Expert Opinion on Drug Metabolism & Toxicology最新文献

Introduction: Interstitial lung disease (ILD) or pneumonitis remains an important adverse event identified with treatment with antibody-drug conjugates (ADCs). Drug-induced ILD (DILD) accounts for 3%-5% of common ILD cases and is a significant problem in clinical practice. Hence, with the anticipation of the widespread use of ADCs, it will be important for guidelines and recommendations to be established to direct and standardize the management of DILD by a multidisciplinary team (MDT).

Areas covered: A thorough literature search was conducted using PubMed to identify relevant articles related to ADCs published between 1 January 2010 and 31 November 2022. Based on the review of the literature combined with expert opinions, this review article offers an overview of incidences of ILDs associated with the use of newer anticancer therapies, specifically ADCs, and discusses local-regional best practices in optimal monitoring, early diagnosis, and management of DILD involving an MDT.

Expert opinion: Multidisciplinary input and consensus are crucial in the accurate diagnosis of DILD. The core group of essential attendees in the MDT are oncologists, pulmonologists, thoracic radiologists, and pathologists. This allows for the integration of expertise from different specialists to achieve a 'best fit' diagnosis and management.

Introduction: The kidney is vulnerable to various injuries based on its function in the elimination of many xenobiotics, endogenous substances and metabolites. Since transporters are critical for the renal elimination of those substances, it is urgent to understand the emerging role of transporters in nephrotoxicity.

Areas covered: This review summarizes the contribution of major renal transporters to nephrotoxicity induced by some drugs or toxins; addresses the role of transporter-mediated endogenous metabolic disturbances in nephrotoxicity; and discusses the advantages and disadvantages of in vitro models based on transporter expression and function.

Expert opinion: Due to the crucial role of transporters in the renal disposition of xenobiotics and endogenous substances, it is necessary to further elucidate their renal transport mechanisms and pay more attention to the underlying relationship between the transport of endogenous substances and nephrotoxicity. Considering the species differences in the expression and function of transporters, and the low expression of transporters in general cell models, in vitro humanized models, such as humanized 3D organoids, shows significant promise in nephrotoxicity prediction and mechanism study.

Introduction: Although N-acetyl-cysteine (NAC) has long been used for the treatment of acetaminophen poisoning/overdose, the optimal NAC dosing regimen for varying patterns or severity of the poisoning/overdose is still unknown.

Areas covered: Relevant literature was searched for in the MEDLINE (from 1964 until August 31^st, 2022), SCOPUS (from 2004 until August 31^st, 2022) and GOOGLE SCHOLAR (from 2004 until August 31^st, 2022) databases, without restriction in terms of publication date. The inclusion criteria were: original clinical studies reporting results, and studies investigating efficacy and safety of NAC dosing regimens in case(s) of overdose or poisoning with acetaminophen.

Expert opinion: For a more effective treatment of acetaminophen poisoning in the future, it will be crucial to advance the technology of measuring acetaminophen, its metabolites and NAC in the serum, preferably with the point-of-care technique, so that in real time it can be continuously assessed whether it is necessary to administer NAC, and further to increase the dose of NAC and extend the duration of its administration, or not.

Introduction: CYP2D6 contributes to the metabolism of approximately 20-25% of drugs. However, CYP2D6 is highly polymorphic and different alleles can lead to impacts ranging from null to increase in activity. Moreover, there are commonly used drugs that potently inhibit the CYP2D6, thus causing 'phenoconversion' which can convert the genotypic normal metabolizer into phenotypic poor metabolizer. Despite growing literature on the clinical implications of non-normal CYP2D6 genotype and phenoconversion on patient-related outcomes, implementation of CYP2D6 pharmacogenetics and phenoconversion to guide prescribing is rare. This review focuses on providing the clinical importance of CYP2D6 pharmacogenetics and phenoconversion in precision medicine and summarizes the challenges and approaches to implement these into clinical practice.

Areas covered: A literature search was performed using PubMed and clinical studies documenting the effects of CYP2D6 genotypes and/or CYP2D6 inhibitors on pharmacokinetics, pharmacodynamics or treatment outcomes of CYP2D6-metabolized drugs, and studies on implementation challenges and approaches.

Expert opinion: Considering the extent and impact of genetic polymorphisms of CYP2D6, phenoconversion by the comedications, and contribution of CYP2D6 in drug metabolism, CYP2D6 pharmacogenetics is essential to ensure drug safety and efficacy. Utilization of proper guidelines incorporating both CYP2D6 pharmacogenetics and phenoconversion in clinical care assists in optimizing drug therapy.

Introduction: Patients with severe mental illness (SMI) have a high risk for diabetes, dyslipidemia, and other components of metabolic syndrome. Patients with these metabolic comorbidities and cardiac risk factors should receive not only antipsychotics but also medications aiming to reduce cardiovascular risk. Therefore, many patients may be exposed to clinically relevant drug-drug interactions.

Areas covered: This narrative review summarizes data regarding the known or potential drug-drug interactions between antipsychotics and medications treating metabolic syndrome components, except for hypertension, which has been summarized elsewhere. A literature search in PubMed and Scopus up to 7/31/2021 was performed regarding interactions between antipsychotics and drugs used to treat metabolic syndrome components, aiming to inform clinicians' choice of medication for patients with SMI and cardiometabolic risk factors in need of pharmacologic interventions.

Expert opinion: The cytochrome P450 system and, to a lesser extent, the P-glycoprotein transporter is involved in the pharmacokinetic interactions between antipsychotics and some statins or saxagliptin. Regarding pharmacodynamic interactions, the available information is based mostly on small studies, and for newer classes, like PCSK9 inhibitors or SGLT2 inhibitors, data are still lacking. However, there is sufficient information to guide clinicians in the process of selecting safer antipsychotic-cardiometabolic risk reduction drug combinations.

Introduction: The introduction of monoclonal antibodies to the chemotherapy backbone treatment has challenged the paradigm of metastatic colorectal cancer (mCRC) treatment. Their mechanism of action and pharmacokinetics are complex but important to understand in order to improve patient selection and treatment outcomes for mCRC population.

Areas covered: This review examines the scientific data, pharmacodynamics, and pharmacokinetics of approved monoclonal antibodies used to treat mCRC patients, including agents targeting signaling via VEGFR (bevacizumab and ramucirumab), EGFR (cetuximab and panitumumab), HER2/3 target therapy, and immunotherapy agents such as pembrolizumab or nivolumab. Efficacy and mechanism of action of bispecific antibodies are also covered.

Expert opinion: mCRC is a heterogeneous disease and the optimal selection and sequence of treatments is challenging. Monoclonal antibodies have complex pharmacokinetics and pharmacodynamics, with important interactions between them. The arrival of bioequivalent molecules to the market increases the need for the characterization of pharmacokinetics and pharmacodynamics of classic monoclonal antibodies to reach bioequivalent novel molecules.

Introduction: Clozapine-induced myocarditis in children (age ≤18 yo) was studied from a PubMed search (18 July 2022) (9 cases) and from the World Health Organization's pharmacovigilance database, called Vigibase, of adverse drug reaction (ADR) reports (72 non-duplicated cases). VigiBase uses a logarithmic measure of disproportionality called the information component (IC). A logistic regression model of presence/absence (40/32) of seriousness in VigiBase was developed.

Areas covered: VigiBase provided a significant myocarditis IC = 4.2 with an IC₀₂₅ = 3.8; only 4 clozapine-induced myocarditis cases were expected, while 72 were observed. The PubMed search identified 9 cases, while VigiBase identified 72 cases (of which 67 did not overlap with published cases). These 76 combined cases included 35 doubtful (most with missing information on the day of diagnosis), 19 possible and 22 probable, according to the ADR scale. After adjusting for confounders, quetiapine increased the risk of seriousness with an odds ratio (OR) of 17.6 (95% confidence interval CI, 1.56 to 198.6), while Australian origin decreased it with an OR = 0.13 (CI, 0.04 to 0.47).

Expert opinion: These 41 cases of at least possible clozapine-induced myocarditis indicated that this ADR can definitively occur in children, particularly in the first 30 days of up-titration. Children's and adult cases appeared similar.

Introduction: Transporters are significant in dictating drug pharmacokinetics, thus inhibition of transporter function can alter drug concentrations resulting in drug-drug interactions (DDIs). Because they can impact drug toxicity, transporter DDIs are a regulatory concern for which prediction of clinical effect from in vitro data is critical to understanding risk.

Area covered: The authors propose in vitro strategies to assist mitigating/removing transporter DDI risk during development by frontloading specific studies, or managing patient risk in the clinic. An overview of clinically relevant drug transporters and observed DDIs is provided, alongside presentation of key considerations/recommendations for in vitro study design evaluating drugs as inhibitors or substrates. Guidance on identifying critical co-medications, clinically relevant disposition pathways, and using mechanistic static equations for quantitative prediction of DDI is compiled.

Expert opinion: The strategies provided will facilitate project teams to study the right transporter at the right time to minimize development risks associated with DDIs. To truly alleviate or manage clinical risk, the industry will benefit from moving away from current qualitative basic static equation approaches to transporter DDI hazard assessment towards adopting the use of mechanistic models to enable quantitative DDI prediction, thereby contextualizing risk to ascertain whether a transporter DDI is simply pharmacokinetic or clinically significant requiring intervention.

Introduction: Hydralazine is a vasodilator used to treat hypertension, pre-eclampsia, and heart failure. The current article reviews the clinical pharmacokinetics (PK) of hydralazine, which can be useful for clinicians in optimizing its dose and dosing frequency to avoid adverse effects and unexpected interactions that could risk patients' lives.

Areas covered: This review has summarized the PK parameters for hydralazine after performing an extensive literature search. It includes 20 publications that were selected after applying eligibility criteria out of a pool of literature that was searched using Google Scholar, PubMed, Cochrane Central, and EBSCO databases. The included studies consisted of concentration vs. time profiles of hydralazine. If the PK data were not tabulated in the given study, the concentration vs. time profiles were scanned for the extraction of the PK data. The PK parameters were calculated by applying a non-compartmental analysis (NCA).

Expert opinion: The current review will aid clinicians in understanding hydralazine PK in different disease populations. This clinical PK data might also be helpful in the development of a pharmacokinetic model of hydralazine.