European Journal of Drug Metabolism and Pharmacokinetics最新文献

Background and objective: Lidocaine is increasingly used perioperatively as a systemic analgesic. Quantification of lidocaine and its active metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), is essential for understanding its pharmacokinetics and pharmacodynamics. Existing methods have limitations in throughput, concentration ranges, or do not simultaneously measure lidocaine and metabolites. This study aims to develop and validate a simple, rapid, and robust high-performance liquid chromatography-mass spectrometry (HPLC-MS)/MS method for their simultaneous quantification in plasma from surgical patients receiving intravenous lidocaine.

Methods: Analytes were extracted from 75 µL of plasma by protein precipitation with 300 µL of methanol containing lidocaine-d10 (internal standard). After centrifugation for 5 minutes and filtration, 5 µL was injected onto a Phenomenex Luna C8(2) column (100 × 2.0 mm, 5 µm), achieving chromatographic separation within 5 minutes by gradient elution with 0.01% formic acid in water (mobile phase A) and acetonitrile-methanol 50:50 (mobile phase B). Mass spectrometry detection employed positive electrospray ionization with multiple reaction monitoring. The method uses a widely accessible HPLC-MS/MS platform, requires low plasma volume, and features streamlined sample preparation.

Results: This method demonstrated good selectivity and specificity, minimal carryover, and reproducible recovery and matrix effects. Calibration curves were linear over 0.01-5 mg/L for lidocaine and 0.01-1.5 mg/L for MEGX and GX. Within-day and between-day accuracy and precision met acceptance criteria, and analytes remained stable under relevant conditions.

Conclusions: This validated assay requires low plasma volume and minimal preparation for simultaneous quantification of lidocaine and metabolites. It was successfully applied in a population pharmacokinetic study of surgical patients receiving intravenous lidocaine, supporting optimized dosing strategies.

Background and objectives: Focusing on pharmacokinetic-derived individual dose-intensity parameter values (DIPs), we modeled the pharmacokinetics of polyethylene glycol-conjugated asparaginase (PEG-ASNase) in all treatment phases and different trial groups of AIEOP-BFM ALL 2009.

Methods: Children with acute lymphoblastic leukemia received 1-10 weekly or biweekly repetitive doses (2500 U/m²/dose intravenously). A population pharmacokinetic (popPK) model was extended to all phases to describe the pharmacokinetics and the impact of anti-PEG- and anti-asparaginase-antibodies in the German/Czech group (2535 patients, aspartic acid β-hydroxamate (AHA) assay) and validated the model in the Italian group (1603 patients, medac asparaginase activity test (MAAT) assay). DIPs, also for 279 Australian patients, were derived. Allergic reactions and silent inactivation were exclusion criteria.

Results: Treatment phase dependency and drug accumulation were modeled by up to -60% lower clearance and -30% lower volume of distribution compared with the first administration in induction. Apart from the impact of high preexisting anti-PEG-antibody levels on clearance in induction, no further impact of antibodies was identified. Independent modelling of the Italian data (conversion factor 1.23/1.42: ≤ 600/> 600 U/L) confirmed the model. Time above 100 U/L correlated to the time-interval between the first and last dose within a phase, whereas the area under the concentration-time curve (AUC) was linked to the cumulative dose showing higher drug accumulation after repetitive doses than expected by linear extrapolation.

Conclusion: A popPK model was adapted to all phases and different trial groups integrating asparaginase antibodies as long as they did not lead to silent inactivation or allergic reaction. The model allows strategic development of trial schedules and the calculation of intended or realized individual DIPs.

Trial registration: EU clinical trails register; European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) Number 2007-004270-43.

Introduction: An increasing number of patients in clinical practice are transitioning from intravenous (IV) to subcutaneous (SC) dosing of infliximab. In this simulation study, we evaluated hypothetical dosing scenarios both for typical adults and adults with obesity and for children switching from steady-state IV to SC infliximab, as well as those initiating SC infliximab therapy.

Methods: By combining two previous published infliximab models, we were able to simulate both IV and SC dosing in adults and children. Various dosing regimens were simulated using a large virtual population. In each scenario, the distribution of trough concentrations and area under the plasma concentration-time curve (AUC) was calculated.

Results: Peak levels were higher after IV dosing compared with SC dosing, while trough levels were higher after SC dosing, leading to more stable infliximab levels over time. Overall exposure remained largely similar when switching from a standard IV to SC dosing regimen. Patients with a high body mass index and those on high-frequency IV dosing regimens of infliximab demonstrated reduced exposure when transitioned to the fixed SC dose. Paediatric patients exhibited higher exposure on the fixed SC dose. Simulation of SC induction schemes demonstrated early achievement of steady-state plasma levels.

Conclusion: Infliximab exposure (AUC) remains largely similar when transitioning from standard IV to SC dosing. Current dosing regimens may not be optimal for patients with severe obesity, paediatric patients and patients on high-frequency infliximab regimens. These findings provide a foundation for future clinical research to refine SC infliximab dosing in these populations.

Background and objectives: Epstein-Barr virus (EBV) is a common herpesvirus among pediatric liver transplant recipients, but it can have serious complications, such as post-transplant lymphoproliferative disease. EBV is hypothesized to influence tacrolimus concentrations by increasing inflammatory cytokines that regulate the expression of cytochrome-P-450 enzymes involved in tacrolimus pharmacokinetics. This study aims to examine the association between EBV serostatus and viral load, and tacrolimus trough concentrations corrected for the dose and recipient weight [weight-adjusted concentration-to-dose (C/D) ratios].

Materials and methods: This retrospective study includes pediatric liver transplant recipients aged 0-18 years old, transplanted at the University Medical Center Groningen between January 2008 and September 2021. This study utilized two cohorts: a cross-sectional and a longitudinal study database.

Results: The association between EBV serostatus and the tacrolimus pharmacokinetics was examined using 45 recipients from both cohorts. The effect of EBV viral load on tacrolimus pharmacokinetics was examined using the longitudinal study database, which included 25 EBV-positive recipients. No significant effect of EBV on the tacrolimus weight-adjusted C/D ratios was found, for either EBV serostatus (p = 0.85) or EBV viral load (p = 0.85).

Conclusions: This study suggests that the standard protocol of tacrolimus dosing does not seem to require adjustments due to changes in EBV serostatus or viral load.

Background and objectives: With diabetes prevalence rising and original formulations unable to meet demand, establishing generic equivalence is crucial for treatment accessibility. This study evaluated the bioequivalence of generic metformin hydrochloride (0.25 g) versus the reference drug in Chinese volunteers under fasting and fed conditions.

Methods: In this randomized, open-label, two-period crossover trial, 26 healthy volunteers per group received single doses under fasting and fed conditions. Plasma concentrations were measured using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, pharmacokinetic metrics were calculated using the WinNonlin 6.3 software, and bioequivalence was evaluated using SAS 9.4.

Results: Under fasting conditions, the geometric mean ratios (GMRs) between the test and reference groups were 103.12% (C_max), 103.65% (AUC_0-t), and 103.31% (AUC_0-∞), with 90% CIs of 92.64-114.78%, 96.04-111.85%, and 96.00-111.17%, respectively. Fed conditions yielded GMRs of 93.98% (C_max), 97.34% (AUC_0-t), and 96.97% (AUC_0-∞), with 90% CIs of 89.42-98.78%, 92.72-102.18%, and 92.40-101.78%, respectively. All these parameters met bioequivalence criteria (80-125%). Median T_max was delayed under fed conditions (2.125 h vs. 4.000 h), with consistent food effects (reduced C_max and AUC) and safety profiles between formulations.

Conclusion: These results demonstrate that the generic metformin formulation is bioequivalent to the innovative product and well tolerated in Chinese healthy volunteers under both fasting and fed conditions.

Background/objectives: Tacrolimus (TAC, FK-506) is a calcineurin inhibitor commonly used to prevent organ rejection in transplant patients. It has a narrow therapeutic index and nephrotoxic effects, characterized by interindividual dose variability. TAC is metabolized by the CYP450 (CYP3A5, CYP3A4) enzyme system and transported by P-glycoprotein (ABCB1). Additionally, the CYP2C8 enzyme has been suggested to play a protective role against both graft rejection and drug-induced toxicity. Genetic polymorphisms in these pathways may influence the risk of tacrolimus-related nephrotoxicity. This retrospective cohort study was conducted to evaluate the association between CYP3A5, ABCB1, and CYP2C8 gene polymorphisms and renal function in kidney transplant recipients METHODS: This study investigated the impact of CYP3A5, ABCB1 and CYP2C8 polymorphisms on blood TAC level and kidney function in renal transplant patients. Genotyping was conducted to determine allele frequencies for CYP3A5 (6986A>G), ABCB1 (13435C>T), and CYP2C8 (A1196G) polymorphisms. Renal function was assessed by measuring serum creatinine, estimated glomerular filtration rate (eGFR), and protein/creatinine ratios at 3, 6, and 12 months post-transplantation.

Result: At 12 months post-transplant, the median serum creatinine level was significantly higher in patients with CYP2C8 (*1/*3 and *3/*3) genotypes compared to those with the CYP2C8*1/*1 genotype (p = 0.021). Additionally, the increase in creatinine from the 3rd to the 12th month was significantly greater in the CYP2C8 (*1/*3 and *3/*3) group (p = 0.036). No significant differences were observed in TAC dosage, blood concentration, or renal function between ABCB1 genotype groups. Although daily TAC doses differed significantly between CYP3A5 genotypes, renal function did not significantly vary.

Conclusion: In light of these data, CYP2C8 gene polymorphism has been associated with an increase in serum creatinine, one of the key markers of renal function. ABCB1 gene polymorphism showed no association while CYP3A5 gene polymorphism influenced TAC dose; however, further studies with larger cohorts are required to clarify these associations.

Background: Ticagrelor is an oral P2Y₁₂ receptor antagonist used mostly in combination with aspirin, in patients with acute coronary syndromes (ACS). Ticagrelor is discontinued 3-5 days before major procedures. Due to its reversible effect, discontinuation is likely to increase the risk of thrombosis. While the effect of dose interruptions on the risk of thrombosis has not been directly studied, pharmacokinetic/pharmacodynamic (PK/PD) simulations provide useful insights.

Objectives: The objective of the current study was to simulate the impact of therapy interruption on the PK/PD of ticagrelor.

Methods: The oral absorption of ticagrelor was described by a transit compartment model, and population PK/PD parameters were obtained from published literature. The PD of ticagrelor was described using a sigmoidal direct-response I_max model. A population PK/PD model describing the relationship between ticagrelor dose, plasma concentrations, and P2Y₁₂ reaction units (PRU) was used to perform simulations using Simulx (Lixoft, France). Simulated patients (n = 1000) received a loading dose of 180 mg followed by a maintenance dose of 90 mg twice daily orally for 15-days. Doses were stopped on day 8 for 0-5 days and resumed with or without a loading dose.

Results: During uninterrupted ticagrelor use, median PRUs ranged between ~ 13 to ~ 40, with > 70% below low platelet reactivity (LPR). The % of PRUs below high platelet reactivity (HPR) drops to ~ 47%, ~ 11%, ~ 2% and 0% upon dose interruption of 1, 2, 3, and 5 days, respectively. Within 2 h of dose resumption with either the loading or the maintenance dose, > 94% of PRUs were below LPR.

Conclusion: Our results suggest the need for individualizing duration of dose interruption prior to surgery and its resumption afterwards.

Background and objectives: Iclepertin, a selective glycine transporter-1 inhibitor, was investigated as a potential treatment for cognitive impairment associated with schizophrenia. The objective of this trial was to determine the effect of food on the pharmacokinetics of iclepertin 10 mg.

Methods: This Phase I, open-label, 2-period cross-over trial randomised (1:1) healthy volunteers to 2 treatment sequences (fasted-fed or fed-fasted) to receive a single oral dose of iclepertin 10 mg once daily in either the fasted or fed state followed by cross-over to the other state. Primary endpoints included maximum measured concentration in plasma (C_max) and area under the concentration-time curve over the time interval from 0 to the last quantifiable data point (AUC_0-tz). The secondary endpoint was area under the concentration-time curve over the time interval from 0 extrapolated to infinity (AUC_0-inf). Relative bioavailability was estimated by calculating an adjusted geometric mean (gMean) fed/fasted ratio using analysis of variance. Safety was assessed.

Results: Of 16 participants enrolled [mean (SD) age: 37.1 (10.1) years], 15 were included in the analysis. The C_max, AUC_0-tz and AUC_0-inf of iclepertin were higher in the fed versus fasted state; adjusted gMean ratios (90% confidence intervals) were 118.33% (110.01, 127.28), 114.61% (110.13, 119.27) and 114.38% (110.11, 118.80), respectively. Iclepertin 10 mg was well tolerated.

Conclusion: Iclepertin exposure was higher in fed versus fasted conditions, but the increase was minor, suggesting food has no meaningful effect on the pharmacokinetics of iclepertin 10 mg.

Study registration: ClinicalTrials.gov (NCT05347004; registered: 20 April 2022).