Expert Review of Clinical Pharmacology最新文献

Introduction: Chronic rhinosinusitis with nasal polyps (CRSwNP) primarily displays type 2 inflammation, characterized by the activation of interleukin (IL)-4, IL-5, and IL-13 in the pathway. The purpose of this study is to determine the efficacy and safety of dupilumab (an IL-4 antagonist) in treating CRSwNP.

Methods: A detailed search was performed in PubMed, Embase and the Cochrane Library databases. All published English-language randomized controlled trials (RCTs) that employed dupilumab to treat CRSwNP in adult patients (≥18 years old) were considered.

Results: Three RCTs and 25 studies with 784 individuals were included. The use of dupilumab revealed improvement in polyp size (MD -1.80; 95% CI -2.25 to -1.36), Lund-Mackay score (MD -7.01, 95% CI -9.64 to -4.38), congestion (MD -0.86, 95% CI -0.99 to -0.73), smell (MD 10.83, 95% CI 9.59 to 12.08) and health-related quality of life (MD -19.61, 95% CI -22.53 to -16.69). Systemic corticosteroid use (RR 0.28, 95% CI 0.20-0.39) and revision surgery (RR 0.17, 95% CI 0.05-0.52) were reduced. Serious adverse events were reduced in dupilumab group (RR 0.47; 95% CI 0.29 to 0.76) with no change in risk of adverse events (RR 0.98, 95% CI 0.87 to 1.11).

Conclusions: Dupilumab is effective with minimal adverse events.

Protocol registration: www.crd.york.ac.uk/prospero identifier is CRD42023413004.

Introduction: Meropenem is a first-line antibiotic used in the treatment of severe infections. However, patients with critical infections often exhibit a notably low pharmacokinetic/pharmacodynamic (PK/PD) compliance rate, especially in cases involving multidrug-resistant gram-negative bacteria and in specific patient populations.

Areas covered: This article reviews the relevant literature on the use of meropenem in treating severe infections, with data primarily sourced from PubMed, Web of Science, Embase, and Cochrane databases before July 2024. The primary analysis focuses on determining the optimal clinical efficacy target value for meropenem in treating multidrug-resistant Gram-negative bacteria infection, exploring PK/PD research, individualizing drug regiments for special populations, and evaluating safety.

Expert opinion: Based on the PK/PD properties of meropenem across different special populations such as children and elderly patients, as well as its efficacy against severe infections and multidrug-resistant Gram-negative infections, prolonged and continuous infusion regimens of meropenem have already shown some clinical benefit. Personalized dosing of meropenem for critical infections should be guided by real-time therapeutic drug monitoring (TDM). However, there is a notable lack of sufficient data, highlighting the necessity for large-scale, multi-center clinical trials to validate the safety and effectiveness of meropenem in treating severe infections.

Introduction: Therapeutic drug monitoring (TDM) is important to optimize drug exposure and minimize toxicity for the individual patient.

Areas covered: This narrative review covers the pharmacokinetics (PK), -dynamics (PD) and-genetics of classic chemotherapeutic drugs used in frontline therapy for acute lymphoblastic leukemia (ALL), including anthracyclines, asparaginase, busulfan, cyclophosphamide, cytarabine, glucocorticoids, methotrexate, nelarabine, thiopurines, tyrosine kinase inhibitors, and vincristine. Furthermore, novel immunotherapies including blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor T-cells that are rapidly moving into frontline therapy are addressed. This review focuses on TDM already used in clinical practice as well as the unused potential and feasibility of TDM. Finally, important factors affecting PK/PD such as obesity and transition to adolescence and young adulthood are discussed.

Expert opinion: Investigation of TDM as standard of care for antileukemic agents is highly warranted to personalize curative yet toxic anticancer regimens within frontline ALL treatment. Some of the drugs have been used in ALL treatment regimens for decades, but a wide range of new compounds are being introduced, some like blinatumomab reaching standard-of-care designation. Not least, optimized drug efficacy and reduction of the risk of serious toxicities may render TDM implementation cost-effective.

Background: Thiopurine S-methyltransferase (TPMT) and Nudix hydrolase (NUDT15) polymorphisms predispose to thiopurine-related leukopenia.

Methods: Retrospective evaluation of inflammatory bowel disease (IBD) patients harboring NUDT15 polymorphisms and exposed to thiopurines. We report the frequency of NUDT15 polymorphism, frequency of leukopenia, the tolerated dose of azathioprine, and the clinical efficacy of thiopurines.

Results: Of 1440 patients, 118 (8.2%) had NUDT15 polymorphism. Among 51 with complete details, 46 were heterozygous (90.2%), and 5 homozygous (9.2%) for NUDT15. Twenty (43.5%) heterozygous and all homozygous patients developed leukopenia. Leukopenia was significantly more in NUDT15 heterozygous group compared to controls (43.45% vs 7.8%, Odds ratio: 9, 95% CI 3.57-22.9). The maximum tolerated dose of azathioprine was lower in NUDT15 heterozygous group (1.1 ± 0.4 mg per kg vs 1.7 ± 0.7 mg per kg, p = 0.002). The mean time to leukopenia was earlier in the heterozygous group vs controls (19 ± 56 weeks vs 70 ± 53 weeks, p-value 0.002). Seven (35%) of 20 heterozygous patients who developed leukopenia, could be maintained at a lower dose of thiopurine. Twenty-five maintained clinical remission while on thiopurines.

Conclusion: Thiopurines should be avoided in NUDT15 homozygous but can be used cautiously at lower dosages with frequent monitoring among heterozygous patients.

Introduction: Medication management after bariatric surgery is a major and complex challenge. The altered gastrointestinal anatomy/physiology post-surgery may impact oral drug absorption/pharmacokinetics, with potential clinical implications. Along with multiple studies/cases of impaired post-surgery drug absorption/pharmacokinetics, leading to potential treatment failure, reports of increased drug exposure, leading to post-bariatric safety issues and adverse effects risk, are also available; yet, this second scenario of increased post-surgery drug levels, is less familiar in practice.

Areas covered: In this article, we highlight and overview the literature reports of increased post-bariatric drug exposure and safety issues, and discuss the underlying relevant mechanisms. Finally, we provide clinical recommendations for managing this therapeutic challenge.

Expert opinion: Around 25 drugs were found to exhibit post-bariatric enhanced pharmacokinetics and risk of adverse effects. Among them, toxicity with lithium treatment is well-established. Clear safety concerns were also raised for other drugs, including levothyroxine, atorvastatin, paracetamol and, importantly, immediate-release morphine. Cautious use, while closely monitoring clinical signs of toxicity, is advised for these drugs. Realizing the potentially altered post-bariatric pharmacokinetics of various drugs, and, in particular, the risk of increased exposure with related adverse effects, is essential for providing optimal pharmacological therapy and overall patient care to the growing bariatric population.

Objective: To evaluate the association between sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and the risk of neoplasm in patients with Type 2 diabetes (T2D).

Methods: Literature retrieval was conducted using databases from inception to June 2024. Randomized controlled trials (RCTs) comparing SGLT-2i with placebo or other treatments in patients with T2D, and with reports of neoplasm events were included. Results were computed as the risk ratio (RR) with 95% confidence intervals (CI).

Results: A total of 53 RCTs with 126,232 participants were included. No significant differences were found for the risk of overall neoplasm (RR = 1.08, 95% CI: 0.99 to 1.19, I² = 23%) in patients with SGLT-2i treatment compared with non-users. However, decreased risk of pulmonary neoplasm (RR = 0.83, 95% CI: 0.69 to 0.99, I² = 0.0%) was observed in SGLT-2i users compared to non-users, while increased risk of prostate neoplasm in SGLT-2i users was found (RR = 1.21, 95% CI: 1.00 to 1.47, I² = 0.0%).

Conclusion: Compared with non-users, the use of SGLT-2i was not associated with the risk of overall neoplasm. However, pulmonary neoplasms were less frequent in SGLT-2i users, while an increased risk of prostate neoplasm was observed in SGLT-2i users compared to non-users.

Protocol registration: www.crd.york.ac.uk/prospero identifier is CRD42021273681.

Introduction: Since its synthesis in 1962, ketamine has been widely used in diverse medical contexts, from anesthesia to treatment-resistant depression. However, interpretations of ketamine's subjective effects remain polarized. Biomedical frameworks typically construe the drug's experiential effects as dissociative or psychotomimetic, while psychedelic paradigms emphasize the potential therapeutic merits of these non-ordinary states.

Areas covered: Ketamine's psychoactive effects have inspired diverse interpretations. In this review, we trace the historical evolution of these perspectives - which we broadly categorize as 'dissociative,' 'dream-like,' and 'psychedelic' - and show how they emerged out of these clinical contexts. We highlight the influence of factors such as language, dose, and environmental context on ketamine's effects and therapeutic outcomes. We discuss potential mechanisms underlying these context-dependent effects and explore the broader clinical and research-related ramifications.

Expert opinion: Ketamine's subjective effects are undeniably powerful, yet their therapeutic significance remains debated. A nuanced, interdisciplinary approach is essential for maximizing ketamine's potential. Future research should focus on how explanatory models, treatment environments, and patient preparation can optimize ketamine's benefits while minimizing distress. We suggest that, rather than being a tiger to be tamed as its creator once described, ketamine may best be understood as a chameleon whose color shifts depending on its context.