Clinical Pharmacokinetics最新文献

Background and objectives: Efsubaglutide alfa is a long-acting GLP-1 receptor agonist and is designed by fusion of two human GLP-1 molecules with IgG2 Fc via a natural immunoglobulin hinge region. This study evaluates the exposure-response (E-R) relationship of efsubaglutide alfa in patients with type 2 diabetes (T2D) treated with metformin.

Methods: Data were derived from an operational seamless design of randomized, double blind, placebo clinical trial (YN011-302) involving 406 subjects with T2D on stable metformin therapy. Participants received weekly subcutaneous injections of 1 mg or 3 mg efsubaglutide alfa, or placebo. The trial included a 24-week double-blind period and a 28-week open-label period.

Results: Participants had a median age of 55.0 years, mean body weight of 73.7 kg, fasting plasma glucose (FPG) of 9.72 mmol/L, and glycated hemoglobin (HbA1c) of 8.63%. A robust inverse correlation was observed between efsubaglutide alfa exposure and improvements in HbA1c, FPG, glucose area under the curve (AUC) during mixed-meal tolerance test (MMTT), body weight, and body mass index. Efsubaglutide alfa exposure also positively correlated with C-peptide AUC during MMTT, indicating improved beta-cell function. The E-R model indicates that doubling steady-state trough concentrations (C_min,ss) reduced HbA1c by 0.211%, while every 100 ng/mL increase in C_avg,ss led to 0.5 kg reduction in body weight at Week 24. Baseline HbA1c was a predictor of treatment response. Safety analysis revealed a positive correlation between exposure and gastrointestinal adverse events, which decreased over time, suggesting tolerance development.

Conclusions: Efsubaglutide alfa, combined with metformin, significantly improves glycemic control and weight management, with an acceptable safety profile. This E-R model provides insights for dose optimization and trial design, and supports its use as an effective add-on therapy for patients with T2D, as indicated in the drug specification.

Trial registration: The trials were registered at Clinicaltrials.gov (identifier: NCT04998032).

Background and objective: Pyronaridine is a blood schizonticide with a high blood-to-plasma ratio, effective against Plasmodium parasites. As a lipophilic, moderately strong base, it accumulates in low-pH compartments such as lysosomes and parasite food vacuoles, leading to tissue accumulation and differences in drug exposure between healthy individuals and patients with malaria. This study applied physiologically based pharmacokinetic (PBPK) modeling to evaluate the effects of lysosomal sequestration, red blood cell (RBC) accumulation, and parasitemia on pyronaridine pharmacokinetics.

Methods: Data were available from a phase I clinical trial and the PYRAPREG study. PBPK models were developed in PK-Sim® and MoBi®. A standard multicompartment structure was expanded by adding lysosome compartments to relevant organs. To account for malaria infection, Plasmodium parasite compartments were incorporated into RBCs, with volume scaled by parasitemia.

Results: Data from 52 healthy individuals and 25 patients with malaria were used for model optimization. Incorporating lysosomal sequestration was essential for capturing pyronaridine distribution. In patients with malaria, incorporating low hemoglobin (Hb) and drug accumulation in the parasite compartment enabled an adequate description of whole blood pharmacokinetics. Simulations showed that free pyronaridine concentrations in the parasite compartment were over 10-fold higher than that in whole blood. Higher parasitemia was associated with increased area under the curve (AUC)_0-24h and C_max, mainly on day 1, as parasitemia decreased rapidly. However, the subsequent decrease in Hb had the opposite effect, lowering AUC_0-24h and C_max on the following days.

Conclusions: This study demonstrates the value of PBPK modeling in elucidating key pharmacokinetic mechanisms, revealing the critical roles of lysosomal sequestration, Hb level, and parasitemia in pyronaridine disposition.

Background: Suboptimal peak inspiratory flow rates (PIFR) are common in patients with chronic obstructive pulmonary disease (COPD), hindering effective medication dispersion and aerosol delivery. This study aimed to assess whether administering a preliminary bronchodilator dose via a pressurized metered-dose inhaler (pMDI) improves aerosol drug delivery via dry powder inhaler (DPI) in patients with COPD with suboptimal PIFR (< 60 L/min), compared with those with optimal PIFR (≥ 60 L/min).

Methods: Overall, 24 patients with COPD were evaluated. PIFR was measured using the In-Check Dial^© G16, dividing patients into optimal and suboptimal groups. All patients received a 200 µg dose of salbutamol via Diskus^® DPI. Patients with COPD with suboptimal PIFR received two puffs (100 µg each) preceded by a preliminary salbutamol dose administered via pMDI^®. Urine salbutamol levels (USAL30) and salbutamol that was eluted from filters (SALF) were measured after 30 min to assess lung deposition through high-performance liquid chromatography (HPLC).

Results: Patients with COPD with suboptimal PIFR without a preliminary dose had significantly lower USAL30 than the optimal group (4.99% versus 6.18%, p = 0.013). A preliminary dose improved USAL30 in the suboptimal group but did not reach statistical significance (5.45% versus 4.99%, p = 0.071).

Conclusions: A significant difference in aerosol drug delivery was observed between optimal and suboptimal groups without a preliminary dose, suggesting that inhaler selection in patients with COPD may need to be individualized on the basis of inspiratory flow capability. Administering a preliminary dose of pMDI^® before using a DPI minimally affects the suboptimal inhalation through DPI.

Background and objective: Population pharmacokinetic (PK) model-based Bayesian estimation is widely used for dose individualization, particularly when sample availability is limited. However, its predictive accuracy can be compromised by factors such as misspecified prior information, intra-patient variability, and uncertainties in PK variations. In this study, we developed a hybrid approach that combines machine learning (ML) with population PK-based Bayesian methods to improve the prediction of infliximab concentrations in children with Crohn's disease.

Methods: We calculated prediction errors between Bayesian-estimated and observed infliximab concentrations from 292 measurements across 93 patients. Incorporating clinical patient features, we explored various ML algorithms, including linear regression, random forest, support vector regression, neural networks, and XGBoost to correct the Bayesian-based prediction errors. The predictive performance of these ML models was assessed using root mean square error (RMSE) and mean prediction error (MPE) with 5-fold cross-validation.

Results: For Bayesian estimation alone, the RMSE and MPE were 4.8 µg/mL and - 0.67 µg/mL, respectively. Among the ML algorithms, the XGBoost model demonstrated the best performance, achieving an RMSE of 3.78 ± 0.85 µg/mL and an MPE of - 0.03 ± 0.69 µg/mL in 5-fold cross-validation. The ML-corrected Bayesian estimation significantly reduced the absolute prediction error compared with Bayesian estimation alone.

Conclusion: This hybrid population PK-ML approach provides a promising framework for improving the predictive performance of Bayesian estimation, with the potential for continuous learning from new clinical data to enhance dose individualization.

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.

Polyethylene glycols (PEGs) are inert polymers of repeating ethylene oxide subunits. Attaching PEGs to therapeutic proteins may reduce the protein's immunogenicity and antigenicity, improve solubility and stability, slow protein degradation, and increase the half-life (t_½). This usually results in less frequent administration, improved quality of life and convenience, and potentially better adherence and lower costs. The advantages and disadvantages of PEGylated proteins differ according to the structure of the PEG moiety, particularly its molecular weight. The larger the PEG molecular weight, the longer the t_½ and time to steady state. PEGs have low toxicity and undergo minimal metabolism. The PEG moiety usually undergoes renal elimination and is excreted in urine, but with greater molecular weights, renal elimination declines and biliary excretion increases. Because PEG molecules are not broken down, there is potential for PEGs to accumulate in the cytoplasm, forming vacuoles, mostly in macrophages, although this does not affect their function. The risk of vacuolation increases with molecular weights > 30 kDa. However, even high molecular weight PEGs are used at doses markedly lower than the European Medicines Agency safety threshold for paediatric use. People can develop antibodies to PEGs, and this may increase the overall clearance of the PEGylated protein if antibody levels are sufficiently high (> 500 ng/mL according to one modelling study). In conclusion, it is important for physicians to understand how PEG molecular weight and architecture can impact stability, immunogenicity, glomerular filtration and cellular uptake, to better understand the overall safety, efficacy and pharmacological profile of PEGylated proteins.

Background: Tacrolimus is a cornerstone of acute graft-versus-host disease (aGVHD) prophylaxis in allogeneic hematopoietic cell transplant (allo-HCT) recipients. However, a narrow therapeutic index and high interindividual variability in pharmacokinetics (PK) make starting dose selection a major challenge in clinical practice.

Methods: Data from two PK studies conducted at the University of North Carolina Medical Center (UNCMC) were used to develop an oral tacrolimus population pharmacokinetic (popPK) model specific to adult allo-HCT recipients. Monte Carlo simulations were performed to compare the likelihood of achieving the UNCMC institutional target trough concentration range (ITR) (5-10 ng/mL) on the day of transplant (D0) under the current institutional dosing protocol, dosing recommendations from the Clinical Pharmacogenetics Implementation Consortium (CPIC), and model-derived dosing recommendations.

Results: In total, 290 allo-HCT recipients contributed a total of 906 PK samples to the final analysis. A two-compartment popPK model adequately described the PK data. Population typical values of apparent clearance (TVCL/F) for 70 kg individuals receiving reduced intensity conditioning were 0.33 L/h/kg for CYP3A5 poor metabolizers (PMs) and 0.70 L/h/kg for intermediate and normal metabolizers (IMs and NMs). The probability of the population-level average D0 trough concentration being within the UNCMC ITR under the current UNCMC weight-based dosing protocol, CPIC-based, and model-derived dosing strategies were estimated to be 37%, 45%, and 76%, respectively. CYP3A5 IMs and NMs were predicted to require a 100% dose increase relative to CYP3A5 PMs.

Conclusions: We propose a new oral tacrolimus dosing strategy for adult allo-HCT recipients, which suggests the current weight-based dosing paradigm is insufficient. This new strategy includes CYP3A5 metabolizer phenotypes and conditioning regimen intensity, and could increase the percentage of allo-HCT recipients achieving target concentrations on D0.

Clinical trial registration number: Clinicaltrials.gov NCT04645667.

Introduction: Whole-body dynamic (WB4D) positron emission tomography (PET) imaging data using radiolabeled analogs of drugs are mostly analyzed using descriptive approaches, with no relationship to traditional pharmacokinetic studies based on blood sampling. Here, we build a pharmacokinetic (PK) model from WB4D PET data obtained using a microdose of radiolabeled glyburide ([¹¹C]glyburide) in humans, aiming to describe the biodistribution of this drug and compare estimated pharmacokinetic parameters with the parameters obtained in standard PK studies.

Methods: The present work analyzes data acquired over 40 min after injection of [¹¹C]glyburide in 16 healthy subjects using non-linear mixed-effect models (NLMEM). In 10 subjects, a second PET acquisition was performed after rifampicin administration, which may cause a drug-drug interaction and inhibit the liver uptake transport of glyburide. Arterial blood, liver, kidneys, pancreas, and spleen kinetics were modeled using NLMEM. The model-building strategy involved selecting the structural model using baseline [¹¹C]glyburide PET data and then selecting the covariate model (rifampicin, age, and gender) and refining the structure of the interindividual variability model using both administration periods. Model selection was based on the corrected Bayesian information criterion and implemented in Monolix software.

Results: The final model included seven compartments, with two compartments each for the Liver and kidneys to account for within-tissue exchanges. Rifampicin decreased the Liver distribution by 261%.

Discussion: The estimated central volume of distribution (V = 3.6 L) and elimination rate (k = 0.8 h^-1) were consistent with the known pharmacokinetics of glyburide, which is a promising first step in leveraging microdose data to study the WB4D biodistribution.

Registration: EudraCT identifier no. 2017-001703-69.

Background: Patent ductus arteriosus is a common complication of extreme prematurity. Prophylactic treatment with indomethacin or ibuprofen has shown efficacy on ductus closure but without reducing mortality and morbidity. Prophylactic treatment by paracetamol could be a safer alternative.

Objective: The aim was to build a pharmacokinetic-pharmacodynamic (PKPD) model describing the effect of paracetamol on the time-course of the ductus arteriosus diameter.

Methods: Extremely preterm neonates of 23-26 weeks of gestational age were recruited within 12 h after birth and were treated with prophylactic intravenous paracetamol for 5 days (two dose levels: 20 mg/kg followed by 7.5 mg/kg or 25 mg/kg followed by 10 mg/kg every 6 h). The diameter of ductus arteriosus was determined by echocardiography performed daily until day 7. The PKPD model was built using an I_max model with effect compartment and exponential disease progression model. Concentrations of paracetamol in the effect compartment were simulated with different doses over time for 500 virtual patients.

Results: A total of 29 extremely preterm neonates with median birth weight of 800 g (IQR: 670-860) were included in the study. Between-subject variability was estimated on transfer rate constant between the central compartment and the effect compartment (ke₀) and maximum drug inhibition (I_max) parameters. Two subpopulations with different I_max values were identified: 99% for a first subpopulation of 10 patients and 42% for the second subpopulation of 19 patients. A negative effect of maximum fraction of inspired oxygen (FiO₂) used during transfer to intensive care unit and a positive effect of intubation and ventilation during treatment were significant on ke₀. Simulations showed that both dose levels generally enabled patients to reach the concentration needed to achieve 95% of maximal inhibition by the end of treatment. However, the second dose level enabled more than 90% of patients to reach this inhibition threshold as early as day one.

Conclusion: The relationship between paracetamol and the time-course of ductus arteriosus diameter has been described in extremely preterm neonates. Intravenous paracetamol treatment with a loading dose of 25 mg/kg within 12 h after birth followed by 10 mg/kg every 6 h appears to be effective to accelerate time to ductus closure with limited benefit of a further dose increase.