Expert Opinion on Drug Metabolism & Toxicology最新文献

Introduction: In the United States, obesity affects approximately ⅖ adults and ⅕ children, leading to increased risk for comorbidities, like gastroesophageal reflux disease (GERD), treated increasingly with proton pump inhibitors (PPIs). Currently, there are no clinical guidelines to inform PPI dose selection for obesity, with sparse data regarding whether dose augmentation is necessary.

Areas covered: We provide a review of available literature regarding the pharmacokinetics (PK), pharmacodynamics (PD), and/or metabolism of PPIs in children and adults with obesity, as a step toward informing PPI dose selection.

Expert opinion: Published PK data in adults and children are limited to first-generation PPIs and point toward reduced apparent oral drug clearance in obesity, with equipoise regarding obesity impact on drug absorption. Available PD data are sparse, conflicting, and limited to adults. No studies are available to inform the PPI PK→PD relationship in obesity and if/how it differs compared to individuals without obesity. In the absence of data, best practice may be to dose PPIs based on CYP2C19 genotype and lean body weight, so as to avoid systemic overexposure and potential toxicities, while monitoring closely for efficacy.

Introduction: Every year thousands of children undergo surgery for congenital heart disease. Cardiac surgery requires the use of cardiopulmonary bypass, which can have unexpected consequences for pharmacokinetic parameters.

Areas covered: We describe the pathophysiological properties of cardiopulmonary bypass that may influence pharmacokinetic parameters, with a focus on literature published in the last 10 years. We performed a PubMed database search with the keywords 'Cardiopulmonary bypass' AND 'Pediatric' AND 'Pharmacokinetics'. We searched related articles on PubMed and checked the references of articles for relevant studies.

Expert opinion: Interest in the influence of cardiopulmonary bypass on pharmacokinetics has increased over the last 10 years, especially due to the use of population pharmacokinetic modeling. Unfortunately, study design usually limits the amount of information that can be obtained with sufficient power and the best way to model cardiopulmonary bypass is yet unknown. More information is needed on the pathophysiology of pediatric heart disease and cardiopulmonary bypass. Once adequately validated, PK models should be integrated in the patient electronic database integrating covariates and biomarkers influencing PK, making it possible to predict real-time drug concentrations and guide further clinical management for the individual patient at the bedside.

Background: Apixaban is a superior direct oral anticoagulant exihibiting interindividual variability in concentration and response in the real world. The present study aimed to identify genetic biomarkers associated with pharmacokinetics (PK) and pharmacodynamics (PD) of apixaban in healthy Chinese subjects.

Methods: This multicenter study included 181 healthy Chinese adults taking a single dose of 2.5 mg or 5 mg apixaban and assessed their PK and PD parameters. Genome-wide single nucleotide polymorphism (SNP) genotyping was performed using the Affymetrix Axiom CBC_PMRA Array. Candidate gene association analysis and genome-wide association study were conducted to identify genes with a predictive value for PK and PD parameters of apixaban.

Results: Several ABCG2 variants were associated with C_max and AUC_0-t of apixaban (p < 6.12 × 10^-5) and also presented significant differences of anti-Xa_3h activity and dPT_3h according to different ABCG2 genotypes (p < 0.05). Besides, ABLIM2 variants were found to be associated with PK characteristics and F13A1 and C3 variants were associated with PD characteristics of apixaban (p < 9.46 × 10^-8).

Conclusion: ABCG2 variants were found to be ideal genetic biomarkers for both PK and PD characteristics of apixaban. ABLIM2, F13A1 and C3 were identified as potential candidate genes associated with inter-individual variability of apixaban. This study was registered on ClinicalTrials.gov NCT03259399.

Introduction: Determining antibiotic exposure in the lung and the threshold(s) needed for effective antibacterial killing is paramount during development of new antibiotics for the treatment of nosocomial pneumonia, as these exposures directly affect clinical outcomes and resistance development. The use of pharmacokinetic and pharmacodynamic modeling is recommended by regulatory agencies to evaluate antibiotic pulmonary exposure and optimize dosage regimen selection. This process has been implemented in newer antibiotic development.

Areas covered: This review will discuss the basis for conducting pharmacokinetic and pharmacodynamic studies to support dosage regimen selection and optimization for the treatment of nosocomial pneumonia. Pharmacokinetic/pharmacodynamic data that supported recent hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia indications for ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/cilastatin/relebactam, and cefiderocol will be reviewed.

Expert opinion: Optimal drug development requires the integration of preclinical pharmacodynamic studies, healthy volunteers and ideally patient bronchoalveolar lavage pharmacokinetic studies, Monte-Carlo simulation, and clinical trials. Currently, plasma exposure has been successfully used as a surrogate for lung exposure threshold. Future studies are needed to identify the value of lung pharmacodynamic thresholds in nosocomial pneumonia antibiotic dosage optimization.

Introduction: Various pharmacogenomic (PGx) variants differ widely in different ethnicities. and clinical outcomes associated with these variants may also be substantially varied. Literature was searched in different databases, i.e. PubMed, ScienceDirect, Web of Science, and PharmGKB, from inception to 30 June 2022 for this review.

Areas covered: Certain PGx variants were distinctly varied in Asian populations compared to the other human populations, e.g. CYP2C19*2,*3,*17; CYP2C9*2,*3; CYP2D6*4,*5,*10,*41; UGT1A1*6,*28; HLA-B*15:02, HLA-B*15:21, HLA-B*58:01, and HLA-A*31:01. However, certain other variants do not vary greatly between Asian and other ethnicities, e.g. CYP3A5*3; ABCB1, and SLCO1B1*5. As evident in this review, the risk of major adverse cardiovascular events (MACE) was much stronger in Asian patients taking clopidogrel and who inherited the CYP2C19 loss-of-function alleles, e.g. CYP2C19*2 and*3, when compared to the western/Caucasian patients. Additionally, the risk of carbamazepine-induced severe cutaneous adverse drug reactions (SCARs) for the patients inheriting HLA-B*15:02 and HLA-B*15:21 alleles varied significantly between Asian and other ethnicities. In contrast, both Caucasian and Asian patients inheriting the SLCO1B1*5 variant possessed a similar magnitude of muscle toxicity, i.e. myopathy.

Expert opinion: Asian countries should take measures toward expanding PGx research, as well as initiatives for the purposes of obtaining clinical benefits from this newly evolving and economically viable treatment model.

Introduction: Asparaginase is essential to chemotherapy regimens for acute lymphoblastic leukemia (ALL). Survival of patients with ALL has improved since incorporating asparaginase into chemotherapy backbones. Hispanic patients have a higher incidence of ALL than other ethnicities and suffer inferior outcomes. The inferior outcome of Hispanics is due to several factors, including the increased incidence of high-risk genetic subtypes and susceptibility to treatment-related toxicity.

Areas covered: We summarize the current knowledge of asparaginase-related toxicity by comparing their incidence between Hispanic and non-Hispanic patients. These toxicities include hypersensitivity, hepatotoxicity, pancreatitis, thrombosis, and hypertriglyceridemia. The PubMed database and Google Scholar were used to search for this review from October 2022 to June 2023.

Expert opinion: Except for hepatotoxicity and hypertriglyceridemia secondary to asparaginase-based treatments, which may develop more frequently among Hispanic patients with ALL, other toxicities were comparable between Hispanic and non-Hispanic patients. Nevertheless, studies with larger cohorts and more accurate capturing of Hispanic ethnicity should be conducted to fill the gaps in the current knowledge.

Background: 4-Hydroxy-N,N-methylpropyltryptamine (4-OH-MPT) is a psychedelic tryptamine whose use is regulated in several countries. Due to unspecific effects, consumption can be ascertained only through toxicological analyses. However, the trace amounts of tryptamines are usually challenging to detect in biological samples. 4-OH-MPT metabolism was characterized to identify optimal metabolite markers of intake in clinical/forensic toxicology.

Research design and methods: 4-OH-MPT was incubated with 10-donor-pooled human hepatocytes to simulate in vivo conditions; samples were analyzed by liquid chromatography-high-resolution tandem mass spectrometry (LC-HRMS/MS), and data were processed with Compound Discoverer from Thermo Scientific. LC-HRMS/MS and data mining were supported by in silico metabolite predictions (GLORYx).

Results: Three phase I and four phase II metabolites were identified, including N-oxidation and N-demethylation at the alkylamine chain, and O-glucuronidation and sulfation at the hydroxylindole core.

Conclusions: 4-OH-MPT metabolic fate was consistent with the human metabolism of tryptamine analogues: we suggest 4-OH-MPT-N-oxide and 4-hydroxy-N,N-propyltryptamine (4-OH-PT) as metabolite biomarkers of 4-OH-MPT consumption after glucuronide/sulfate hydrolysis in biological samples to improve detection of 4-OH-MPT and phase I metabolites; 4-OH-MPT-glucuronide is suggested as an additional biomarker when hydrolysis is not performed. Further research on the metabolism of structural analogues is necessary to evaluate the specificity of 4-OH-MPT metabolite biomarkers.

Introduction: Clopidogrel is the only antiplatelet agent whose activity is significantly affected by CYP2C19 polymorphism.

Areas covered: This review has summarized the available evidence on the clinically significant association between CYP2C19 polymorphism and clopidogrel-based therapy; reviewed the current recommendations for clinical use of CYP2C19 genotype test results in patients on clopidogrel treatment; and discussed possible pitfalls of routine application, and future perspectives of antiplatelets pharmacogenetics.

Expert opinion: The available body of evidence, reflected in several meta-analyses and high-quality clinical practice guidelines, shows that the presence of CYP2C19 LOF alleles, especially CYP2C19*2, correlates with impaired activation of clopidogrel and variable platelet inhibition, followed by minimal or no antiplatelet effect, and higher risk of treatment failure. In combination with other known risk factors, CYP2C19 genetic testing could be very valuable in predicting low clopidogrel efficacy. At the same time, it could be very successful in selecting patients who will most probably benefit from the clopidogrel-based therapy, thus decreasing the pool of those who might need more expensive and otherwise riskier antiplatelet alternatives.