Clinical Pharmacology & Therapeutics最新文献

Extended interval dosing regimens of immune checkpoint inhibitors have been implemented widely. However, their approval was mainly based on pharmacokinetic modeling and simulations. Consequently, comparative safety data of extended interval dosing regimens in a real-world setting are limited. This study compares grade ≥3 immune-related adverse events between standard and extended interval dosing of nivolumab in patients with melanoma and explores associated risk factors. This retrospective cohort study included patients with melanoma treated with nivolumab monotherapy from April 2016-September 2021 in the MULTOMAB study. Data on baseline characteristics and immune-related adverse events were collected from patients' electronic medical records with a maximum follow-up of 6 months. A total of 236 patients (125 metastatic and 111 adjuvant) were included, with 146 in the standard cohort and 90 in the extended interval cohort. Grade ≥3 immune-related adverse events occurred in 20 patients: 13 (8.9%) patients in the standard cohort and 7 (7.8%) in the extended interval cohort. No significant differences in grade ≥3 immune-related adverse events were observed between the two cohorts (P = 0.763). This study suggests that the risk of severe immune-related adverse events is comparable between both interval dosing regimens of nivolumab in patients with melanoma. Therefore, the extended interval dosing of nivolumab appears to be safe for application in standard care.

Verekitug, a novel, high-affinity, fully human monoclonal antibody targeting thymic stromal lymphopoietin receptor (TSLPR), is in development as a potential treatment for severe asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), and chronic obstructive pulmonary disease (COPD). This phase 1b, double-blind, randomized, placebo-controlled, multiple ascending-dose trial assessed the safety, tolerability, immunogenicity, pharmacokinetics, and pharmacodynamics of verekitug administered subcutaneously in patients with mild–moderate asthma. Thirty-two participants were randomized in 4 placebo-controlled dosing cohorts (3 × 100-mg or 200-mg doses, once every 4 weeks; 2 × 300-mg doses, once every 12 weeks; single 25-mg dose) and observed for 32 weeks. The primary endpoint was safety; secondary endpoints were pharmacokinetics and immunogenicity. Exploratory endpoints included TSLPR occupancy and biomarker effects. Treatment-emergent adverse events were mild or moderate. Complete TSLPR occupancy was observed at the first timepoint (2 weeks post dose) and maintained for 24 weeks (doses ≥100 mg). Rapid mean reductions in fractional exhaled nitric oxide, eosinophils, and interleukin-5 (up to −54%, −65%, and −64%, respectively) were sustained up to 24 weeks (doses ≥100 mg). The mean verekitug half-life was ~20 days. Low-titer antidrug antibody response was observed in some participants, without clinically meaningful impact on pharmacokinetics, pharmacodynamics, or safety. Verekitug was generally well tolerated, with rapid, substantial, and sustained effects on asthma biomarkers. These findings support further development of verekitug for treating severe asthma, CRSwNP, and COPD.

Advancing pharmacoequity is both a public health imperative and a scientific opportunity. While policy efforts have focused largely on post-approval issues like pricing, insurance, evidence-based prescribing practices, and pharmacy access, science offers powerful tools to address inequities much earlier. This perspective outlines how clinical translational pharmacology (CTP) is uniquely positioned as a scientific discipline to advance pharmacoequity through its principles, innovation, methods, and patient-centered applications across the discovery, development, regulation, and utilization (DDRU) continuum.

The Pharmacogene Variation Consortium (PharmVar) provides nomenclature for the highly polymorphic human N-acetyltransferase 2 (NAT2) gene. NAT2 metabolizes several clinically used drugs including isoniazid, hydralazine, amifampridine, procainamide, and sulfonamides such as dapsone, and also some highly carcinogenic arylamines. Systematic nomenclature describing NAT2 variation is essential for pharmacogenetic testing, genotype interpretation, and translation to phenotype in research and clinical settings. This GeneFocus provides an overview of NAT2 variation and describes important changes to its star allele-based nomenclature that were made as it was transitioned to PharmVar in March 2024. We also highlight and discuss challenges regarding the characterization of allelic variation and determination of allele frequencies across world populations. The "new" NAT2 PharmVar nomenclature is utilized by ClinPGx (formerly PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC).

Pharmacogenomic research has historically focused on individuals of European ancestry, leading to the underrepresentation of genetic variants common in non-European populations. This bias is exemplified by CYP3A5*6, a functionally consequential variant common in individuals of African ancestry (MAF: 11-19%) but virtually absent in Europeans (MAF: 0.15%). We conducted a retrospective, longitudinal cohort study using real-world data from 1,461 adult kidney transplant recipients across 67 countries, analyzing 4,293 dose-normalized 24-hour area-under-the-curve (AUC_0-24) measurements of tacrolimus. Patients with CYP3A5*1/*1 were excluded. Linear mixed-effects models (LME) were used to assess the association between CYP3A5*6 carriage and tacrolimus exposure, adjusting for clinical factors and ancestry using both HLA-based principal components and country of birth. CYP3A5*6 carriers had a 17% lower dose-normalized AUC_0-24 than CYP3A5*3 carriers (P = 0.015). Sensitivity analyses using dose-normalized trough concentrations (C₀) confirmed these findings, with a 20% lower exposure in CYP3A5*6 carriers (P = 0.011). An interval-based analysis demonstrated persistently lower tacrolimus exposure across the first post-transplant year. All CYP3A5*6-containing genotypes showed significantly lower dose-normalized AUC_0-24 compared to CYP3A5*3/*3, the most common genotype in European populations, with the largest reductions observed in CYP3A5*1/*6 (-39%; P < 0.001) and CYP3A5*3/*6 (-18%; P = 0.006). African origin, defined by country of birth, was independently associated with a 23% higher AUC_0-24 (P < 0.001). This is the first study to demonstrate a differential effect on tacrolimus exposure between the CYP3A5*6 and CYP3A5*3 loss-of-function alleles. Our results may help bridge the ethnicity gap, advance the applicability of pharmacogenomic findings, and promote health equity.

Disrupted homeostasis and transneuronal spread of hyperphosphorylated Tau protein (pTau) are hypothesized to be key pathogenic drivers of Alzheimer's disease (AD). Posdinemab (JNJ-63733657), a humanized IgG1/kappa monoclonal antibody that targets phosphorylated Tau protein at amino acid 217 (p217+tau), is currently in clinical development for the treatment of AD. In a first-in-human Phase 1 study (NCT03375697), posdinemab was well tolerated at doses up to 60 mg/kg, demonstrated linear pharmacokinetics (PK) in serum, and induced dose-dependent reductions in p217+tau levels in cerebrospinal fluid (CSF). The objective of the current analysis was to develop a mechanism-based population pharmacokinetic-pharmacodynamic (popPK-PD) model to guide the Phase 2 (Auτonomy) dose selection of posdinemab in participants with AD using the Phase 1 data from 69 adults. A two-compartment model was selected, which successfully described the available clinical PK-PD data and demonstrated that posdinemab PK in serum is linear, dose-proportional, and time-independent. Suppression of free p217+tau in CSF was used to reflect free antibody available to bind tau seeds in interstitial fluid (ISF). The PK-PD model-based simulations for fixed intravenous doses of 1,000 mg and 3,000 mg every 4 weeks predicted >90% reduction in tau seeds in ISF by Day 391 and Day 154, respectively, following treatment initiation. This model provides a physiologically relevant simulation-framework to investigate the impact of various posdinemab dose levels on PK-PD profiles, thereby supporting the clinical trial design of the Auτonomy study (NCT04619420).

This meta-analysis evaluated the risk of malignancies and major adverse cardiovascular events (MACE) associated with the use of JAK inhibitors in patients with RA through a comprehensive meta-analysis of available clinical trials. A systematic search was conducted in PubMed, EMBASE, and Web of Science from inception to February 7, 2025, to identify relevant clinical trials. Data on malignancies and MACE incidence were extracted, and pooled risk ratios (RR) were calculated using a random-effects model. A total of 18 studies (N = 111,260) met the inclusion criteria. JAK inhibitors were associated with a significantly increased risk of malignancies excluding NMSC (RR = 1.30, 95%CI: 1.05, 1.60; P = 0.016), NMSC (RR = 1.54, 95%CI: 1.23, 1.93; P < 0.01), overall malignancies (RR = 1.53, 95%CI: 1.18, 2.00; P = 0.002), lung cancer (RR = 1.52, 95%CI: 1.11, 2.08; P = 0.009), lymphoma (RR = 3.69, 95%CI: 1.19, 11.42; P = 0.024), non-small cell lung cancer (RR = 1.70, 95%CI: 1.01, 2.86; P = 0.047), cutaneous squamous cell carcinoma (RR = 2.30, 95%CI: 1.44, 3.65; P < 0.01), and thyroid cancer (RR = 7.51, 95%CI: 1.39, 40.74; P = 0.019). In contrast, JAK inhibitors did not significantly alter the risk of MACE (RR = 0.75, 95%CI: 0.38, 1.45; P = 0.390), venous thromboembolism (VTE) (RR = 1.52, 95%CI: 0.90, 2.56; P = 0.117), or deep vein thrombosis (DVT) (RR = 1.77, 95%CI: 0.84, 3.34; P = 0.079). Trial sequential analysis (TSA) confirmed data adequacy, and meta-regression indicated that sample size, treatment duration, and patient age did not influence outcomes. JAK inhibitors are associated with an elevated risk of malignancies but do not significantly affect MACE, VTE, or DVT risk in RA patients. Further large-scale post-marketing surveillance is warranted to refine the safety profile of JAK inhibitors in RA management.

Limited evidence exists synthesizing the risk of acute kidney injury (AKI) associated with the concomitant administration of multiple nephrotoxic drugs, and even less examining the concept of nephrotoxic burden. The objective of this scoping review was to (1) identify definitions of nephrotoxic burden; (2) methods used to quantify (use of calculations) nephrotoxic burden; and (3) determine the association between nephrotoxic burden and AKI risk. Additionally, we assessed studies reporting the risk of AKI with the concurrent use of three or more nephrotoxic drugs. Following PRISMA guidelines, a comprehensive literature search was conducted. Observational studies in hospitalized patients were included if they assessed nephrotoxic burden or the risk of AKI with concurrent nephrotoxic drug use. Sixteen studies met the inclusion criteria. Four studies assessed nephrotoxic burden, two of which defined and quantified it, and two additional studies adopted those definitions to evaluate associations with AKI. All four reported a significant relationship between increased nephrotoxic burden and AKI risk. Twelve studies evaluated the likelihood of AKI with concurrent administration of three or more nephrotoxic drugs, with reported odds ratios ranging from 1.15 to 3.18 per additional drug. The deleterious effects of concomitant exposure to three or more nephrotoxins on the kidney are evident, stressing a need to take conscious action from a clinician and institutional perspective in the attempt to prevent AKI. Future research should incorporate drug-specific weighting and consistent reporting standards to improve nephrotoxic burden assessment and guide clinical decision-making to reduce AKI.