European Journal of Drug Metabolism and Pharmacokinetics最新文献

Background and objectives: A pharmacokinetic model has been developed to quantify the drug-drug interactions of tacrolimus with concentration-dependent inhibition of cytochrome P450 (CYP) 3A4 from voriconazole and clarithromycin based on the CYP3A5 and CYP2C19 genotypes.

Methods: This retrospective study recruited unrelated bone marrow transplant recipients receiving oral tacrolimus concomitantly with voriconazole and clarithromycin. The published population pharmacokinetic model that implemented genotypes of CYP3A5 (tacrolimus) and CYP2C19 (voriconazole) was integrated. The tested CYP3A4 inhibition models (Sigmoid efficacy maximum [E_max], E_max, log-linear, and linear) were a function of competitive inhibition of voriconazole and mechanism-based inhibition of clarithromycin in a virtual enzyme compartment.

Results: The total tacrolimus trough concentrations were 119 points, with a median of 4.3 (range: 2.0-9.9) ng/mL (n = 3). The final model comprised the Sigmoid E_max model for voriconazole and clarithromycin, which depicted time-course alterations in tacrolimus concentration and clearance when given voriconazole and clarithromycin.

Conclusions: These findings could facilitate the model-informed precision dosing of tacrolimus after unrelated bone marrow transplant.

Background: The pharmacokinetics of immunosuppressant drugs may change with advancing age, potentially affecting patient outcomes.

Objective: To characterise the effects of age on the pharmacokinetic and exposure parameters of tacrolimus, mycophenolate, and prednisolone.

Methods: Pharmacokinetic profiling, involving whole blood tacrolimus, total and free plasma mycophenolic acid (MPA), total plasma mycophenolic acid glucuronide (MPAG), and total and free plasma prednisolone, was performed in an older and younger adult cohort. Thirteen samples were drawn on a single occasion, pre-oral dose and then at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 9, and 12 h post-dose. Non-compartmental analysis was conducted using the PKNCA package, and pharmacokinetic and exposure parameters were compared between age groups using a Mann-Whitney test. A regression analysis was conducted for free MPA and MPAG using significant variables of interest.

Results: This exploratory study included 21 older and 18 younger adults. Dose-adjusted tacrolimus, total MPA and free prednisolone pharmacokinetic parameters were not different between age groups; however, for free MPA and MPAG, older recipients had significantly greater minimum and maximum concentrations, trough concentrations, and half-life. There was a two-fold increase in free MPA exposure in older adults (median dose-adjusted AUC_0-12: 1284 vs. 684 μg h/L, p < 0.0001); MPAG exposure similarly increased. Age was significantly associated with free MPA and MPAG exposure, and free MPA exposure was associated with haematocrit (p < 0.05).

Conclusion: Differences in MPA were found with advancing age and may be due to altered kidney function, haematocrit, plasma protein binding and/or drug absorption. Future research should explore specific covariate contributions to this further.

Background and objectives: Finerenone, a novel selective non-steroidal mineralocorticoid receptor antagonist, has been indicated in chronic kidney disease associated with type 2 diabetes mellitus. Considering the potential complications of diabetes, finerenone can be co-administered with various drugs, including fluconazole, diltiazem, and ritonavir. Given that finerenone is a substrate of cytochrome P450 (CYP) 3A4, the concurrent administration of finerenone with CYP3A4 inhibitors (diltiazem or fluconazole or ritonavir) could potentially lead to drug interactions, which may cause adverse events such as hyperkalemia. No studies have investigated interactions between finerenone and diltiazem or fluconazole or ritonavir. Therefore, this study aims to investigate the pharmacokinetic interaction of finerenone with diltiazem or fluconazole or ritonavir and to evaluate the impact of fluconazole on the pharmacodynamics of finerenone.

Methods: The pharmacokinetic study included four rat groups (n = 8 rats/group), including a control group (finerenone alone) and test groups (finerenone pretreated with diltiazem or fluconazole or ritonavir) using both non-compartment analysis (NCA) and population pharmacokinetic (pop-PK) modeling. The pop-PK model was developed using non-linear mixed-effects modeling in NONMEM^® (version 7.5.0). In the pharmacodynamic study, serum potassium (K⁺) levels were measured to assess the effects of fluconazole on finerenone-induced hyperkalemia.

Results: The NCA results indicated that the area under the plasma concentration-time curve (AUC) of finerenone increased by 1.86- and 1.95-fold when coadministered with fluconazole and ritonavir, respectively. In contrast, diltiazem did not affect the pharmacokinetics of finerenone. The pharmacokinetic profiles of finerenone were best described by a one-compartment disposition with first-order elimination and dual first-order absorption kinetics. The pop-PK modeling results demonstrated that the apparent clearance of finerenone decreased by 50.3% and 49.2% owing to the effects of fluconazole and ritonavir, respectively. Additionally, the slow absorption rate, which represents the absorption in the distal intestinal tract of finerenone, increased by 55.7% due to the effect of ritonavir. Simultaneously, a pharmacodynamic study revealed that finerenone in the presence of fluconazole caused a significant increase in K⁺ levels compared with finerenone alone.

Conclusions: Coadministration of finerenone with fluconazole or ritonavir increased finerenone exposure in rats. Additionally, the administration of finerenone in the presence of fluconazole resulted in elevated K⁺ levels in rats. Further clinical studies are required to validate these findings.

Background and objective: Heated tobacco products (HTPs) are a class of non-combustible, inhaled tobacco products with the potential to reduce the harm associated with cigarette smoking due to reduced cigarette smoke toxicant exposure. Subjective and nicotine pharmacokinetics measures taken over the course of product use provide a framework for abuse liability (AL) assessment of tobacco and nicotine products as well as information on adoption potential for a new tobacco product, which are important aspects for premarket tobacco product authorization by the US Food and Drug Administration. This study aimed to assess the AL of glo HTPs, operated in either Standard or Boost Modes, compared with high- and low-AL comparators (subjects' usual brand cigarettes and nicotine gum, respectively).

Methods: Nicotine uptake and pharmacodynamics measures (including subjective and physiological measures) were assessed in a clinical study of 75 healthy adult non-menthol or menthol smokers using an open-label, randomized crossover study design. Comparisons were made between glo HTPs (Standard or Boost Modes) and each of usual brand (UB) cigarettes and nicotine gum to evaluate nicotine exposure and subjective effects measures.

Results: Nicotine uptake, as reflected in the area under the curve (AUC) at 15 and 240 min after product use (AUC_0-15 and AUC_0-240, respectively) and maximum nicotine concentration (C_max) were significantly lower for all glo HTPs compared to UB cigarettes, regardless of the glo device mode. AUC_0-15 values for glo HTPs ranged from 41.26 to 75.71 ng × min/mL, versus 158.04 to 165.53 ng × min/mL for UB cigarettes. Similarly, AUC_0-240 values for glo HTPs ranged from 379 to 596 ng × min/mL, compared to 1123.73 and 1283.37 ng × min/mL for UB cigarettes. The C_max for glo HTPs ranged from 5.46 to 9.00 ng/mL, whereas UB cigarettes had C_max values of 16.29 to 16.76 ng/mL. The time to reach maximum nicotine concentration (T_max) was significantly shorter for glo HTPs (4-5 min) compared to UB cigarettes (6-7 min), except for one variant of glo HTP in Standard Mode. Nicotine gum exhibited a slower nicotine absorption profile, with a T_max of 45 min and C_max of 4.60 ng/mL. AUC_0-15 and AUC_0-240 values for nicotine gum were 6.18 and 5.22 ng × min/mL, and 647.80 and 687.68 ng × min/mL for non-menthol and menthol groups, respectively. Subjective measures indicated that glo HTPs were rated significantly lower than UB cigarettes in terms of product liking, smoking urge reduction, product effects, and intent to use again, but were comparable to nicotine gum.

Conclusion: glo HTPs demonstrated lower AL than combustible cigarettes while delivering sufficient nicotine to support product adoption among current smokers. This positions glo HTPs as a poten

Background and objectives: Fimasartan, an angiotensin II receptor antagonist, exhibits low bioavailability due to its poor solubility; consequently, using solubilization technologies is essential to improve its bioavailability. In this study, novel fimasartan fluidized solid dispersion (FFSD) was developed using a fluid bed granulator to enhance the drug solubility and oral bioavailability.

Methods: An appropriate FFSD was prepared in 50% ethanol using a fluid bed granulator, and its drug dissolution, morphology, and crystallinity were evaluated in comparison to the powdered drug. Moreover, the dissolution in various pH conditions and pharmacokinetics of the FFSD tablet in beagle dogs were investigated compared to the commercial fimasartan tablet.

Results: Among the hydrophilic polymers tested, hydroxypropyl methylcellulose (HPMC) showed the highest solubility. The FFSD, composed of fimasartan, HPMC, and microcrystalline cellulose at the weight ratio of 20:10:25, gave a granular aggregation of several particles with a smooth surface. The drug in this FFSD existed as an amorphous state, leading to a greatly increased drug dissolution. The FFSD tablet was prepared by compressing a mixture of FFSD, mannitol, croscarmellose sodium, and magnesium stearate at the weight ratio of 55:40:5:1. The FFSD tablet gave significantly higher drug dissolution, plasma concentrations, maximum plasma concentration (C_max) and area under the whole blood concentration-time curve (AUC) values than did the commercial fimasartan tablet. In the beagle dogs, the FFSD tablet (140.39 ± 27.40 ng·h/ml) had about a 1.7-fold higher AUC than the commercial fimasartan tablet (80.58 ± 22.18 ng·h/ml), indicating an enhancement in the bioavailability.

Conclusions: This novel FFSD tablet could be a potential oral pharmaceutical product with the improved oral bioavailability of fimasartan.

Background

An increase in Staphylococcus aureus infections has been reported in pediatric patients with cystic fibrosis (CF) over the last few years. This pathogen is commonly treated with vancomycin, an antibiotic for which therapeutic drug monitoring (TDM) is recommended. Updated guidelines were recently published regarding new targets of exposure for the TDM of vancomycin through a Bayesian approach, using population pharmacokinetic (popPK) models.

Objectives

This study aims to assess the predictive performance of vancomycin popPK models in pediatric patients with CF and to recommend optimal initial dosing regimens based on simulations.

Methods

Patient data were collected from two centers in Canada, and a literature review was conducted to identify all published vancomycin popPK models for pediatric CF patients. External evaluation and simulations were performed according to patient and occasion of treatment.

Results

A total of 53 vancomycin concentrations were collected from six pediatric CF patients. Only two popPK models of vancomycin for pediatric CF patients were identified through the literature review. The external evaluation results for both centers combined revealed a population bias of 28.1% and an imprecision of 33.7%. A re-estimation of parameters was performed to improve predictive performance. The optimal initial dosing regimen was 15 mg/kg/dose administered every 6 hours according to the per occasion remodel.

Conclusion

The predictive performance and identified optimal initial dosing regimens associated with the model were different depending on the data used, showing external evaluation’s importance before implementing a model in clinical practice.

Background and Objectives

Voriconazole administered concomitantly with flucloxacillin may result in subtherapeutic plasma concentrations as shown in a patient with Staphylococcus aureus sepsis and a probable pulmonary aspergillosis. After switching our patient to posaconazole, therapeutic concentrations were reached. The aim of this study was to first test our hypothesis that flucloxacillin competes with voriconazole not posaconazole for binding to albumin ex vivo, leading to lower total concentrations in plasma.

Methods

A physiologically based pharmacokinetic (PBPK) model was then applied to predict the mechanism of action of the drug–drug interaction (DDI). The model included non-linear hepatic metabolism and the effect of a severe infectious disease on cytochrome P450 (CYP) enzymes activity.

Results

The unbound voriconazole concentration remained unchanged in plasma after adding flucloxacillin, thereby rejecting our hypothesis of albumin-binding site competition. The PBPK model was able to adequately predict the plasma concentration of both voriconazole and posaconazole over time in healthy volunteers. Upregulation of CYP3A4, CYP2C9, and CYP2C19 through the pregnane X receptor (PXR) gene by flucloxacillin resulted in decreased voriconazole plasma concentrations, reflecting the DDI observations in our patient. Posaconazole metabolism was not affected, or was only limitedly affected, by the changes through the PXR gene, which agrees with the observed plasma concentrations within the target range in our patient.

Conclusions

Ex vivo experiments reported that the unbound voriconazole plasma concentration remained unchanged after adding flucloxacillin. The PBPK model describes the potential mechanism driving the drug–drug and drug–disease interaction of voriconazole and flucloxacillin, highlighting the large substantial influence of flucloxacillin on the PXR gene and the influence of infection on voriconazole plasma concentrations, and suggests a more limited effect on other triazoles.

Cytochrome P450 enzymes (CYPs) represent a diverse family of heme-thiolate proteins involved in the metabolism of a wide range of endogenous compounds and xenobiotics. In recent years, proteomics and metabolomics have been used to obtain a comprehensive insight into the role of CYPs in health and disease aspects. The objective of the present work is to better understand the status of proteomics and metabolomics in CYP research in optimizing therapeutics and patient safety from a personalized medicine approach. The literature used in this narrative review was procured by electronic search of PubMed, Medline, Embase, and Google Scholar databases. The following keywords were used in combination to identify related literature: “proteomics,” “metabolomics,” “cytochrome P450,” “drug metabolism,” “disease conditions,” “proteome,” “liquid chromatography-mass spectrometry,” “integration,” “metabolites,” “pathological conditions.” We reviewed studies that utilized proteomics and metabolomics approaches to explore the multifaceted roles of CYPs in identifying disease markers and determining the contribution of CYP enzymes in developing treatment strategies. The applications of various cutting-edge analytical techniques, including liquid chromatography-mass spectrometry, nuclear magnetic resonance, and bioinformatics analyses in CYP proteomics and metabolomics studies, have been highlighted. The identification of CYP enzymes through metabolomics and/or proteomics in various disease conditions provides key information in the diagnostic and therapeutic landscape. Leveraging both proteomics and metabolomics presents a powerful approach for an exhaustive exploration of the multifaceted roles played by CYP enzymes in personalized medicine. Proteomics and metabolomics have enabled researchers to unravel the complex connection between CYP enzymes and metabolic markers associated with specific diseases. As technology and methodologies evolve, an integrated approach promises to further elucidate the role of CYPs in human health and disease, potentially ushering in a new era of personalized medicine.

Background and objectives: Numerous clinical concerns have been expressed regarding the potential worsening of cyclin-dependent kinase 4/6 inhibitor effects in breast cancer patients because of co-administration of proton pump inhibitors. Hence, this study evaluated the effects of proton pump inhibitors on the pharmacokinetics of palbociclib and ribociclib in terms of  cytochrome P450 (CYP) 3A4 and P-glycoprotein involvement.

Methods: The effects of omeprazole and rabeprazole on drug metabolism and efflux of these drugs were investigated using molecular docking, metabolic stability assay in rat liver microsomes, human recombinant CYP3A4 (rCYP3A4) enzymes, and Caco-2 cell monolayers, and in vivo pharmacokinetics with omeprazole and rabeprazole in (5 and 10 mg/kg) 30 min and 7 days before orally dosing palbociclib and ribociclib (10 mg/kg).

Results: Omeprazole and rabeprazole inhibited CYP3A4 enzyme activity in rCYP3A4 baculosomes with a 50-60% inhibition at 30 μM. Additionally, both omeprazole and rabeprazole (10 µm) significantly reduced the P-glycoprotein-mediated drug efflux of palbociclib and ribociclib. The 7-day pretreatment of omeprazole at a dose of 10 mg/kg resulted in 24% and 26% reductions in palbociclib's mean maximum plasma concentration) C_max and area under the plasma concentration-time curve (AUC_{0-24 h}), respectively. Palbociclib's pharmacokinetics were not significantly altered by the pretreatment with rabeprazole; however, ribociclib pharmacokinetics exhibited an 83.94% increase in AUC_{0-24 h}.

Conclusion: The findings indicate that long-term treatment with therapeutic doses of both omeprazole and rabeprazole can alter the pharmacokinetics of palbociclib and ribociclib. The co-administration of rabeprazole may alter the pharmacokinetics of palbociclib and ribociclib via CYP enzyme and P-glycoprotein inhibition.