Clinical Pharmacology & Therapeutics最新文献

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.

In Ontario, biologics have historically represented a small proportion of public drug claims but a large proportion of spending. Biosimilars, lower cost alternatives to biologics, offer a potential solution to the rising spending on biologics. From March 2023 to January 2024, the Ontario Ministry of Health required public drug program beneficiaries on eight innovator biologics to transition to biosimilars. Clinicians were reimbursed for supporting patients who transitioned. To evaluate the impact of this biosimilar switch policy, we conducted a repeated cross-sectional study using administrative data from April 2019 to June 2024. For the biologics (innovator and biosimilar) included in the policy, we reported the biosimilar market share, public drug program spending, and clinician support fees. We used interrupted time series analyses to evaluate the policy's impact, and forecasting to estimate drug cost savings. From March 2023 to June 2024, the percentage of affected individuals on biosimilars increased from 21.7% to 96.5%. Drug cost savings were $65.2 million between April 2023 to June 2024, with most savings attributed to non-insulin biosimilars. We estimated savings of $46.6 million in Year 1 (April 2023 to March 2024) and $95.9 million in Year 2 (April 2024 to March 2025). Clinician support fees totaled $3.4 million across the study period. Ontario's biosimilar policy achieved high biosimilar uptake and substantial cost savings. Future research should examine the impact of this policy on clinical outcomes to assess its broader implications for patient care and long-term sustainability.

Lung cancer remains the leading cause of cancer-related mortality globally. While immune checkpoint inhibitors (ICIs) are the standard of care for metastatic non-small cell lung cancer (NSCLC), real-world data from Australia are limited. We conducted a population-based cohort study using national Pharmaceutical Benefits Scheme and National Death Index data, accessed via the Australian Bureau of Statistics DataLab. Adults initiating pembrolizumab monotherapy for metastatic NSCLC (2017-2022) were included. Overall survival (OS) and time to treatment discontinuation (TTD) were assessed using Kaplan-Meier analyses and multivariate Cox regressions. Immune-related adverse events (irAEs) were inferred from incident corticosteroid and levothyroxine prescriptions. Subgroup analyses were performed by age (18-64 and ≥ 65) and sex. Among 4,334 patients, median OS was 13.2 months. Younger patients had longer OS than those ≥ 65 (17.9 vs. 12.4 months; adjusted hazards ratio [aHR] 1.29, 95% confidence interval [CI]: 1.18-1.41). Females had longer OS than males (14.8 vs. 12.1 months; aHR 0.89, 95% CI: 0.83-0.96). TTD did not differ significantly by age or sex. Incident corticosteroid and levothyroxine use occurred in 19.1% and 8.0% of patients, respectively, with higher levothyroxine use in females (9.8% vs. 6.7%, P < 0.001). In this real-world study, survival outcomes with pembrolizumab were shorter than those reported in clinical trials. Observed differences by age and sex in survival and irAE proxies suggest potential biological variation in treatment response and toxicity. These findings highlight the need for integrated clinical data to support personalized use and inform treatment strategies that improve outcomes across diverse populations.

Major depressive disorder is a highly prevalent psychological disorder worldwide and its main treatment is the use of Selective Serotonin Reuptake Inhibitors. However, few studies have demonstrated the relationship between the presence of genetic variants in pharmacogenes and the efficacy of these drugs, especially in populations with a unique genetic profile, such as the Indigenous peoples of the Amazon. Our study characterized the molecular profile of nine genes related to drug administration, metabolization, distribution, and elimination pathways and pharmacodynamic mechanisms of drug response through Whole Exome Sequencing applied in 64 Indigenous located in the Amazon. We compared the allele frequencies of the variants in Indigenous peoples and other world populations using Fisher's exact test carried out in RStudio v.3.5.1. We identified a total of 125 variants, of which 6 are possible new variants in our population on the HTR2A, HTR2C, CYP2D6, and CYP1A2 genes. At least 9 variants showed a significant difference in the Indigenous population compared with other populations worldwide. Our study reaffirms the unique genetic profile of the Brazilian Amazon Indigenous population and allows us to contribute population-specific variants that may serve as future pharmacogenomic biomarkers that help in the understanding of the individual genetic profiles of Indigenous people. Although the present study does not evaluate clinical drug response, the characterization of these variants provides a foundation for future studies exploring their potential impact on antidepressant efficacy in Indigenous populations and the application of this knowledge in the development of specific treatment protocols guided by pharmacogenomics.

Few studies have quantified the effects of non-pharmacological interventions (e.g., rescue breathing) in the setting of community opioid overdose. We extended a previously validated model for opioid antagonists by incorporating the mechanism of rescue breathing, and quantified combinatorial effects between rescue breathing and various formulations of naloxone under different fentanyl overdose scenarios in a virtual patient population suffering from opioid-induced respiratory failure. We defined successful reversal of an overdose as fewer than 5% of the virtual population experiencing cardiac arrest after intervention. Our model showed that timely rescue breathing reduced the naloxone dose needed for successful overdose reversal from greater than 8 mg (intranasal) to less than 2 mg (intramuscular) and extended the naloxone rescue window to 10 minutes under a median fentanyl intravenous overdose scenario. Administration of 4 mg naloxone intranasally reduced the duration of rescue breathing needed from 11 hours to 5 minutes under a median fentanyl transmucosal overdose scenario. High-quality (as delivered by well-trained rescuers), but not low-quality (as delivered by laypersons), rescue breathing could successfully rescue severe opioid overdose scenarios. Even in cases where virtual subjects survived without naloxone, 4 mg intranasal naloxone provided benefit by shortening the time to recovery of spontaneous. Our results highlight the importance of utilizing both pharmacological and non-pharmacological interventions in reversal of overdose.

Students and trainees are integral to clinical pharmacology, as they have the potential to shape the field. This perspective highlights how the ASCPT Student and Trainee Community engages members worldwide, providing opportunities and resources to advance scientific and professional development. It also discusses strategies to foster equitable access and how these efforts promote pharmacoequity, including peer mentorship, international engagement, fair access to leadership roles, and diverse representation.