Clinical Pharmacokinetics最新文献

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: 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.

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).

Obesity is becoming more prevalent, and it significantly alters drug pharmacokinetics (PK), potentially impacting the efficacy and safety of β-lactam antibiotics. Population pharmacokinetic (popPK) modeling plays a crucial role in optimizing dosing strategies, yet there is variability in how these models account for obesity-related physiological changes. This review aims to synthesize published popPK studies on β-lactams in obese populations, highlighting key findings and modeling approaches. A literature review was conducted to identify popPK studies evaluating β-lactam antibiotics in obese individuals. Relevant databases were searched for studies reporting PK parameters, covariates, and dosing recommendations. A total of 24 studies met the predefined selection criteria. The majority employed two-compartment models with creatinine clearance (CL_CR) and total body weight (TBW) as the most common covariates for clearance (CL) and volume of distribution (V_d). Estimated PK parameters differed within the same β-lactam, which indicates that obesity influences the PK of β-lactams, though the extent of its impact differs based on the specific drug, patient characteristics, and selected covariates. This review highlights the key aspects of popPK models in obese populations treated with β-lactams. Despite the growing prevalence of obesity, its influence on β-lactam antibiotics remains uncertain.

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 and objective: Sodium benzoate (SB) is used as a second-line therapy to treat rare urea cycle disorders (UCDs) in paediatric and adult patients. However, lactation data for SB do not exist, leading to uncertainties regarding the extent of infant drug exposure due to breastfeeding while taking this medication. These uncertainties may lead to cessation of breastfeeding, unnecessarily depriving both mother and infant of its numerous benefits. Thus, this study aims to develop and apply a paediatric physiologically based pharmacokinetic (PBPK) model to predict the compounded neonatal SB exposure from both in utero and from breastfeeding.

Methods: An adult whole-body PBPK model for SB was first developed and validated with literature-based plasma concentrations after oral or intravenous doses. To account for age-related changes in SB pharmacokinetics, the adult model was scaled to paediatric populations using age-dependent algorithms to capture physiological and anatomical changes, while ontogeny functions were developed to capture maturation of enzymes and transporters where possible. A published cord-coupled PBPK modelling workflow was followed to simulate the cumulative pre- and post-natal drug exposure levels in breastfed infants, accounting for variability in milk ingestion volumes and assuming a conservative milk-to-plasma ratio of 1:1. The upper area under the curve (AUC) ratio (UAR) was used for risk assessment, taking the ratio between the AUC for the highest risk (95^th percentile simulated AUC) infants and the median maternal AUC following a therapeutic SB dose and multiplying by 100% to report as a percentage.

Results: The paediatric PBPK model captured observed SB plasma concentrations in both neonates and children with acceptable bias and precision, supported by the average-fold error (AFE: 1.17) and the absolute AFE (AAFE: 1.24) evaluation metrics, respectively. Neonatal SB exposure levels were the highest on the first day of life (UAR: 14.2%) due to the presence of residual prenatal drug levels. Subsequent UAR values were low (1.5-3.3%) on postnatal days 1-31, suggesting rapid neonatal clearance and negligible contribution of prenatal exposure relative to breastfeeding exposure for the infant's total drug burden.

Conclusion: This study is the first to report a paediatric PBPK model of SB pharmaceutical use, incorporating prenatal and lactational exposure to assess the cumulative risk of exposure for the breastfed infant. Model predictions suggest that SB exposure through breastfeeding is minimal and unlikely to cause adverse outcomes when compared with clinical studies. These findings may support clinical decision making in the absence of clinical lactation data; however, empirical studies are needed to validate the predictions given the limited information on milk transfer, enzyme ontogeny, and neonatal concentrations.

Background and objective: Direct oral anticoagulants have largely replaced vitamin K antagonists, for example, warfarin, because of their favorable safety profile and predictable pharmacokinetics, with apixaban being the most widely used direct oral anticoagulant. Although routine therapeutic drug monitoring is not required, measuring apixaban plasma concentrations may be useful in high-risk clinical scenarios. This aim of this study was to evaluate the impact of a repeat apixaban concentration measurement combined with a pharmacokinetic analysis and dose adjustment on drug concentrations and clinical outcomes.

Methods: We conducted a retrospective observational cohort study at Hadassah Mount Scopus Hospital, including elderly patients hospitalized between January 2020 and September 2024 with prescriptions for apixaban. Patients with two appropriately timed, maximum apixaban plasma concentrations within 90 days were analyzed.

Results: A total of 127 patients were included (median age 79 years, maximum age 97 years; 51% female). At baseline, 16% had subtherapeutic apixaban plasma concentrations and 20% had supratherapeutic concentrations. Female sex was associated with subtherapeutic concentrations while a standard dose (10 mg/day) of apixaban was associated with supratherapeutic plasma concentrations. Dose adjustment was more common in patients with standard dose therapy and in patients with an out-of-range baseline apixaban measurement with adjusted odds ratio of 6.1 and 95% confidence interval of 2.2-16.9 and 4.9 (95% confidence interval 1.9-12.7), respectively. In patients who had undergone repeated apixaban maximum plasma concentration measurements, we found 24 bleeding events and six thrombotic or embolic events within a 1-year follow-up from the second maximum plasma concentration measurement. Bleeding events were more common in patients whose maximum plasma concentration was out of the therapeutic range (28% vs 15%), CONCLUSIONS: Dose adjustment based on apixaban plasma concentration monitoring increased the proportion of patients who have apixaban concentrations within the therapeutic range. In high-risk elderly patients, an apixaban concentration measurement coupled with active intervention (e.g., dose adjustment) is likely to be clinically beneficial in avoiding bleeding and thromboembolic events.

Background and objectives: The efficacy of asciminib was proven in newly diagnosed (first-line, 1L) patients with Philadelphia-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) and in patients treated with at least two prior tyrosine kinase inhibitors (third-line, 3L+). Given that no randomized controlled trial has been conducted for second-line (2L) patients with CML, this analysis aims to infer the efficacy of asciminib in the 2L setting using the 80 mg once-daily dosing regimen and to support the use of asciminib in patients with CML-CP irrespective of line of therapy.

Methods: Data (n = 430) were used from three studies, including first-in-human and ASCEMBL in 3L+ and ASC4FIRST in 1L trials, to evaluate the effect of line of therapy on efficacy on the basis of the time-course of BCR::ABL1 mRNA transcripts. Previously adapted to characterize the effect of nilotinib as a 1L and 2L therapy on a CML surrogate marker, the model has three compartments representing quiescent leukemic stem cells and proliferating drug-susceptible and resistant bone marrow cells, wherein the effect of asciminib was modeled as an enhancement of the elimination of susceptible cells.

Results: Asciminib efficacy in 2L was inferred from 1L by borrowing information from nilotinib data. A credibility assessment showed robust prediction accuracy and precision of the model with external 2L data from the ASC2ESCALATE study (n = 36). Major molecular response (MMR) rates in 2L were predicted to be 61-67% at week 48 and 70-76% at week 96, with the 80 mg total daily dose.

Conclusions: A model-informed drug development (MIDD) approach was applied to predict 2L efficacy and supported global regulatory approval of asciminib across treatment lines, despite limited clinical data in 2L.

Background and objectives: Levofloxacin is an essential drug in multidrug-resistant tuberculosis (MDR-TB) treatment, but high pharmacokinetic variability necessitates therapeutic drug monitoring (TDM) to optimise exposure and improve outcomes. Traditional TDM requires invasive blood sampling, limiting feasibility. Saliva sampling, a non-invasive matrix may simplify implementation. We aimed to develop a levofloxacin population pharmacokinetic (popPK) model integrating plasma and saliva data, and to evaluate saliva-based limited sampling strategies to support model-informed TDM for levofloxacin in practice.

Methods: Adults receiving oral levofloxacin for ≥ 7 days had plasma and saliva samples collected at 0, 2, and 5 h post-dose. A plasma-and-saliva popPK model was developed using NONMEM, including covariate evaluation. Predictive performance of saliva-based limited sampling strategies for estimating plasma AUC₂₄ was assessed using Bayesian estimation and Monte Carlo simulations.

Results: A total of 57 patients with 342 paired plasma-saliva samples were evaluated. One-compartment model incorporating saliva bio-compartment with first-order absorption (with a lag time) and elimination best described the data. No significant covariates were identified. Simulations showed that the three-point saliva strategy (0, 2, 5 h) predicted plasma AUC₂₄ within clinically acceptable limit (< 15% prediction error). A single 2-h sample yielded comparable accuracy. Two- and three-sample saliva strategies up to 16 h post-dose also showed clinically acceptable accuracy.

Conclusions: The developed popPK model enables reliable estimation of levofloxacin exposure from limited saliva samples. A single 2-h post-dose saliva concentration may support model-informed levofloxacin TDM in routine MDR-TB care. This approach may be beneficial in settings where plasma-based TDM is logistically or ethically challenging.

Background: DPP-4 inhibitors are a class of oral hypoglycemic drugs commonly used in the treatment of type 2 diabetes mellitus (T2DM). Fultagliptin benzoate is a novel and high-selective DPP-4 inhibitor. The renal excretion of many medications, including DPP-4 inhibitors, can be altered in patients with renal impairment. This study investigates the pharmacokinetics, pharmacodynamics, and safety of fultagliptin benzoate tablets in mild and moderate renal impairment (RI) compared with normal renal function to ensure safety and efficacy across these groups.

Methods: A single-dose, non-randomized, open-label, and parallel-control phase I study was performed. Pharmacokinetics, pharmacodynamics, and safety of fultagliptin benzoate tablets were evaluated.

Results: A total of 18 participants were enrolled and completed the study. After oral administration of a single dose of fultagliptin benzoate tablets 12 mg under fasted conditions, fultagliptin was absorbed with median time to reach peak concentration (T_max) of 4.50, 3.00, and 5.50 hours in healthy participants, patients with mild RI, and patients with moderate RI, respectively, and eliminated with mean elimination half-life (t_½) of 32.27, 40.22, and 46.38 h, respectively. Compared with healthy participants, patients with mild RI had similar peak concentration (C_max), while area under the concentration-time curve from time zero to the last measured concentration (AUC_0-t) and AUC from time zero to infinity (AUC_0-∞) increased by 24.7% and 25.0%, respectively. In patients with moderate RI, C_max, AUC_0-t, and AUC_0-∞ increased by 27.5%, 86.4%, and 87.9%, respectively. Comparing the renal clearance rate (CL_R) with that of the healthy participants (8.96 ± 2.24 L/h), the CL_R values (mean ± SD) of patients with mild RI and patients with moderate RI were 6.615 ± 1.34 L/h and 4.54 ± 1.20 L/h, respectively, which were approximately 73.8% and 50.6% of that of the healthy participants. For pharmacodynamic biomarkers, the DPP-4 inhibition rate (E_max) in all groups of participants was > 90%. The duration of DPP-4 inhibition rate over 80% in the three groups showed an increasing trend. Fultagliptin benzoate tablets were well tolerated in all participants during the study.

Conclusion: In patients with mild RI, the small increase in exposure to fultagliptin was not considered clinically relevant. Although a significant increase in exposure was observed in patients with moderate RI without eliciting issues related to efficacy and safety, a half-dose reduction may be considered for the protection of participants.

Trial registration: ClinicalTrials.gov (NCT06883656); registered 12 March 2025 (retrospectively registered).