Expert opinion on drug metabolism & toxicology最新文献

Introduction: Kidney transplantation requires lifelong immunosuppressive therapy, yet substantial interindividual variability in drug exposure and toxicity remains a clinical challenge. Emerging evidence indicates that sex and gender influence pharmacokinetics, pharmacodynamics, and safety profiles of immunosuppressive agents highlighting the need for dosing strategies to optimize efficacy and minimize adverse events. In addition to biological sex differences, gender-related factors such as treatment adherence, healthcare access, and reporting of adverse events may influence therapeutic response in transplant recipients, although available evidence remains limited.

Areas covered: This review summarizes current evidence on sex- and gender-specific differences of major immunosuppressants used in kidney transplantation and discusses their implications for therapeutic drug monitoring and personalized medicine. A comprehensive literature search was conducted in PubMed, Scopus and Web of Science form database through July 2025, focusing on clinical studies evaluating pharmacokinetics, toxicity profiles, and therapeutic drug monitoring strategies.

Expert opinion: Integration of sex-informed therapeutic strategies and individualized drug monitoring may improve safety and long-term graft outcomes. Prospective sex-stratified studies are essential to define optimized dosing algorithms and facilitate implementation in clinical practice.

Introduction: Dermatology is rapidly transitioning from broad-spectrum therapies toward biologics, nanotechnology-based drug delivery, and precision therapeutics, placing pharmacokinetics (PK) at the center of treatment optimization. Conventional PK approaches are limited by the complexity of skin biology, inter-individual variability, and heterogeneous real-world clinical settings. Artificial intelligence (AI) offers new opportunities to integrate multimodal data, improve dose-exposure prediction, and enable personalized, model-informed therapeutic strategies.

Areas covered: This review summarizes AI applications in topical and systemic PK, focusing on AI-driven PK prediction compared with conventional compartmental and population PK models, AI-enhanced physiologically based pharmacokinetic (PBPK) and systems pharmacology models, and clinically relevant dermatologic applications. We discuss AI for optimizing drug delivery systems, precision dosing, therapeutic drug monitoring, prediction of biologic treatment response, and pharmacovigilance. The review also addresses methodological considerations, including model development, validation, reproducibility, data quality, regulatory requirements, cost-effectiveness, and ethical issues. A literature search of PubMed/MEDLINE, Embase, and Scopus identified relevant English-language studies published between January 2000 and February 2026.

Expert opinion: AI is expected to complement rather than replace traditional PK approaches. Hybrid AI-mechanistic models, rigorous external validation, transparent reporting, and equity-focused implementation will be essential to improve personalization, safety, treatment durability, and clinical outcomes in dermatology.

Introduction: Soon after their discovery, antiretroviral drugs were used for post-exposure prophylaxis (PEP) and soon after that for preventing mother-to-child transmission (MTCT) of HIV. About 15 years ago, they were first used for pre-exposure prophylaxis (PrEP), which is nowadays widely available across the globe.

Areas covered: Quantitative systems pharmacology (QSP) of PrEP and PEP provides a framework to investigate the dynamic interplay of antiviral pharmacology, virology and immunology which may ultimately determine prophylactic efficacy. Following a comprehensive literature search, we will elaborate on the state-of-knowledge and modeling regarding pharmacometrics, viral and immune dynamics and their potential to modulate pharmacokinetic target concentrations for HIV prevention.

Expert opinion: QSP modeling can inform the design of clinical trials, which are challenging to conduct due to expenditure, ethics and sample size requirements. Moreover, once clinical data is available, interpreting outcomes is challenging due statistical limitations, the heterogeneous composition of trial arms and heterogeneity in adherence to the intervention. These limitations warrant integrative mathematical modeling to help extract insight, fill persistent knowledge gaps and to optimize PrEP and PEP guidelines based thereon.

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a key drug class in the management of the cardio-nephro-metabolic continuum. Their effects extend to the cardiac, vascular, and renal systems, providing a pathophysiological basis for the results of cardiovascular outcomes trials. Their pharmacokinetic properties substantially contribute, as structural modifications prolonged plasma half-life and increased systemic exposure through resistance to enzymatic degradation, albumin binding, and optimization of molecular size.

Areas covered: This review integrates current evidence on pharmacokinetics, pharmacodynamics, and clinical effects of GLP-1RA, focusing on the heart, vascular system, and kidney. A literature search up to March 2026 was performed using MEDLINE, EMBASE, Google Scholar, Web of Science, and the Cochrane Controlled Trials Register. GLP-1RAs exert modest chronotropic effects and provide cardiac protection in ischemia-reperfusion, although direct myocardial effects remain incompletely defined. Vascular benefits appear to be mediated by improved endothelial function, reduced oxidative stress, and modulation of nitric oxide pathways. In the kidney, GLP-1RAs modulate proximal tubular sodium reabsorption and tubuloglomerular feedback, leading to reduced albuminuria and a slower decline in renal function. Clinical trials and meta-analyses have documented reductions in major cardiovascular and renal outcomes.

Expert opinion: In our view, pharmacokinetics are a major determinant of the clinical profile of GLP‑1RAs, beyond glycemic control alone.

Introduction: The efficacy of tamoxifen in breast cancer endocrine therapy may be compromised by factors such as low adherence, drug interactions, and polymorphisms in CYP2D6, which is essential for converting tamoxifen into its active metabolite, endoxifen. Despite the recognized inter-individual variability, dose adjustment strategies based on CYP2D6 status or endoxifen levels have not yet been established as standard clinical practice.

Areas covered: This narrative review examines evidence on optimizing TAM therapy through dose escalation in patients with altered CYP2D6 function. We explore the impact of tamoxifen dose escalation on endoxifen concentrations, safety, and clinical efficacy in patients with altered CYP2D6 enzyme function. A literature search in PubMed and LILACS yielded articles published between 2015 and 2025, utilizing descriptors for tamoxifen, breast cancer, CYP2D6, and dose escalation/adjustment.

Results: Tamoxifen dose escalation strategies show promise in optimizing endoxifen concentrations for patients with impaired CYP2D6 metabolism, without significant short-term adverse effects. However, the lack of data on long-term toxicity and clinical efficacy raises concerns about the sustainability of this approach. For dose escalation to become standard practice, further research is essential to understand the long-term implications of higher tamoxifen doses on patient outcomes. Its integration into clinical protocols requires comprehensive evidence clarifying long-term effects.

Introduction: Depression is common among people living with HIV and is often linked to poorer adherence, disease progression, and quality of life. The widespread use of lifelong antiretroviral therapy alongside antidepressants requires careful consideration of potential drug-drug interactions that may compromise treatment outcomes.

Areas covered: This review discusses current evidence on pharmacokinetic and pharmacodynamic interactions between antiretroviral agents and antidepressants. We examined key metabolic pathways, including cytochrome P450 enzymes and drug transporters, and their overlapping effects on the central nervous system and metabolism. A comprehensive literature search was performed using electronic databases, including PubMed, Embase, Google Scholar, and relevant regulatory body resources, covering studies from database inception through 2026. The literature was identified by evaluating clinical studies, pharmacokinetic analyses, systematic reviews, and major drug-drug interaction databases relevant to HIV and psychopharmacology.

Expert opinion: Although newer antiretroviral regimens have reduced many of the classic CYP-mediated interactions, clinically relevant risks remain through pharmacokinetic and pharmacodynamic overlap. Effectively managing HIV and depression together, therefore, requires mechanistically informed prescribing, personalized treatment strategies, and close collaboration among healthcare providers across disciplines.

Introduction: Carbapenem-resistant Gram-negative bacteria represent a major global health threat driven by diverse β-lactamase enzymes, particularly KPC, metallo-β-lactamases, and OXA-type carbapenemases, leading to limited treatment options and high mortality. The development of novel β-lactam/β-lactamase inhibitor (BLBLI) combinations has significantly improved outcomes in resistant infections by restoring β-lactam activity against key resistance mechanisms, primarily among Enterobacterales.

Areas covered: This expert review summarizes the pharmacology, clinical efficacy, and safety of approved and emerging BLBLIs, including ceftolozane-tazobactam, cefepime-enmetazobactam, ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, aztreonam-avibactam, and sulbactam-durlobactam. Emphasis is placed on activity against carbapenem-resistant Enterobacterales, difficult-to-treat Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii. Evidence derives from clinical trials, real-world studies, and pharmacokinetic/pharmacodynamic (PK/PD) analyses from major databases (PubMed, Scopus, Web of Science) from inception through January 2026, focusing on dosing optimization and outcomes.

Expert opinion: BLBLIs have transformed the management of KPC-producing infections, markedly reducing mortality compared with legacy therapies. However, their impact is threatened by the rising prevalence of metallo-β-lactamases and the persistent therapeutic gap in carbapenem-resistant A. baumannii. Future success will depend on next-generation inhibitors with broader enzyme coverage, optimized dosing strategies guided by PK/PD principles, and robust antimicrobial stewardship to preserve long-term efficacy.

Background: Rifampin (RIF) is a first-line therapy for Mycobacterium avium complex (MAC) in people with cystic fibrosis (CF); but it induces CYP3A, leading to significant drug-drug interactions (DDIs) with elexacaftor/tezacaftor/ivacaftor (ETI). Clarithromycin (CLR), a strong CYP3A inhibitor, may counteract rifamycin-mediated induction, potentially enabling co-administration with ETI.

Research design and methods: DDIs between RIF, CLR, and ETI were evaluated using physiologically based pharmacokinetic (PBPK) modeling. Two-drug (e.g., RIF-CLR, RIF-ivacaftor, CLR-ivacaftor) and three-drug combinations (e.g., RIF-CLR-midazolam) were validated against published data. The models were then used to predict interactions between RIF, CLR, and ETI.

Results: Predicted AUC_0-24h ratios for ETI with RIF and CLR administration were 0.29 (95% CI 0.26-0.32), 0.30 (95% CI 0.26-0.35), and 0.19 (95% CI 0.16-0.23) for elexacaftor, tezacaftor, and ivacaftor, respectively. Steady-state concentrations exceeded the EC₅₀ targets in 99%, 94%, and 43% of the simulated population, respectively. Lower RIF or higher CLR doses modestly improved ivacaftor target attainment.

Conclusions: Concomitant RIF and CLR reduced ETI plasma exposures. Elexacaftor and tezacaftor concentrations remained above EC₅₀ targets, while ivacaftor was slightly below. Variability in CLR pharmacokinetics during RIF co-administration may contribute to interindividual differences in ETI exposure.

Introduction: Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer is the most common subtype, yet resistance to therapy remains a major clinical challenge. Up to 40% of patients carry PIK3CA mutations that activate PI3K/AKT/mTOR signaling and drive relapse, highlighting the need for more selective and tolerable targeted therapies.

Areas covered: This review summarizes the pharmacology, development, and therapeutic role of inavolisib, a next-generation, PI3Kα-selective inhibitor with dual inhibitory and degradation activity against mutant p110α. Preclinical studies demonstrate improved isoform selectivity versus earlier agents, reducing off-target toxicity while maintaining potent pathway suppression. In the phase III INAVO120 trial, adding inavolisib to palbociclib and fulvestrant nearly doubled progression-free survival and extended overall survival by seven months versus standard therapy. Safety data indicates a manageable profile, with hyperglycemia and stomatitis as the most common adverse events. Additional phase III trials are testing inavolisib in CDK4/6 inhibitor-resistant disease and HER2-positive settings, as well as in novel combinations.

Expert opinion: Inavolisib offers a significant advance for PIK3CA-mutated HR+/HER2-negative breast cancer by pairing potent PI3Kα selectivity with degradation of mutant p110α. Its clinical activity and improved tolerability position it as a strong candidate for future therapeutic strategies and evolving precision-oncology applications.