Expert Review of Clinical Pharmacology最新文献

Introduction: Fezolinetant is a first-in-class non-hormonal pharmacological treatment recently approved for moderate-to-severe vasomotor symptoms (VMS) associated with menopause. Its mechanism of action selectively targets the pathophysiology of VMS at hypothalamic level, antagonizing binding of neurokinin B, overexpressed in estrogen deprived menopausal women, to the neurokinin 3 receptor (NK3R) in the thermoregulatory center.

Areas covered: Fezolinetant reduced VMS frequency and severity in phase 3 randomized placebo-controlled trials in healthy menopausal women (SKYLIGHT 1 and 2) and in women unsuitable for menopause hormone therapy (MHT) (DAYLIGHT). The effect on VMS positively translated into improvements in menopause-specific quality of life, as well as sleep disturbances and impairment. Safety data were reassuring across studies, especially 52-weeks safety trials (SKYLIGHT 4 and MOONLIGHT 3).

Expert opinion: Fezolinetant represents a highly anticipated innovation, offering the possibility to bridge the therapeutic gap for many women who cannot or do not wish to use MHT. While the potential application of fezolinetant in some clinical settings will add substantial value to the management of VMS, some research gaps need to be addressed in order to provide meaningful insight into the benefit-risk profile that ultimately will improve counseling and prescription tailoring in symptomatic menopausal women.

Background: While there are relatively large number of studies on the retention of biologics in psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), very long-term retention studies are scarce.

Research design and methods: Retrospective longitudinal study including patients with up to a decade of follow-up. Survival rate was analyzed using Kaplan-Meier curves and drug discontinuation-associated factors using multivariate Cox regression. Hazard Ratio (HR) was used as a measure of the association.

Results: Ninety PsA patients and 93 with axSpA were included. Retention rate ranged from 64% at year 1 to 25% at year 11 in PsA, whereas in axSpA, these figures ranged from 68% at year 1 to 34% at year 12. The rate of any event leading to drug discontinuation was 20.9/100PYs and 14.8/100PYs in PsA and axSpA, respectively. Age at arthritis onset (HR 0.93, 95%CI: 0.87-0.99, p = 0.048) and psoriasis duration (HR 1.08, 95%CI: 1.0-1.2, p = 0.036) were linked to drug discontinuation in PsA. In axSpA, retention rate was significantly higher in men compared to women (long-rank p = 0.037).

Conclusion: In this real-world study, a non-negligible retention of GOL is observed. The two diseases differ in the factors that appear to determine drug persistence.

Introduction: Psychedelic compounds are emerging treatments for depression, capable of producing rapid and lasting symptom reduction after 1-2 administrations in the context of psychotherapy - a stark contrast to traditional antidepressants. Despite promising outcomes, the mechanisms underlying psychedelics' reported antidepressant effects remain poorly understood and are often framed in fragmented ways. Clarifying these mechanisms is crucial for guiding future research and clinical innovation with psychedelics.

Areas covered: This review critically examines current evidence on the mechanisms by which psychedelics may exert antidepressant effects. We highlight key mechanisms of action within biological, psychological, social, and spiritual domains that we believe are among the most compelling and deserving of further investigation. Throughout, we compare these mechanisms to those proposed for traditional antidepressants, identifying points of overlap and divergence.

Expert opinion: Although mechanistic research is valuable, an overemphasis on identifying discrete pathways may limit psychedelic science. Psychedelics likely work through complex, interwoven biological, psychological, and experiential processes that cannot be fully reduced to single mechanisms. Future research should move beyond frameworks and metrics used to validate conventional antidepressants to explore how suprapharmacological factors - set, setting, therapy modality, and integration - shape outcomes. Embracing this complexity is essential to realizing psychedelics' full therapeutic potential for depression.

Background: Adalimumab has been approved for treating juvenile idiopathic arthritis (JIA). This study aimed to develop a physiologically-based pharmacokinetic (PBPK) model for adalimumab in JIA patients to optimize personalized treatment.

Methods: A comprehensive literature search identified 13 clinical studies as the dataset for constructing and validating a PBPK model of adalimumab. Initially, a PBPK model for adalimumab in adults was constructed using PK-Sim and Mobi software. Subsequently, virtual pediatric populations were created by incorporating age-dependent parameters from the PK-Sim database, extending the model to JIA patients. Finally, based on the developed PBPK model for adalimumab in JIA patients, dosing regimens were evaluated for different age groups.

Results: This study successfully developed and validated a PBPK model for adalimumab in both adult and pediatric populations. The model for adults accurately predicted 92.90% of the concentrations within 0.5-2 times the observed values, while the pediatric model predicted 90.62% of the concentrations within 0.5-2-fold range. For pediatric patients with JIA, age- and weight-based dosing is recommended to achieve trough concentrations comparable to those in adults.

Conclusion: A PBPK model for adalimumab in pediatric patients with JIA was developed, providing a basis for personalized dosing regimens in this population.

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.