European Journal of Drug Metabolism and Pharmacokinetics最新文献

Background and objective: This study evaluated the pharmacokinetic characteristics, bioequivalence, and safety of propafenone hydrochloride tablets under fasting conditions in healthy Chinese subjects.

Methods: This was a single-center, randomized, open-label, two-formulation, single-dose study using a four-period fully replicated crossover design. A total of 36 subjects were randomized 1:1 to two sequence groups and received the test (T) or reference (R) formulation in each period. Plasma concentrations of propafenone and its active metabolite, 5-hydroxypropafenone, were quantified using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Pharmacokinetic parameters were derived by noncompartmental analysis using Phoenix WinNonlin 7.0. Bioequivalence was assessed using reference-scaled average bioequivalence (RSABE) based on the within-subject standard deviation (S_WR) of the reference product for area under the concentration-time curve from time 0 to the last time (AUC_0-t), area under the concentration-time curve from time 0 to infinity (AUC_0-∞), and maximum plasma drug concentration (C_max).

Results: Overall, 35 subjects completed the study. After administration of T and R, mean (± standard deviation [SD]) propafenone C_max, AUC_0-t, and AUC_0-∞ were 52.81±70.44 versus 50.11±60.96 ng/mL, 174.98±220.13 versus 165.25±204.39 h/ng/mL, and 184.19±222.71 versus 171.31±206.53 h/ng/mL, respectively. For 5-hydroxypropafenone, C_max, AUC_0-t, and AUC_0-∞ were 68.95±42.09 versus 66.55±33.52 ng/mL, 234.08±150.88 versus 223.33±141.50 h/ng/mL, and 241.43±151.53 versus 230.11±142.83 h/ng/mL, respectively. RSABE analysis indicated that the geometric mean ratios (T/R) for propafenone C_max, AUC_0-t, and AUC_0-∞ were 101.04%, 106.27%, and 105.32%, all within the acceptance range of 80.00-125.00%.

Conclusions: Under fasting single-dose conditions, the test and reference propafenone hydrochloride tablets met bioequivalence criteria in healthy Chinese subjects.

Background and objective: Infections in the central nervous system (CNS) are serious and carry a significant risk of morbidity and mortality. Though commonly used as prophylaxis for neurosurgical interventions, cefazolin as a treatment for CNS infections due to methicillin-susceptible Staphylococcus aureus (MSSA) has been debated owing to the perceived inability to achieve adequate concentrations at the site of infection. The objective of the current study was to evaluate the dose-exposure-response relationship of cefazolin in the CNS.

Methods: To leverage sparse data of cefazolin in the cerebrospinal fluid (CSF) and derive an understanding of the dose-exposure-response profile in the CNS, a physiologically-based pharmacokinetic (PBPK) model was created in PK-Sim. Simulations were performed using standard cefazolin dosing of 2000 mg every 8 h and alternative regimens to maximize the probability of target attainment (PTA). The pharmacodynamic target used was 100% fT > MIC (100% of free drug concentrations above the minimum inhibitory concentration). Furthermore, a neurotoxicity threshold of ≥ 300 mg/L and ≥ 30 mg/L for trough concentrations was set as the safety indicator in plasma and CSF, respectively.

Results: The cefazolin CSF-PBPK model was successfully validated such that predicted CSF:plasma ratios were within a 1.5-fold error compared with the observed values. In addition, the median predicted CSF:epidemiological cut-off (ECOFF) concentration ratio was 2.52, compared with an observed value of 2.8. In silico simulations demonstrate that intermittent doses of 2000 mg every 6 h or a continuous infusion of 8-10 g/day may be required to ensure 90% PTA for MSSA to a MIC ≤ 2 mg/L. Predicted plasma and CSF concentrations were well below concentrations associated with neurotoxicity.

Conclusions: This study is the first to use sparse observed CNS data to develop a mechanistic model to describe the pharmacokinetics of cefazolin in the CSF. This work supports existing research on the viability of cefazolin as a therapeutic alternative for CNS infections attributed to MSSA and can be used for future clinical trial planning.

Background and objective: Tramadol is a widely used opioid, and pharmacogenetics is partially responsible for the variability in its response. The objective was to develop a tramadol population pharmacokinetic (popPK) model including pharmacogenetic information.

Methods: A single oral dose of 37.5 mg tramadol + 400 mg ibuprofen arginine was administered to 24 European healthy volunteers, and 18 blood samples were obtained from 0.25 h to 24 h after drug intake. Subjects were genotyped for the main pharmacogenes and a popPK model was built using NONMEM^® (version 7.3). The role of CYP2D6, CYP2B6, and CYP3A4 phenotypes was analyzed. The final parameter estimates were compared with results obtained by noncompartmental analysis (NCA) in the same cohort. Simulations depending on CYP2D6 phenotype were performed in single dose and steady state conditions.

Results: A two-compartment model, with transit absorption into the depot compartment and first-order elimination, was the best fit to the data. In total, 8 volunteers were CYP2D6 intermediate metabolizers (IMs) and 14 were normal metabolizers (NMs), merged for the analysis with the two ultrarapid metabolizers (UMs), whereas no poor metabolizers (PMs) were present (European frequencies: 38.3%, 49.2%, 2.3%, and 6.5%, respectively). CYP2D6 phenotype affected clearance, which was 20% reduced in IMs compared with NMs + UMs. CYP2B6 (NMs = 11, IMs = 11, and PMs = 2) and CYP3A4 (NMs = 20, IMs = 3) phenotypes did not affect clearance. PopPK and NCA estimates were in close agreement. Simulations indicated a 20% and even 40% higher area under the curve after single dose and steady state conditions, respectively, in CYP2D6 IMs compared with NMs and UMs.

Conclusions: A popPK model including CYP2D6 phenotype well described the data. Further research with increased sample size is needed to analyze the clinical impact and effect of CYP2B6 and CYP3A4 phenotype on tramadol pharmacokinetics.

Background and objective: Therapeutic drug monitoring (TDM) typically uses total drug concentration (C_t), but pharmacological effects depend on free concentration (C_f), especially for highly protein-bound drugs like rifapentine (RFPT) (96-99% bound). Monitoring C_f is critical for optimizing efficacy and minimizing hepatotoxicity in patients with tuberculosis (TB) with individual variability. Addressing limitations of existing assays, this study developed a sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying free RFPT and evaluated C_f, C_t, and clinical factor correlations in adults and children.

Methods: A validated LC-MS/MS method used Centrifree ultrafiltration (CF-UF) for free RFPT isolation and isotope internal standard (rifapentine-d8) for quantification. Validation included specificity, linearity (3.00-299.60 ng/mL), accuracy, precision, matrix effects, and stability. Clinical samples from 58 patients with TB (adults and children) receiving RFPT were analyzed. Total and free RFPT, albumin, and biochemical parameters were compared.

Results: The method showed excellent linearity (R² = 0.9999), accuracy (93.11-102.67%), and precision (intra-/inter-day RSD ≤ 7.40%). The lower limit of quantification (LLOQ) was 3.00 ng/mL, suitable for clinical C_f detection. C_f correlated nonlinearly with C_t. C_t was significantly higher in adults than children (20.91 ± 14.08 versus 14.64 ± 8.47 μg/mL, P = 0.03), but C_f (0.085 ± 0.09 versus 0.054 ± 0.05 μg/mL, P = 0.06) and free fractions (0.38 ± 0.29% versus 0.35 ± 0.20%, P = 0.65) showed no significant difference.

Conclusions: The LC-MS/MS method is rapid, sensitive, and suitable for routine free RFPT TDM. Nonlinear C_t-C_f relationships highlight the necessity of direct C_f monitoring, particularly with altered protein binding. Similar free fractions in adults and children despite dose-related C_t differences suggest tailored dosing may mitigate toxicity. Adjustments based solely on C_t may not be universally applicable.

Migraine affects up to 11% of children and adolescents, leading to substantial disability through school absenteeism, cognitive impairment, and reduced quality of life. Traditionally, preventive treatment options for this population have been limited to the off-label use of nutraceuticals, antiseizure medications, calcium channel blockers, serotonin modulators, antidepressants, or beta-blockers, with limited efficacy and tolerability data. Monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway have transformed adult migraine prevention, and fremanezumab is the first in this class to receive regulatory approval for pediatric use. In August 2025, the US Food and Drug Administration approved fremanezumab for the preventive treatment of episodic migraine in patients aged 6-17 years weighing at least 45 kg, based on the pivotal phase three SPACE trial. This randomized, placebo-controlled study demonstrated significant reductions in monthly migraine and headache days, with nearly half of treated participants achieving a ≥50% response rate, and a safety profile consistent with adult data. In this review, we provide an integrated, pediatric-focused synthesis of the pharmacokinetic, pharmacodynamic, and regulatory evidence supporting fremanezumab use in children and adolescents. In particular, we contextualize population pharmacokinetic modeling and pediatric phase 1 data to explain the rationale for weight-based dosing, exposure matching with adults, and the selection of the dosing regimens used in clinical trials and regulatory labeling. Pharmacokinetic analyses indicate that fremanezumab follows a two-compartment model with first-order absorption and a terminal half-life of approximately 30 days in pediatric patients, similar to adults, with body weight as the primary determinant of exposure. Finally, we discuss unresolved issues related to long-term CGRP blockade during growth, including theoretical effects on vascular regulation, bone metabolism, and neurodevelopment. Overall, fremanezumab represents a novel, mechanism-based preventive option for older children and adolescents with episodic migraine, while highlighting the need for continued longitudinal studies to define its long-term safety and optimal role in pediatric migraine management.

Background: This study investigated the effects of temperature and concentration on the short-term stability of colistin and colistin methanesulphonate in three biological matrices; whole blood, plasma and serum.

Methods: Human whole blood, plasma or serum containing colistin (2; 10; 20 mg/L) or colistin methanesulphonate (2; 10; 20 mg/L) was stored at room temperatrure or at 37 °C for a predetermined time interval. The concentrations of colistin in colistin spiked samples, and formed colistin in colistin methanesulphonate spiked samples, were analysed by LC-MS method.

Results: Findings indicate that colistin A and B were stable at the room temperature, but degradation accelerated at 37 °C, particularly at lower concentrations. The conversion of CMS to colistin was also temperature-dependent, where the concersion was significantly accelerated at elevated temperatures. Freeze-thaw stability were tested, COL A as well as COL B were stable for at least three freeze-thaw cycles.

Conclusion: These results underscore the importance of rapid sample processing to ensure reliable therapeutic drug monitoring and emphasize the importance of considering temperature and concentration factors in clinical practice to optimise dosing and minimise toxicity. Further research is required to investigate the full range of factors affecting the stability of colistin and colistin methanesulphonate in biological matrices.

Background and objective: Obtaining pharmacokinetic curves is crucial for drug dosage selection, and for assessment of efficacy and adverse effects in clinical practice. The aim of this study was to utilize a minimal physiologically-based pharmacokinetic model to predict concentration-time profiles of cinacalcet hydrochloride, a poorly soluble drug, under fasting and fed conditions, and further to establish correlations between in vivo and in vitro dissolution profiles of cinacalcet hydrochloride.

Methods: The mPBPK model consisted of six tissue compartments, and an additional compartmental absorption and transit model, incorporating the stomach, seven small intestinal compartments, and the large intestine along with Johnson's equation, was integrated to enable precise calculations of in vivo dissolution.

Results: External validations for three dosages showed that the average fold error and the absolute average fold error were all within a two-fold error range, indicating the accuracy and reliability of the established model. Subsequently, the model was used to calculate the in vivo dissolution profile and to establish a correlation with the in vitro dissolution profile (R² = 0.991 in fasting conditions and R² = 0.991 in fed conditions, both in water medium). Notably, under fasting conditions, this correlation exhibited superior performance compared to convolution, deconvolution, and Wagner-Nelson methods. However, under fed conditions, all four methods demonstrated satisfactory correlations.

Conclusion: The mPBPK model can accurately predict the plasma concentration-time curves under both fasted and fed conditions, and provides a new perspective for establishing in vivo-in vitro correlations of drug products such as incomplete in vivo release, sustained/controlled release, and poor absorption.

Background and objective: BT-114143 is a novel, small-molecule antifibrinolytic agent that promotes hemostasis by inhibiting the conversion of plasminogen to plasmin. Due to its strong binding to this target, the drug exhibits target-mediated drug disposition (TMDD). This is characterized by nonlinear pharmacokinetics (PK) at low doses that transition to linearity at higher, target-saturating doses. In this study, a population pharmacokinetic-pharmacodynamic (PopPK-PD) model for BT-114143 was developed to guide dose selection for a subsequent multiple ascending dose (MAD) study.

Method: Using PK and PD data from a single ascending dose (SAD) study of intravenously administered BT-114143, a PopPK-PD model was developed.

Results: The PopPK-PD analysis established that a TMDD PK model, combined with a sigmoid E_max PD model, adequately characterized the nonlinear PK and antifibrinolytic activity of intravenous BT-114143 in healthy subjects. The model identified the primary drivers of this TMDD behavior as the rapid binding of BT-114143 to plasminogen (association rate constant, Kₒₙ = 1.42 µM⁻¹·h⁻¹), its slow dissociation (dissociation rate constant, K_off = 0.0518 h⁻¹), and the estimated total target concentration (Rₜₒₜ = 1.6 µmol/l). Furthermore, simulations predicted that twice-daily regimens of 2.4, 4.8, and 9.6 mg/kg would maintain steady-state trough concentrations (C_trough) above the therapeutic threshold (≥ 2 µmol/l) throughout the dosing period.

Conclusion: This study reports the first PopPK-PD model for a novel, plasminogen-targeting small-molecule exhibiting TMDD properties. The model was subsequently used to inform and support the design of multiple-dose regimens for future clinical studies in patients.