Cts-Clinical and Translational Science最新文献

Increasing antimicrobial resistance poses a serious challenge for the treatment of Shigella infections, and there is an urgent need for alternative antibacterial treatments. We conducted a clinical trial to investigate the efficacy of oral tebipenem pivoxil, compared to intravenous ceftriaxone, in Bangladeshi children with shigellosis. Using demographic data of 2249 Bangladeshi children with suspected shigellosis, population pharmacokinetic (PK) simulations were conducted to simulate tebipenem PK profiles in children with the proposed dosing regimen. Subsequently, the model predictions estimated each virtual participant's fraction of time over the 3-day treatment period during which simulated free tebipenem plasma concentration was above the minimum inhibitory concentration (fT > MIC). Variability associated with the prevalence of different Shigella species in Bangladeshi children and the MIC distributions were incorporated. Shigella treatment effect was assumed for participants that had fT > MIC for at least 40% of the 3-day treatment period (40% fT > MIC). The probability of achieving 40% fT > MIC was 86.4% for 4 mg/kg tebipenem pivoxil three times daily (TID) dosing and 92.4% with 3 mg/kg tebipenem pivoxil four times daily (QID) dosing. Lastly, the probability of tebipenem pivoxil being non-inferior to ceftriaxone, in a clinical trial containing 66 participants per arm, was evaluated for two dosing regimens. Three levels of ceftriaxone resistance were simulated to examine how dynamic ceftriaxone resistance may impact the trial outcome. Our findings suggest that more frequent tebipenem pivoxil dosing may increase the chance of producing treatment effects, contribute valuable insights to inform dosing strategy selection, and demonstrate a workflow that can be adapted to other drugs and diseases.

Funding freezes can strike active clinical trials without warning. Participants still need care. Science still needs integrity. This paper offers a practical, seven-day playbook for safely pausing active clinical trials when funding stops.

Cannabidiol (CBD) use has increased in America due to its widespread availability. Cannabidiol is metabolized by multiple polymorphic enzymes including CYP3A, CYP2C9, and CYP2C19. We sought to evaluate the genotype-specific adverse events and pharmacokinetic profiles of cannabidiol, 7-OH cannabidiol (an active metabolite), and 7-COOH cannabidiol. We completed a secondary analysis of an open-label, fixed-sequence, single-center study of cannabidiol in 33 healthy subjects. Patients first received a single dose of cannabidiol 5 mg/kg orally with serial plasma concentrations measured. Later, patients were titrated to 5 mg/kg twice daily for 14 days to reach steady state with serial plasma concentrations measured. CYP3A, CYP2C9, and CYP2C19 genotypes were assessed. Pharmacokinetic parameters were calculated by noncompartmental analysis. Diarrhea was observed more frequently in individuals with both CYP3A5 poor metabolism and CYP2C19 intermediate/normal metabolism (39%) compared to individuals with other genotypes (7%, p = 0.0463). Individuals with both CYP3A5 poor metabolism and CYP2C19 intermediate/normal metabolism had increased 7-OH cannabidiol and 7-COOH cannabidiol exposure at steady state. Cannabidiol parent drug exposure varied by CYP2C19 metabolizer status, with lower cannabidiol exposure and parent to metabolite ratios in intermediate metabolizers after single dose (p = 0.014) and at steady state (p = 0.0033). Similar CYP2C19 genotype-specific exposure was observed in an external validation cohort. Minor differences in exposure of cannabidiol and its metabolites were observed between CYP3A5 and CYP2C9 genotype groups. Significant changes in pharmacokinetics were observed between CYP2C9, CYP2C19, and CYP3A5 genotype groups. Future studies should assess whether pharmacogenomics can predict intestinal concentrations of CBD, its metabolites, and diarrhea.

Historically, clonal hematopoiesis (CH) has been recognized as a confounder of cell-free DNA (cfDNA) testing. Recent evidence now demonstrates the role of CH as a risk factor in health, generating distinct sources of cfDNA that can be leveraged for liquid biopsy diagnostics. Nonetheless, gaps in standardization challenge the advancement of such diagnostics from development to regulatory approval, through clinical trials, and ultimately, to routine implementation. In 2024, the Blood Profiling Atlas in Cancer (BLOODPAC) Consortium, a collaborative infrastructure for developing standards and best practices for liquid biopsy assays, established the CH/clonal hematopoiesis of indeterminate potential (CHIP) Working Group to address the need for accurate identification and removal of CH from liquid biopsy results. As a first step to support the interpretability of CH/CHIP results, the Working Group developed this lexicon to standardize terms and provide a unified vocabulary related to CH and liquid biopsy, DNA sequencing tests, biomarkers, and clinical use cases, facilitating communication within the field. BLOODPAC's CH/CHIP Working Group believes that terminology agreement across these various stakeholders can improve communication in the field and unify future data collection efforts across studies.

Juvenile idiopathic arthritis (JIA) is a chronic autoimmune disease that negatively affects ~100,000 children under the age of 16 in the United States. About ~30% of these patients fail first-line drug therapy with low-dose methotrexate (MTX) due to poor tolerability or lack of efficacy. The SLCO1B1*14 allele is associated with increased MTX clearance and has been linked to reduced overall drug exposure and nonresponse to MTX in JIA patients. Herein, we describe transgenic hSLCO1B1*14 and hSLCO1B1*1 DBA1/J mSlco1b2 knock-out mice, which we used to assess arthritic response to MTX using the collagen-induced arthritis model. Mass spectrometry-based proteomics analysis revealed that OATP1B1 protein abundance was 2.1-fold higher in hSLCO1B1*14 mice compared to hSLCO1B1*1 mice. Following treatment with 1 mg/kg MTX for 3 weeks, hSLCO1B1*14 mice exhibited a 39% increase in median arthritic disease burden (p = 0.02) and a 22% reduction in MTX AUC (p = 0.14) compared to hSLCO1B1*1 mice. Pharmacokinetic modeling estimated that the hSLCO1B1*14 mice would need a 30% higher dose to equalize exposure and response to hSLCO1B1*1 mice. When hSLCO1B1*14 mice received 1.3 mg/kg MTX, the arthritic disease burden and overall MTX exposure were less than the 1 mg/kg MTX in hSLCO1B1*1 mice, reinforcing that differences in MTX elimination and therapeutic response can be accounted for by using pharmacogenetic-guided dosing of MTX in JIA patients.

Feeding tubes are essential for patients unable to maintain adequate oral intake, serving multiple purposes including nutrition delivery and medication administration. The impact of administering medications through feeding tubes on their stability requires systematic investigation. This review aims to systematically evaluate factors affecting medication stability when administered via enteral feeding tubes versus oral administration in healthy populations, focusing on solid dosage forms converted to liquid formulations. A comprehensive search was conducted across PubMed/MEDLINE, Embase, and CINAHL databases from July to October 2024, using a combination of MeSH and non-MeSH terms. Studies that assessed medication stability in enteral feeding tubes were included, while those that did not report on this outcome were excluded. The risk of bias was evaluated using ROBINS-I, RoB- II, Cochrane tools, and the QUIN tool. From 2368 articles, 115 were retained for further assessment, and finally 24 met the inclusion criteria and were included, comprising 16 in vivo, 4 in vitro, and 4 combined studies. Approximately 20.8% of the studies found reduced stability/bioavailability for certain medications, such as warfarin and tolvaptan, while 8.3% of the studies found enhanced absorption, as observed with clopidogrel. Most medications maintained their stability. This systematic review suggests that enteral feeding tube administration can variably affect medication stability, influenced by factors such as tube material and preparation methods. Although most medications remain stable, concerns regarding instability and quality persist. The findings of this review provide a foundation for developing evidence-based guidelines to optimize clinical practice and improve patient outcomes.

A recent article offers a useful summary of steps to consider concerning drug–drug interactions during drug development [1]. However, the article focused mainly on anticipating pharmacokinetic and drug metabolism-based interactions. The more important issue is that while in some cases such changes can anticipate potentially clinically important interactions, for example, with drugs acting directly on peripheral cardiovascular receptors or having a small volume of distribution, for many classes of drugs such studies cannot usefully predict clinically important interactions in individual patients [2, 3]. The reasons are mainly because of the large variation among patients in the extent of kinetic and metabolism changes combined with much larger variation in pharmacodynamic and therapeutic effects. Preoccupation with kinetic and metabolic-based interactions mechanisms has occurred because these are more easily studied than the more important pharmacodynamic consequences in individual patients. Population (average) changes in kinetics, metabolites and pharmacodynamics are not useful in actual clinical dose adjustment. This shortcoming is compounded by the relative lack of clinical studies in actual conditions and settings of drug use and in neglected study populations including different ancestry groups, low socioeconomic groups and individuals with restricted access to health care services. As a result of being understudied, much clinical use of drugs and management of drug–drug interactions is largely trial and error. Many more “real” world post-marketing studies of drug–drug interactions are needed.

As final comment, these authors elect to distinguish the drugs involved in drug–drug interactions as the “perpetrator” and the “victim.” This is a useful categorical and semantic shortcut but belies the complexity of the etiology and complexity of drug–drug interactions where often multiple drugs are administered concurrently in disease states that modify mechanism and consequences. In clinical practice, the perpetrator is often the prescriber and the victim the patient!

The author has nothing to report.

The author declares no conflicts of interest.

Interleukin (IL)-13 plays a central role in Type 2 inflammation, contributing to the pathogenesis of atopic dermatitis, asthma, and related inflammatory diseases. APG777 is a novel anti-IL-13 monoclonal antibody engineered for improved pharmacokinetics and reduced dosing frequency. This first-in-human, randomized, double-blind, placebo-controlled phase 1 study evaluated the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of single and multiple subcutaneous doses of APG777 in healthy adults. Forty participants were enrolled in single ascending dose (300–1200 mg) and multiple dose (300 mg × 2) cohorts. APG777 was well tolerated, with only mild-to-moderate treatment-emergent adverse events, predominantly unrelated to the study drug. No serious or severe drug-related treatment-emergent adverse events occurred. Following single doses, APG777 exhibited dose-proportional increases in C_max and area under the curve, with a terminal half-life ranging from 75.3 to 77.5 days across the dose range tested. Immunogenicity was low, with anti-drug antibodies detected in 23.3% of treated participants, generally without impact on pharmacokinetics or safety. APG777 led to rapid and durable inhibition of the IL-13-driven biomarkers phosphorylated signal transducer and activator of transcription 6 (pSTAT6), thymus and activation-regulated chemokine (TARC), and immunoglobulin E (IgE), with near-complete suppression of pSTAT6 observed for up to 12 months post-dose. The safety and optimized pharmacokinetic profile of APG777 supports evaluation of extended dosing intervals (every 3–6 months) and higher exposures, which could improve outcomes and reduce injection burden in patients with Type 2 inflammatory diseases including atopic dermatitis and asthma.

The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative proposes integrating multi-cardiac ion channel pharmacology to improve the prediction of drug-induced Torsade de Pointes (TdP) risk. However, several studies under CiPA have demonstrated misalignment between nonclinical and clinical data. One study showed ECG changes induced by chloroquine, lopinavir, and ritonavir suggestive of Ca_V1.2 and Na_V1.5 channel block. However, ion channel data used to design the clinical study showed no such interactions. Another study reported TdP cases in patients treated with vanoxerine, a drug with literature data demonstrating similar block potencies for hERG and Ca_V1.2 channels suggesting lower TdP risk than selective hERG blockers. Finally, astemizole, risperidone, and clarithromycin—“intermediate TdP risk” CiPA drugs—were reported to have hERG-active metabolites, yet hERG data for metabolites were not integrated when developing in silico human myocyte models for risk prediction. To increase the confidence of using nonclinical data in regulatory decision-making, the sources of these inconsistent nonclinical-clinical findings and data gap for metabolites need to be addressed. Here the effects of chloroquine, lopinavir, ritonavir, and vanoxerine on hERG, Ca_V1.2, and/or Na_V1.5 channels were studied using protocols consistent with ICH S7B Q&A 2.1 best practices. hERG block potencies for astemizole, risperidone, clarithromycin plus their major metabolites were also determined. The results showed improved alignment between ion channel block profiles and drug-induced ECG changes and proarrhythmia, underscoring the importance of using physiologically relevant experimental protocols, accounting for ion channel-active metabolites, and continuing to build the knowledge base of arrhythmogenesis mechanisms. Data may be found at: https://osf.io/7rfua/.

We used miRNA sequencing to identify candidate plasma pharmacodynamic (PD) biomarkers of interferon beta-1a (IFNβ-1a) biologics and explored miRNA-mRNA targeted protein relationships and networks to support identified miRNA candidates. Plasma samples from 36 healthy subjects from a placebo-controlled randomized single-dose clinical study with IFNβ-1a and pegIFNβ-1a were used. Mature miRNAs were measured using an in-house miRNA-seq workflow at baseline, at 9 timepoints over 6 days in the IFNβ-1a group (n = 11 [30 μg]), and at 11 timepoints over 13 days in the pegIFNβ-1a group (n = 11 [125 μg]) and placebo-specific groups (n = 6 each). A miRNA was only considered expressed if it had a read count ≥ 10 in more than 50% of the samples across all treatment groups. Linear mixed-effects models (lmer) regressing miRNA changes with treatment, time, and their interaction were used to identify differentially expressed miRNAs, which were further prioritized based on the magnitude of response and biological relevance using in silico predicted miRNA-protein targets and regulatory network analyses. Ten and 13 miRNAs were impacted by IFNβ-1a and pegIFNβ-1a, respectively (lmer FDR-corrected p value < 0.1), compared to placebo, of which miR-223-3p and miR-21-5p were prioritized as candidate PD biomarkers for both products. Systems-level analysis of integrated proteomics data highlighted miRNAs' protein targets for both miR-223-3p and miR-21-5p that were linked to previously reported top proteomic response proteins and predicted regulatory networks including the IFN beta node. Using miRNA sequencing and linking candidates to predicted target proteins and regulatory networks, results suggest miR-223-3p and miR-21-5p as potential PD biomarkers of IFNβ-1a biologics for further investigation.