Expert Review of Clinical Pharmacology最新文献

Introduction: Older adults with type 2 diabetes mellitus (T2DM) are increasingly numerous worldwide and present particularly difficult therapeutic challenges, especially concerning the proper selection of antidiabetic medications that offer the best efficacy/safety ratio in this age group.

Areas covered: This narrative review summarizes progress toward personalized management involving a three-step process. First, patients should be categorized according to their frailty status. Second, glycemic targets should be properly individualized considering a higher risk of severe hypoglycemia in older patients. Third, the selection of the best antidiabetic medication(s) in order to avoid hypoglycemia but also to offer cardiorenal protection. In this respect, sulfonylureas and insulin therapy are currently less recommended and newer antidiabetic medications are preferred, usually combined with metformin: DPP-4 inhibitors (gliptins) for their better safety profile versus sulfonylureas, GLP-1 analogues or SGLT2 inhibitors (gliflozins) if cardiorenal protection is required. Reducing excessive body weight appears less critical in older patients and sarcopenia should be avoided.

Expert opinion: The two most recognized challenges are undertreating healthy older patients while overtreating frailty/ill people. The increasing armamentarium to treat T2DM offers new opportunities to personalize the use of antidiabetic medications according to the clinical profile and need of every older patient with T2DM.

Background: This study aimed to evaluate the steady-state plasma concentration, efficacy, and safety of bictegravir (BIC) in Chinese people with HIV (PWH) receiving BIC-based therapy for at least 6 months.

Research design and methods: PWH on BIC-based regimens for at least 6 months were enrolled. Plasma BIC concentrations, viral loads, CD4⁺ T cell counts, weight, renal and hepatic function, and adverse reactions were assessed.

Results: A total of 192 subjects were included. Geometric mean C_max was 8.00 μg/mL and C_τ was 3.34 μg/mL, higher than in African and Caucasian populations. For treatment-naïve PWH, viral load < 50 copies/mL increased from 81% at 6 months to 98% at 12 months. For treatment-experienced PWH, the proportion was 90% at baseline and 98% at both 6 and 12 months. Weight increased by 5% and 7% in treatment-naïve PWH at 6 and 12 months, respectively. Renal and hepatic function remained normal, and mild adverse reactions were reported in 14 subjects (11.4%).

Conclusions: BIC's steady-state plasma concentrations in Chinese PWH were higher than those in other ethnic groups, with good efficacy and safety.

Background: Sacubitril/valsartan is used to treat heart failure. It consists of sacubitril (its active metabolite, sacubitrilat, acts as a neprilysin inhibitor) and valsartan (an angiotensin II type 1 receptor blocker).

Research design and methods: In this study, the minimum serum concentrations of valsartan and sacubitrilat were analyzed in patients with heart failure with reduced ejection fraction.

Results: Serum concentrations of valsartan ranged from 75 to 11,700 µg/L and of sacubitrilat from 607 to 17,646 µg/L. Wide interindividual variability was observed in the serum concentrations of valsartan and sacubitrilat after administration of the same dose. Patients with NYHA class III used a significantly lower dose per day and per kilogram of body weight than those with NYHA class I/II; however, the measured concentrations of valsartan and sacubitrilat did not differ between the two groups. For both drugs, an inverse correlation was found between the weight-adjusted apparent clearance and serum creatinine and urea concentrations, sacubitrilat levels, and estimated glomerular filtration rate.

Conclusions: Valsartan and sacubitrilat concentrations showed wide inter-individual variability at the same dose, which could lead to both toxicity and suboptimal concentrations, with the risk of worsening clinical condition. Patients with reduced cardiac and renal functions are at a higher risk of overdose. [Figure: see text].

Introduction: We aimed to synthesize the information relevant for clinical practice on the initiation and adaptation of clozapine treatment in new and long-term older adult users with severe mental illness (SMI).

Methods: Articles were identified with MEDLINE, Web of Sciences and PsycINFO search from inception through March 2025. The search was restricted to studies including clozapine users with SMI aged ≥50 years. Data were synthesized narratively.

Results: We identified 16 studies (14 chart studies, one controlled study, one pharmaco-epidemiological study) including 1244 participants. All observational studies reported a clinical benefit of clozapine, but few used structured assessments. The single controlled study in a small sample did not find clozapine superior to chlorpromazine. No fatal case attributable to clozapine exposure was reported. The increased risks of aspiration pneumonia, constipation, postural hypotension, and falls were identified early by the first chart studies. Most studies included new clozapine users, and none explored the adaptation of clozapine treatment in long-term users reaching old age.

Conclusions: Gaps in knowledge are of particular concern for older adults with SMI who are long-term clozapine users. Further studies are required to document how to adapt clozapine treatment to physiological aging or incident comorbidities and co-prescriptions.

Protocol registration: www.crd.york.ac.uk/prospero identifier is CRD420251038600.

During treatment intensification of injectable therapies among persons with type 2 diabetes mellitus (T2DM) without evidence of severe insulin deficiency, a glucagon-like peptide-1 agonist (GLP-1 RA) is preferred to insulin. However, due to its progressive nature, many individuals over the course of disease will ultimately require insulin treatment. The use of fixed-ratio combination of basal insulin and GLP-1 RA represents a practical and convenient method for treatment intensification. It has been shown to be more efficacious in improving glycemic control, compared with GLP-1 RA or basal insulin alone, and similarly effective with lower insulin dose in reducing glycated hemoglobin (HbA_1c) levels, along with less weight gain, and a lower risk of hypoglycemia compared with basal/bolus insulin therapy. The recently published COMBINE 2 trial reported that switching to weekly combination therapy of basal insulin icodec and semaglutide (IcoSema), compared with semaglutide, results in greater HbA_1c reduction, similar risk of clinically significant or severe hypoglycemia and comparable gastrointestinal tolerability, but unfavorable weight change among individuals with T2DM inadequately controlled with GLP-1 RA therapy, with or without additional oral glucose-lowering drugs. IcoSema represents an effective, safe, and convenient therapeutic choice for treatment intensification in individuals with T2DM inadequately controlled with GLP-1 RA therapy.

Background: This meta-analysis evaluated the prevalence of gastric acid suppressants (GASs) in patients receiving vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) and explored drug-drug interactions (DDIs).

Methods: PubMed, Embase, and Cochrane Library were searched upto 20 October 2024. Studies comparing VEGFR-TKIs monotherapy versus VEGFR-TKIs with GASs, reporting pharmacodynamic (PD), pharmacokinetic (PK), or adverse events (AEs), were analyzed using random-effects models. Subgroups included cancer types and VEGFR-TKI types.

Results: 24 studies comprising 6,406 patients were included. The prevalence of GASs use in VEGFR-TKIs users was 40% (95% CI 31-50%). GASs significantly impaired survival, increasing mortality risk by 29% (OS HR 1.29,95% CI 1.14-1.45) and progression risk by 31% (PFS HR 1.31, 95% CI 1.06-1.61). PK analyses revealed clinically meaningful exposure reductions (AUC_0-24GMR 0.78, 90% CI 0.65-0.94; C_max GMR 0.80, 90% CI 0.70-0.91). AE incidence (except vomiting) did not differ between groups.

Conclusion: GASs may reduce the efficacy of most types of VEGFR-TKIs by decreasing their bioavailability, thereby having a detrimental effect on patient survival outcomes. It is recommended to give priority to H2 receptor antagonists (H2RAs) and monitor blood drug concentrations to optimize efficacy.

Protocol registration: www.crd.york.ac.uk/prospero identifier CRD42024597729.

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.