean ratio, 90% confidence interval 103.7-127.6). No differences in serious adverse events were observed.

Conclusions: Taking cabozantinib with a light breakfast leads to a small increase in exposure. Patients for whom taking cabozantinib in a fasted state is unpleasant are now able to take it with a light breakfast, without an increased risk for exposure-related toxicity.

Clinical trial registration: This study was registered at ClinicalTrials.gov under the number NCT05263245.

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: INS068 is a new soluble, long-acting insulin analog intended to cover basal insulin requirements in patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). The purpose of this study was to determine the molar dose ratio of INS068 to insulin degludec (IDeg) by comparing the clinical pharmacokinetic (PK) and pharmacodynamic (PD) profiles of INS068 and IDeg. The PD endpoints include glucose infusion rate (GIR) and glycated hemoglobin (HbA1c).

Method: Population pharmacokinetic and pharmacodynamic (PopPK/PD) analysis was performed to characterize INS068 and IDeg PK and PD profiles. Data from 307 subjects across three Phase I studies and one Phase II study were used to establish the population pharmacokinetic (PopPK) model, of which two euglycemic clamp (Phase I) studies were used to establish PopPK-GIR model, and one Phase II study was used to establish PopPK-HbA1c model. Nonlinear mixed-effects modeling was used to investigate the PK and PD relationships of INS068 and IDeg. Model-based simulations were performed to determine the molar dose ratio of INS068 to IDeg.

Results: The PopPK model of INS068 and IDeg was described by a one-compartment model with linear absorption with a lag time and elimination. Significant covariate effects of body weight, population, and treatment (INS068 vs IDeg) were identified for PK parameters of INS068 and IDeg. However, except for body weight and T2DM patients, the other significant covariates (treatment and T1DM patients) had no clinically relevant effects on PK exposures. The relationship between GIR and insulin concentrations in effect compartment was described by a direct response model with sigmoidal E_max drug effect. The relationship between insulin concentration and HbA1c was well described by an indirect response model. The covariate analysis of the PopPK-GIR and PopPK-HbA1c models showed that treatment (INS068 vs IDeg) had no significant impact on the PD parameters. The results of model-based simulation demonstrated that the PK and PD of INS068 and IDeg were comparable.

Conclusion: This analysis supported molar dose ratio of INS068 to IDeg as 1. INS068 had similar potency compared to IDeg, with one unit of INS068 composed of 6 nmol of active ingredient (1 U = 6 nmol).

Background and objective: Prosthetic joint infections are serious infections that require perioperative antibiotic prophylaxis. Cefuroxime may be used as prophylaxis, and this study aims to evaluate the current dosing regimen to prevent infection during the perioperative period by performing population pharmacokinetic (PK) analysis of plasma and bone in patients with prosthetic joint infection (PJI).

Methods: Both plasma and bone samples were taken perioperatively and analyzed using NONMEM. Monte Carlo simulations were performed to determine the probability of target attainment (PTA) in both plasma and bone of various dosing regimens.

Results: A total of 44 plasma and 38 bone samples from 25 patients were included. The median bone concentration at 30-60 min after administration was 18.2 (9.9-25.3) mg/L and the bone-to-plasma ratio was 0.269 (interquartile range [IQR] 0.179-0.269), while the median bone concentration at 90-120 min after administration was 12.6 (5.9-18.6) mg/L and the bone-to-plasma ratio was 0.125 (IQR 0.073-0.160). A two-compartment model with allometric scaling and proportional errors best described plasma and bone concentrations. Only estimated glomerular filtration rate could partly explain the inter-individual variability (IIV) of clearance (CL). A single dose of 1500 mg cefuroxime failed to maintain bone concentrations above target concentrations for Staphylococcus aureus beyond 3.83 h post administration.

Conclusion: A population PK model was developed to characterize the disposition of cefuroxime in both plasma and bone compartments. Although adequate cefuroxime bone penetration within 1 h was observed in patients with PJI with rapid clearance, simulations predicted less optimal levels of cefuroxime after 3.5 h. The clinical implications need to be researched and confirmed.

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.