Clinical Pharmacology & Therapeutics最新文献

Pregabalin and duloxetine are widely prescribed non-opioid medications for chronic musculoskeletal pain. Pregabalin may increase the risk of heart failure, and duloxetine increases heart rate and blood pressure; however, little is known about their comparative cardiovascular safety. This study compared cardiovascular outcomes between new users of pregabalin and new users of duloxetine among US Veterans with chronic musculoskeletal conditions. We conducted a retrospective cohort study of US Veterans, aged 18-89 years, with chronic non-cancer musculoskeletal pain who started pregabalin or duloxetine between 2015 and 2021. Veterans with serious illnesses were excluded. The primary outcome was a major adverse cardiovascular event (MACE), a composite of acute myocardial infarction (AMI), stroke, heart failure (HF), or cardiovascular death. We identified cardiovascular events through Veterans Affairs and linked Medicare data and mortality data from the National Death Index. We adjusted for confounding through inverse probability of treatment weighting utilizing a propensity score incorporating 158 covariates. Outcomes were analyzed using Cox proportional hazard regression models. This study included 26,684 new users of pregabalin and 152,808 new users of duloxetine (83% male, 69% reported White race, median age = 56 years). During a total follow-up of 141,112 person-years, there were 1,798 total MACE events. The rate of MACE was higher for pregabalin users compared to duloxetine users (unadjusted HR: 1.61 (95% CI: 1.43-1.81), adjusted HR: 1.24 (95% CI: 1.08-1.41)), driven by higher rates of HF and AMI among pregabalin users. These findings present new considerations regarding the comparative cardiovascular safety of therapeutic options for chronic musculoskeletal pain.

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.

Cannabidiol (CBD) is one of the most abundant bioactive cannabinoids. Research has demonstrated CBD's ability to inhibit metabolic enzymes like cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT), potentially leading to drug interactions. However, clinical knowledge gaps remain, particularly with regard to drugs that are more commonly taken by consumers of unregulated CBD products. This study aimed to characterize the effects of daily CBD consumption, at doses typical of unregulated CBD products, on the pharmacokinetics of citalopram and morphine. These two commonly prescribed medications are metabolized by CYPs and UGTs, respectively. This open-label, sequential study involved two cohorts of 20 healthy participants. Cohort one received a single dose of citalopram (20 mg) on days 1 and 13, with CBD (2.5 mg/kg twice daily) administered for 12 days. Cohort two received a single dose of morphine (15 mg) on days 1, 4, and 11, with CBD (2.5 mg/kg twice daily) given for 9 days. The geometric mean ratio (GMR, [90% confidence interval]) for citalopram with and without CBD for 12 days was 1.43 (1.34-1.52) for the area under the plasma concentration-time curve (AUC_0-inf) and 1.12 (1.06-1.17) for the maximum observed plasma concentration (C_max). The GMR for AUC_0-inf and C_max for morphine coadministered with CBD compared to morphine alone was 1.06 (0.96-1.16) and 1.19 (1.05-1.35), respectively. For morphine with CBD for 9 days compared to morphine alone, the GMR for AUC_0-inf and C_max was 1.12 (1.00-1.26) and 1.11 (0.94-1.30), respectively. While a significant pharmacokinetic interaction between CBD and citalopram was observed, interactions between CBD and morphine, as well as its metabolites, were limited.

Clinical trials are essential to understand the benefit-harm profile of new drugs. Lack of adequate representation in age and sex ratio in clinical trials can result, for example, in higher side effects for underrepresented patients. We quantified differences in age and sex ratios between trial and target populations of new drugs approved by the FDA 2011-2022. We used the FDA's database to identify all new drugs and pivotal randomized trials. Information for average age and sex ratio was obtained from clinicaltrials.gov. Each trial's indication was matched with prevalence estimates of the targeted diseases from the global burden of disease study. A total of 458 drugs (773 trials) were included. The trial populations were significantly younger, on average 4.8 years (95% CI [5.4 years, 4.2 years]), and the female ratio significantly smaller, on average 4.3 percentage points (95% CI [5.4 pp, 3.3 pp]), than the target populations. For diseases with average patient age below 40, the trial population was significantly older than the target population but significantly younger 40 years and older. For diseases with average age between 30 and 39, the female ratio in the trial population was significantly higher than in the target population but significantly lower 50 and older. Better age and sex ratio representation in the trial population is indicated to improve safety and efficacy for patients. Trials targeting diseases below 40 should enroll younger participants and increase their male ratio, while the opposite is true for trials targeting diseases with an older age.

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.

Carfilzomib is highly effective in the treatment of multiple myeloma, but it has been associated with cardiovascular adverse events that impact patient outcomes. Our prior global metabolomic analyses indicated an association between hydrophilic bile acids and carfilzomib-cardiotoxicity risk, although a causal relationship remained to be determined. Here, our objective was to validate the previously identified bile acids in an independent cohort and investigate whether these hydrophilic bile acids play a causal role in carfilzomib-cardiotoxicity using Mendelian randomization. Using targeted metabolomics, we validated the association between glycoursodeoxycholic acid and carfilzomib-cardiotoxicity in an independent cohort (n = 61). We then performed two-sample Mendelian randomization analyses, using metabolome-wide association study results to provide the genetic instruments for bile acid levels as exposure and genome-wide association study summary statistics from the UK Biobank (n = 484,598) as the outcome data for cardiovascular adverse events. Causal inference was assessed with the inverse-variance weighted method, followed by multiple sensitivity analyses. Higher glycoursodeoxycholic acid concentration (odds ratio = 0.34, P = 0.032) was associated with lower cardiotoxicity risk after adjusting for hypertension and high levels of brain natriuretic peptides. Mendelian randomization analysis demonstrated a robust causal effect of glycoursodeoxycholic acid on cardiotoxicity risk (β = -0.00065, P = 6.2 × 10^-5). Gene enrichment analysis indicated pathways involving potassium channel regulation and thromboxane signaling to be implicated. This integrative metabolomic and genetic investigation supports a potential protective role of glycoursodeoxycholic acid in cardiovascular vulnerability and motivates larger, carfilzomib-specific studies to evaluate its utility for risk stratification.

Thiopurine methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15) are key enzymes that catabolize thiopurines. Decreased or no-function alleles in TPMT and NUDT15 are associated with reduced or no enzyme activity and predictive of pronounced adverse effects, including severe myelosuppression, that may occur among individuals treated with standard doses of thiopurines. Genetic variants in these genes are present in all world populations; however, their frequency varies by ancestry. In this updated guideline, we provide recommendations for adjusting starting doses of mercaptopurine, thioguanine, and azathioprine based on TPMT and NUDT15 genotypes, including for individuals with variants in both genes (updates on www.clinpgx.org).

Clesrovimab is a half-life extended monoclonal antibody targeting the respiratory syncytial virus fusion protein. Three studies (phase Ib/IIa [MK-1654-002], phase IIb/III [CLEVER], and phase III [SMART]) were conducted to evaluate the efficacy, safety, and pharmacokinetics (PK) of clesrovimab in infants. The objectives of this analysis were to develop an infant population PK model for clesrovimab and to evaluate the influence of intrinsic and extrinsic factors on clesrovimab PK in infants. A total of 5850 samples from 2942 participants were included in the population PK analysis. A two-compartment model with first-order absorption and elimination well described clesrovimab PK in infants. The estimated half-life for clesrovimab was 44.0 days. Clearance, absorption rate constant, and central volume of distribution had low inter-individual variability. Body weight was included as a covariate on all clearance and volume parameters, with estimated allometric scaling exponents centered on a body weight of 5 kg. A maturation function further described the change in clearance with increasing infant age. In addition to body weight and maturation function, the final model contained an effect of race on clearance. Although body weight, age, and race were identified as statistically significant covariates, the magnitude of the effect of these covariates on clesrovimab exposures was small (< 30%). The results of the population PK modeling support intramuscular administration of clesrovimab for the prevention of respiratory syncytial virus (RSV) disease in all infants, including healthy infants and infants at increased risk for severe RSV disease.