Clinical Pharmacology & Therapeutics最新文献

Fezolinetant is a first-in-class, selective, non-hormonal, neurokinin 3 receptor antagonist that is approved for the treatment of moderate to severe vasomotor symptoms due to menopause. In a phase 2b clinical study (n = 352), nine study participants experienced elevations in serum transaminases exceeding three times the upper limit of normal. DILIsym, a quantitative systems toxicology model of drug-induced liver injury, was used to assess the potential hepatotoxicity of fezolinetant prior to initiating phase 3 trials. In vitro toxicity assays and physiologically-based pharmacokinetic estimates of fezolinetant and primary metabolite exposure were leveraged to simulate the incidence of hepatotoxicity for various fezolinetant treatment regimens and virtual simulated populations. DILIsym simulations indicated a dose-dependent relationship between fezolinetant exposure and hepatotoxicity primarily caused by electron transport chain inhibition. At therapeutic doses, no ALT elevations exceeding three times the upper limit of normal were predicted for healthy volunteers. In a metabolic syndrome-associated fatty liver disease (MAFLD) population with compromised mitochondrial function, mild increases in ALT elevation frequency above placebo were observed in all fezolinetant treatment groups and included a single Hy's Law case at 45 and 60 mg once daily. The predicted Hy's Law case in the MAFLD population was mitigated by the incorporation of mitochondrial biogenesis. These predictions aided discussions with internal and external stakeholders regarding dose selection and initiation of the phase 3 clinical studies. Phase 3 studies were subsequently completed and confirmed the efficacy and acceptable liver safety of fezolinetant at 30 and 45 mg QD, leading to drug approval at 45 mg QD.

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.

Recently, the Chinese government has prioritized enhancing access to rare disease drugs, with the initial objective of addressing the challenge of drugs being "available abroad but not domestically." The United States, a leader in the development of treatments for rare diseases, serves as a benchmark for assessing a nation's progress in this field. This study examined the progression and influencing factors of the availability gap through the application of two principal metrics: "drug loss" and "drug lag" at the indication level. We conducted a retrospective analysis of rare disease indications approved in the United States and China from 2001 to 2024, focusing on diseases listed in China's official Catalogs of Rare Diseases. Our study indicated that "drug loss" in China had continued to escalate, with the total number of unapproved indications reaching 123 by 2024. Although the growth rate had decelerated since 2017, the "drug loss" associated with novel therapies recently approved by the FDA had intensified. Conversely, the "drug lag" in China for indications approved by the FDA after 2015 had decreased in comparison to those approved before 2015, with the median delay reducing from 4,049 to 2,812 days. The principal factors influencing drug availability were the global R&D and commercial strategies of sponsors. This finding highlighted that encouraging multinational sponsors to integrate China into their initial global development plans and to incentivize domestic companies to engage in earlier and more substantial international research and development collaborations were more important for mitigating "drug loss" and "drug lag" in China.

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.

The FDA published guidance on assessing pharmacokinetics (PK) in participants with impaired renal function in 2024. The IQ CPLG Organ Impairment Working Group summarized the industry's perspective on this guidance by highlighting a few key updates in the 2024 guidance, including: (1) the recommendation of using estimated glomerular filtration rate (eGFR) over the Cockcroft-Gault (CG) equation to determine renal function; (2) the designs for dedicated renal impairment studies; and (3) characterizing the impact of impaired renal impairment in phase 2/3 trials. The use of absolute eGFR for dosing recommendations, differentiation between intermittent hemodialysis (IHD) and continuous renal replacement therapy (CRRT) in study design, and a preference for regression analysis over categorical analysis to model the relationship between renal function and PK parameters were also discussed. The updates in the FDA guidance resulted in better alignment with the European Medicines Agency (EMA) guidance on this topic, making global drug development more efficient. The manuscript also presented challenges in using different eGFR equations, the impact of protein binding on dose determination, and the need for further guidance on pediatric equations and novel drug modalities. In conclusion, the manuscript underscores the significance of the updated FDA guidance in enhancing the design, implementation, and data analysis of renal impairment studies while identifying areas for future updates to address emerging topics in drug development.

Optimized dosing precision of antibody-drug conjugates (ADCs) remains challenging due to narrow therapeutic indices, efficacious doses near the maximum tolerated dose, and substantial interindividual variability in exposure. Body size-based dosing can reduce exposure variability when the allometric scaling exponent for clearance α = 1 but may over- or underexpose patients with extreme body size when α ≠ 1. A recent review found α based on body weight (BW) was less than 0.7 for 8 of 10 approved ADCs,¹ indicating room for improvement. This follow-up article outlines the strategy for dosing approach selection to enhance ADC dosing precision. To assess the performance of different body size metrics, α was re-estimated to BW, body surface area (BSA), ideal body weight (IBW), and adjusted IBW (AIBW). Simulations were conducted to evaluate the performance of dose capping. Results showed that all 15 approved ADCs used body size-based dosing, with seven using an upper dose cap, even when α < 0.5. AIBW and BSA commonly had an α closer to 1 compared with BW while IBW performed poorly due to lack of BW consideration. Simulations showed that when α was not close enough to 0 or 1 (e.g., 0.4 ≤ α ≤ 0.7), dose capping helped maintain percent AUC difference between patients extreme and normal body size within the desired range (e.g., 20%) with an upper dose cap when α ≥ 0.5 or a lower dose cap when α ≤ 0.5. Based on these findings, a decision tree is proposed to guide dosing strategy selection across drug development stages, by implementing model-informed approaches to improve ADC therapeutic outcomes.

Quantitative Systems Pharmacology (QSP) and Pharmacometrics (PMX) have historically existed at the two ends of the model-informed drug development (MIDD) spectrum. The session "Mind the gap - successful bridging of QSP and PMX in drug development" at the 2024 American Conference of Pharmacometrics brought together QSP scientists and pharmacometricians with the aim to develop better understandings of how to bridge this gap. The current perspective is based on the concepts that were presented and the follow-up panel discussion.