Expert Review of Clinical Pharmacology最新文献

Background: In antidepressant augmentation strategies, olanzapine or quetiapine are often concomitantly administered to duloxetine. The use of the same enzymes for the degradation of the drugs may lead to clinically relevant drug-drug-interactions, DDIs. So far, DDIs between olanzapine or quetiapine and duloxetine have only been studied in rats or in small numbers of patients.

Methods: Out of a large therapeutic drug monitoring (TDM) database of duloxetine concentrations, three matched study groups were considered to investigate potential DDIs: a group of patients co-medicated with olanzapine (n = 81), a group co-medicated with quetiapine (n = 105) and a control group receiving only duloxetine (n = 105).

Results: Neither in the olanzapine group, nor in the quetiapine group, duloxetine plasma concentrations or dose-adjusted plasma concentrations differed significantly from the control group (p = 0.6759; p = 0.5841). The proportion of patients within the so-called therapeutic reference range was similar in all three groups (p = 0.635). However, smokers showed by 30% lower duloxetine plasma concentrations (p = 0.0179) and 32.5% lower dose-adjusted concentrations (p = 0.0003) compared to nonsmokers.

Conclusion: Our findings indicate that the combination of duloxetine and olanzapine or quetiapine is - from a pharmacokinetic view - a safe treatment option. TDM should be applied in case of co-medications to enhance therapeutic effectiveness and patients' safety.

Background: The COVID-19 pandemic disrupted healthcare delivery, impacting oral anticoagulants (OAC) prescribing due to increased thromboembolic risks, Vaccine-induced immune thrombotic thrombocytopenia, and guidelines favoring Direct Oral Anticoagulants (DOACs) over warfarin. Previous studies were limited to short-term analyses.

Research design and methods: A segmented interrupted time series analysis was conducted using the English primary care Prescription Cost Analysis data from March/2018-March/2024 to assess the impact of the first and second COVID-19 lockdowns in March and November 2020, respectively. Trends in OAC utilisation were measured using number of items per 1,000 inhabitants (NIT) and defined daily dose per 1,000 inhabitants per day (DTD).

Results: Overall, oral anticoagulants prescribing increased significantly. Pre-pandemic, both NIT (β₁: 0.09; 95%CI: 0.02, 0.16) and DTD (β₁:0.13; 95%CI: 0.09, 0.16) showed positive trends. Post-first lockdown, DTD slope declined significantly (β₃:-0.22; 95%CI: -0.42, -0.03). Post-second lockdown, DTD rose in both immediate level (β₄:1.39; 95%CI: 0.34, 2.45) and slope (β₅: 0.20; 95%CI: 0.0015, 0.39). Warfarin usage declined initially but rebounded, while DOACs, particularly apixaban, increased substantially (β₄:0.96; 95%CI: 0.11, 1.81).

Conclusions: The COVID-19 pandemic significantly impacted oral anticoagulant prescribing patterns in England. While DOAC utilisation continued to rise, warfarin use declined significantly post-first lockdown but rebounded after the second lockdown.

Introduction: Approximately 10% of individuals with multiple sclerosis (MS) have pediatric-onset (<18-years-old). Pediatric-specific barriers to accessing disease modifying therapies (DMT) exist. Issues include few pediatric-based randomized controlled trials (RCT), often required for formal regulatory approval, and resultant challenges with cost/coverage. This review assessed real-world DMT uptake in pediatric-MS to better understand potential barriers.

Areas covered: We performed a scoping review of observational studies examining DMTs in patients with pediatric-MS published between 07/1993 and 06/2024. PRISMA guidelines were used. Databases searched included: Cochrane Library, Ovid MEDLINE/Embase, Scopus, and Web of Science. Studies must include >10 DMT exposed pediatric-MS patients with full-text available in English. RCTs/pharmaceutical-industry funded studies were excluded. Of 2114 abstracts screened, 88 studies were included. A total of 21,591 patients (13,411 females) were included. DMTs were used in 68.7% (n = 14,833). Most studies were from Europe (53.4%), North America (22.7%), or the Middle East (10%). Regional variabilities were found in DMT uptake between continents. Only 13 (14.8%) studies included information on DMT funding source.

Expert opinion: Pediatric-MS patients showed low DMT uptake with variability in DMT use based on region. Limited data was found regarding specific barriers to DMT access. Further research is needed to better understand regional barriers to access.

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.

Background: Asthma patients requiring oral corticosteroids (OCS) are at increased risk of adverse effects. Research focusing on asthma patients adhering to guideline-directed therapy remains limited. This study evaluates the adverse effects of corticosteroids in asthma patients treated with high-dose inhaled corticosteroids (ICS) who required additional OCS due to inadequate disease control.

Research design and methods: We conducted a retrospective cohort study of asthma patients from Taiwan's asthma pay-for-performance program, who had used high-dose ICS for at least 90 days, categorizing them based on OCS use. In the short-term period (3 months), patients were classified into a control group (no OCS) and an OCS group (≥450 mg OCS within 90 days). In the long-term period (6 months), the OCS group consisted of patients receiving ≥ 900 mg OCS within 180 days.

Results: A total of 173,835 patients were enrolled for analysis. We assessed the risks of osteoporosis, diabetes, hypertension, infections, cardiovascular diseases, mental health disorders, and ocular conditions. Both short- and long-term OCS users exhibited significantly higher risks of these adverse outcomes compared to the control group.

Conclusions: These findings highlight the substantial health risks associated with OCS. Clinicians should carefully consider alternative strategies to minimize harm while ensuring effective disease control.

Introduction: Smoking cessation improves quality of life and increases life expectancy by up to a decade. Though two-thirds of people who smoke report a desire to quit, less than a quarter plan to quit within the coming month. The relative risks and benefits of e-cigarettes, proposed as a novel tool to support smoking cessation, are critical to monitor as the evidence evolves.

Areas covered: This review summarizes the evidence for smoking cessation treatment, characteristics and pharmacology of e-cigarettes, support for e-cigarettes for smoking cessation, and relevant harm reduction principles. Populations at the highest risk for continued cigarette smoking (e.g. individuals with co-occurring substance use and mental health conditions) and those who are vulnerable to initiating nicotine use through access to e-cigarettes (e.g. adolescents), are also discussed.

Expert opinion: Evidence indicating that e-cigarettes are comparable to nicotine replacement therapy points to their promise as a smoking cessation and harm reduction option for individuals who decline other treatment options. Future work should evaluate the comparative efficacy of e-cigarettes for historically excluded groups and the relative effects of specific products and monitor for any long-term effects. Evidence-based clinical guidelines are also needed to inform clinical practice in this rapidly evolving area.

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.

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.