Clinical Pharmacology & Therapeutics最新文献

India has strengthened its clinical research infrastructure and regulatory frameworks to support new drug development and early-phase clinical trials. However, historical concerns related to participant safety, ethics, and research capacity have limited the conduct of first-in-human (FIH) studies for products developed outside India. A multi-stakeholder panel comprising representatives from regulatory authorities, academia, industry, and funding agencies examined regulatory, ethical, infrastructural, and innovator perspectives relevant to conducting such FIH trials in India.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAbs) lower LDL cholesterol and may influence cancer through immunomodulatory pathways. However, their effect on human cancer incidence remains unknown. We conducted a retrospective, propensity score-matched study (Clalit Health Services, Israel, 2010-2023) comparing PCSK9 mAbs to ezetimibe. Adults prescribed PCSK9 mAbs for 6 months or more were matched 1:3 to ezetimibe-treated patients without prior cancer, applying a 1-year latency. The cohort included 9,876 patients (2,469 PCSK9 mAb; 7,407 ezetimibe; mean age 65). During a median 4.6-year follow-up, cancer occurred in 12% of PCSK9 mAb users and 11% of ezetimibe users (HR 1.09 [95% CI, 0.95-1.25]). In sex-stratified analysis, men on PCSK9 mAbs had a higher cancer incidence (12.5% vs. 10.3%, P = 0.03); no difference was observed in women. All-cause mortality was significantly lower in the PCSK9 mAb group (3% vs. 5%; HR 0.65 [95% CI, 0.54-0.80]). Post-cancer-diagnosis mortality did not differ. In this large cohort, PCSK9 mAb therapy appeared safe regarding overall cancer risk and was associated with a significant reduction in all-cause mortality; the slightly higher cancer incidence in men may likely be attributed to a higher prevalence of baseline risk factors.

In the field of rare diseases-where traditional clinical trials are often impractical-real-world data (RWD) have emerged as a scientifically valid alternative to support regulatory decision making. This study systematically evaluates the utilization of RWD in orphan drug approvals by the FDA Center for Drug Evaluation and Research (CDER) over the past 5 years (2020-2024). We reviewed marketing applications for orphan drugs approved during this period, identifying those that included RWD. Each case was categorized based on the type and purpose of RWD use, sample size, FDA's evaluation, and label inclusion. A total of 129 orphan drugs were approved during this 5-year period, representing approximately 53% of all new drug approvals. Among these, 25 applications (19%) incorporated RWD, and 8 of them (32%) included RWD-derived findings in the product labeling. Among the 26 types of RWD usage, natural history studies were the most frequently employed (n = 14, 53.8%), followed by observational studies and Phase 3 trials utilizing external comparators. The primary purpose of RWD use was comparative evaluation (n = 19, 76%), and nearly half of the RWD data sets (n = 12, 48%) involved fewer than 100 patients. This study offers strategic insights into how RWD can be effectively leveraged in the development and regulatory approval of orphan drugs. The study offers practical guidance on designing regulatory-grade RWD studies and underscores key considerations for future submissions that aim to meet evidentiary standards in support of rare disease drug approvals.

Clinical trials drive therapeutic innovation but often underrepresent populations most affected by the disease. Despite efforts to include women, minorities, and children, participation still lags behind intent. Ensuring equitable representation is essential to maximize the impact of new therapies. This perspective offers actionable insights from a diverse panel-including patients, clinicians, researchers, and advocates-shared during the 2025 American Society for Clinical Pharmacology and Therapeutics Patient Forum.

Drug-induced QT-interval prolongation, a non-specific biomarker of increased risk for Torsades de Pointes (TdP), is a major safety concern in drug development. While in vitro hERG inhibition assays are required for early-phase screening, pharmacovigilance data from sources like the FDA Adverse Event Reporting System (FAERS) provide complementary insights. Integrating these heterogeneous data with molecular structure offers a promising, yet underutilized approach to predict proarrhythmic risk. We developed an interpretable graph neural network (GNN) framework integrating in vitro hERG inhibition data (PubChem AID 588834), FAERS-derived pharmacovigilance signals, and molecular structure information. Canonical SMILES were converted into molecular graphs using RDKit, and atom- and bond-level features were encoded. Four GNN architectures (GINE, GCN, GraphSAGE, and GATv2) were compared via stratified five-fold cross-validation. The best-performing model, GATv2, was further interpreted using Integrated Gradients to identify structural features contributing to QT liability. The final data set comprised 4,808 small molecules with binary QT-risk labels. GATv2 achieved a cross-validated ROC-AUC of 0.838, PR-AUC of 0.830, and F1-score of 0.756. Retraining on the full data set yielded ROC-AUC 0.918, PR-AUC 0.908, and F1-score 0.847. External validation on an independent hERG assay (AID 1671200, n = 2,405) confirmed strong performance (ROC-AUC 0.859, sensitivity 0.80, specificity 0.82). Atomic degree and hydrogen count were dominant predictors, consistent with known SARs. This GNN-based framework integrates structural and pharmacological data to predict QT risk, providing a transparent, structure-based decision-support tool aligned with ICH S7B/E14 and CiPA guidelines.

Older adults with cirrhosis commonly experience chronic noncancer pain managed with chronic opioid therapy. Current guidelines recommend opioid deprescribing for high-risk populations, including in cirrhosis, but data on tapering and discontinuation are scarce. We described opioid discontinuation rates and identified predictors of tapering or discontinuation. This retrospective cohort study of Medicare fee-for-service beneficiaries (N = 800,763) ≥ 65 years with continuous opioid use for ≥ 90 days. The primary outcome was opioid discontinuation (i.e., a gap in refills > 30 days). The secondary outcome included opioid tapering (i.e., a 35% decrease in average daily morphine milligram equivalents; [yes/no]). The primary exposure was diagnosed cirrhosis severity (i.e., none, compensated, decompensated). We estimated discontinuation rates using the Kaplan-Meier method, time to opioid discontinuation using proportional hazards regression, and predictors of tapering with logistic regression. After 1 year, 37% (95% CI = 37-37%) of individuals without cirrhosis discontinued opioids, similar to those with compensated (36% (34-37%)) and decompensated (37% (35-39%)) cirrhosis. Age did not modify the adjusted association between cirrhosis status and discontinuation (Wald χ²(4) = 7.72, p = 0.10) but calendar year (pre/post COVID-19) did (Wald χ²(1) = 26.57, p < 0.001). This finding indicated higher deprescribing rates prior to the pandemic, especially for those without cirrhosis (HR, 1.32; 95% CI, 1.31-1.33) compared with those with cirrhosis (HR, 1.13; 95% CI, 1.06-1.20). Non-opioid analgesic use, fall history, and frailty significantly increased the odds of tapering. In conclusion, these findings may reflect a lack of safe analgesic alternatives or higher pain burden in cirrhosis.

Maternal health remains a critical global concern, particularly in underserved populations and in low- and middle-income countries where access to safe and effective therapeutics is limited. Despite the use of medications by most women during pregnancy, the exclusion of pregnant and lactating women from clinical trials has resulted in significant data gaps, hindering informed treatment decisions. As long-acting therapeutics transition into mainstream treatment and prevention strategies, it is critical to ensure these disparities are neither perpetuated nor widened. This review synthesizes insights from the maternal health session of the July 2025 workshop of the Community of Practice for Long-Acting Therapeutics in Maternal and Pediatric Health. It was convened and hosted by the University of Liverpool Centre of Excellence for Long-Acting Therapeutics with funding from Unitaid. Key themes explored during the session include (1) regulatory initiatives, research networks, and data infrastructures that are driving systemic change in maternal health research over the past two decades; (2) important efficacy and safety considerations during pregnancy and lactation using insights from long-acting antiretrovirals currently in clinical use; and (3) selected long-acting drug delivery systems with potential applications in maternal health. Starting with maternal health priorities, here we included further insights regarding long-acting injectable antipsychotics, long-acting reversible contraceptives, and the role of in silico modeling in bridging existing gaps. Several immediately actionable recommendations are presented on advancing long-acting therapeutics for maternal health priorities during pregnancy and lactation.

Model-informed drug development is increasingly integrated across the drug development continuum, enabling more efficient, cost-effective, and targeted trials while reducing reliance on animal studies. Achieving pharmacoequity requires not only equitable access to medicines but also to the data and knowledge that inform drug development and regulatory decisions. To address challenges in pharmacokinetic data sharing, PKRxiv (https://pkrxiv.org/) was developed as a discipline-specific repository designed around Findable, Accessible, Interoperable, Reusable (FAIR) principles. This tutorial introduces PKRxiv's rationale, design, data submission and access workflows, and practical use cases. Available datasets at the end of September 2025 include over 5,500 individual drug concentration-time data points from over 900 unique participants across 3 continents. The platform supports structured submission of pharmacokinetic, pharmacogenetic, and safety/efficacy data, with persistent digital object identifiers for discoverability and citation. Contributors can apply one of three data sharing models-unrestricted, noncommercial, or contributor-controlled-with optional embargo periods. Users can explore datasets using the Data Explorer or Data Cards, or submit requests after providing a statement of intended use case. It enables pooling of datasets across multiple studies. Recommendations to help advance the field are proposed as data sharing becomes more widely expected: obtaining consent for unspecified future research use of data, sharing data underlying peer-reviewed publications as standard practice, including discipline-specific repositories in data management plans, and incentivizing post-approval data sharing by industry. Supporting data from all therapeutic areas and population groups, PKRxiv is a critical step toward a more transparent, equitable, and collaborative future in clinical pharmacology research.

Cinnamon (Cinnamomum spp.) is used as a culinary spice and dietary supplement. A major constituent, cinnamaldehyde, was previously shown to inactivate cytochrome P450 (CYP) 2A6 in vitro. A mechanistic static model predicted an ~5-fold increase in the AUC of the CYP2A6 substrates nicotine and letrozole. Accordingly, the effects of a well-characterized cinnamon (Cinnamomum verum) product on the pharmacokinetics of nicotine and letrozole were evaluated in 16 healthy, non-nicotine using adults. They were administered a single dose of nicotine gum (2 mg) or letrozole tablet (2.5 mg) (baseline). After a sufficient washout (2-14 days), they self-administered C. verum (2 g thrice daily) for 5 consecutive days. On Day 6, they were administered C. verum with nicotine or letrozole, followed by two more doses of C. verum (cinnamon exposure). Plasma was collected from 0 to 12 (nicotine) or 0-240 (letrozole) hours. The geometric mean plasma concentration vs. time profile for both drugs was nearly superimposable in the presence vs. absence of C. verum. The geometric mean ratio (GMR) [90% confidence interval] of the AUC of nicotine and letrozole in the presence to absence of cinnamon was 0.98 [0.96-1.12] and 1.11 [0.98-1.24], respectively (P > 0.16), indicating no interactions. Application of the "slope approach" involving the 3-hydroxycotinine-to-cotinine ratio provided potential new mechanistic insight into CYP2A6 inhibition. The general lack of effect of a typical dosage of C. verum on the pharmacokinetics of nicotine and letrozole suggests that C. verum may be safe to consume with both drugs, as well as other CYP2A6 substrates.