Cts-Clinical and Translational Science最新文献

ESK-001 is a highly selective allosteric inhibitor of tyrosine kinase 2 (TYK2), which plays an essential role in mediating cytokine signaling in multiple immune-mediated diseases. In 2 phase I studies, a first-in-human single ascending dose (SAD) and multiple ascending dose (MAD) study and a multiple-dose (MD) study, we evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of orally administered ESK-001 in healthy participants using a randomized, double-blind, placebo-controlled study design. ESK-001 was rapidly absorbed with systemic exposures generally increasing dose-proportionally across all cohorts. The mean terminal half-life ranged from 8 to 13 h with no to minimal accumulation of ESK-001 following q.d. doses and ~2-fold accumulation following Q12 doses. Less than 1% of unchanged ESK-001 was eliminated in urine. ESK-001 inhibited the downstream TYK2 pathway as shown by inhibition of pSTAT1 expression. Transcriptomic analysis of unstimulated whole blood samples confirmed dose-dependent inhibition of Type I IFN-induced genes and SIGLEC1, a novel TYK2-responsive biomarker. By correlating PK exposure data with PD readouts, a strong PK/PD relationship was demonstrated. There were no deaths, serious treatment-emergent adverse events (TEAEs), nor severe TEAEs, and most TEAEs were mild in severity. In conclusion, ESK-001 was generally safe and well-tolerated in healthy participants, showed linear dose-dependent PK characteristics, and maximally inhibited TYK2-dependent pathways with a predictable concentration-dependent PK/PD relationship. These findings were used to select the dose range of ESK-001 for the STRIDE phase II trial in plaque psoriasis and to support further clinical development of ESK-001 in other TYK2-mediated diseases.

Whilst chemotherapy regimens have proven to be more successful for pediatric cancer patients over the years, their influence on long-term side effects is relatively poorly understood. One of the possible targets is the gonads, with gonadotoxic agents representing those that threaten the patient's ability to have children post surviving the primary disease treatment. Many risk stratification guidelines have categorized these agents based on the severity of their effect on the pre-pubertal testis. While the consensus is that those agents factored with a cyclophosphamide equivalent dosage pose the highest threat to fertility (e.g. alkylating agents), other agents might still contribute to a reduced testis function; especially in the case of combination therapies. Besides, it is important to note that studies deciphering the effect of other non-alkylating agents on the pre-pubertal testis lack standardized conclusions for clinically relevant outcomes. This makes it imperative to ensure the knowledge gap is addressed between the clinic and pre-clinic to understand potential gonadotoxic effects, ultimately leading to improved patient care. Therefore, this review will summarize the key findings in understanding the gonadotoxic effects of the most commonly researched non-alkylating agents: vincristine, etoposide, doxorubicin, and imatinib on the pre-pubertal testis.

Antiplatelet therapy with a P2Y₁₂ receptor inhibitor, in combination with aspirin, is standard of care for medical management of patients with coronary artery disease, and flexibility in prescribing options among these medications offers great potential for individualizing patient care. Previously, we showed that a loss-of-function missense mutation (G143E) in carboxylesterase 1 (CES1), the primary enzyme responsible for clopidogrel degradation, significantly impacts on-clopidogrel platelet aggregation and recurrent cardiovascular event risk. In the current investigation, we conducted a prospective randomized crossover study of clopidogrel (75 mg/day for 7 days) and ticagrelor (180 mg/day for 7 days) in 50 individuals stratified by CES1 G143E genotype (N = 34 143GG and 16 143GE) to determine the effect of drug choice on inhibition of platelet aggregation (IPA). Consistent with prior reports, we observed strong association between G143E and adenosine diphosphate-stimulated platelet aggregation following clopidogrel administration (IPA = 71.6 vs. 48.0% in 143E-allele carriers vs. non-carriers, respectively, p = 3.8 × 10⁻⁵). Similar significant effects on platelet aggregation were also noted between 143E-allele carriers versus non-carriers in response to stimulation with arachidonic acid (45.8 vs. 25.8%, p = 0.04), epinephrine (44.4 vs. 18.8%, p = 0.03), and collagen (5 μg/mL, 25.8 vs. 11.4%, p = 3.7 × 10⁻³). In contrast, no relationship between CES1 G143E and IPA was observed following ticagrelor administration regardless of the platelet agonist used. Collectively, these data suggest that on-clopidogrel platelet aggregation is substantially modified by CES1 G143E genotype, that this variant does not modify ticagrelor pharmacodynamics, and that more consistent inhibition of platelet aggregation may be achieved by using ticagrelor in patients who carry clopidogrel response-modifying alleles in CES1.

Decentralized clinical trials (DCTs), in which all or part of the trial activities are moved to the participants' immediate surroundings, promise to improve trial conduct. However, no evidence is available on what motivates people to participate in DCTs. Our aim was to determine the drivers and perceptions for participation in clinical trials with different decentralization levels in persons with type 2 diabetes mellitus. Five focus groups were conducted utilizing the nominal group technique in the Netherlands (n = 1), Germany (n = 1), and Austria (n = 3) with four to six participants per group. The focus groups were analyzed using thematic analysis. Of the 26 participants (10 females, median age: 66 years [IQR: 62–72]) 42% had previously participated in a trial, and almost all had internet access at home (96%). A total of seven main themes regarding participation in clinical trials (location, time investment, contact with healthcare professionals (HCPs), digital technologies, data collection, perceived risk, and motivation) were identified, of which a total of 20 drivers emerged. Perceptions regarding trial participation differed widely among participants, and individual preferences influenced which drivers were considered more important by participants. Flexibility of location and time spent on the trial were identified as the most motivating factors for participation in DCTs. Some drivers, such as digital infrastructure, digital literacy, home visits, personal interaction, and relationship with HCPs were perceived as both enablers and barriers, depending on personal preferences. However, most of the potential barriers regarding DCTs may be resolved by addressing them in the design of future DCTs.

Controversies regarding the benefits of statin treatment on clinical outcomes in coronary artery spasm (CAS) without obstructive coronary artery disease (CAD) persist due to limited data. In this retrospective nationwide population-based cohort study from the Taiwan National Health Insurance Research Database during the period 2000–2012, the matched cohorts consisted of 12,000 patients with CAS. After propensity score matching with 1:1 ratio, 2216 patients were eligible for outcome analysis in either statin or nonstatin group, with the mean follow-up duration of 4.8 and 4.6 years, respectively. Statin users versus nonusers had a significantly reduced risk of major adverse cardiovascular events (MACEs) (6.7% vs. 9.5%, hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.55–0.84) and all-cause mortality (6.0% vs. 7.6%; HR 0.77; 95% CI 0.61–0.96). While the results of MACEs were mainly contributed by cardiovascular death (1.9% vs. 3.2%; HR 0.56; 95% CI 0.38–0.83) and ischemic stroke (3.8% vs. 5.4%; subdistribution HR 0.69; 95% CI 0.52–0.91), they were primarily driven by reductions in ischemic but not hemorrhagic stroke. The benefit of statins was significantly pronounced in patients with hypertension and diabetes. Nevertheless, the effect on MACEs was consistent irrespective of age, sex, dyslipidemia, and mental disorder. Statins significantly reduced the risk of MACEs and all-cause mortality in CAS patients. The benefit of statin therapy in reducing MACEs appeared to be linear, with greater risk reduction with higher doses and longer duration without upper threshold, reflecting the dose-dependent relationship of statins with MACEs in CAS patients.

The increase in the availability of real-world data (RWD), in combination with advances in machine learning (ML) methods, provides a unique opportunity for the integration of the two to explore complex clinical pharmacology questions. Here we present a recently developed RWD/ML framework that utilizes ML algorithms to understand the influence and importance of various covariates on the use of a given dose and schedule for drugs that have multiple approved dosing regimens. To demonstrate the application of this framework, we present atezolizumab as a use case on account of its three approved alternative intravenous (IV) dosing regimens. As expected, the real-world use of atezolizumab has generally been increasing since 2016 for the 1200 mg every 3 weeks regimen and since 2019 for the 1680 mg every 4 weeks regimen. Out of the ML algorithms evaluated, XGBoost performed the best, as measured by the area under the precision–recall curve, with an emphasis on the under-sampled class given the imbalance in the data. The importance of features was measured by Shapley Additive exPlanations (SHAP) values and showed metastatic breast cancer and use of protein-bound paclitaxel as the most correlated with the use of 840 mg every 2 weeks. Although patient usage data for alternative IV dosing regimens are still maturing, these analyses provide initial insights on the use of atezolizumab and set up a framework for the re-analysis of atezolizumab (at a future data cut) as well as application to other molecules with approved alternative dosing regimens.

Registry-based randomized controlled trials (RRCTs) can combine the advantages of registries with those of randomization. This review aimed to expand the current knowledge on RRCT utilization and implementation by providing a comprehensive overview of RRCT use cases. A targeted literature search was conducted through July 2023 to identify articles on RRCTs. Information regarding the RRCT characteristics, their utilization, and the registries' contributions and the constraints faced was extracted. Descriptive statistics were used. We identified 102 RRCTs in 110 publications. RRCTs were mostly performed for the assessment of medical devices or surgical/clinical procedures (n = 45), followed by drugs (n = 30). More than half of the RRCTs were conducted in the Nordic countries (n = 58) and the most used registry types were health service registries/administrative health data (n = 63), followed by disease registries (n = 46). Approximately half of the RRCTs (n = 53) utilized additional data sources aside from registry data. The contribution of a registry to the RRCT was mostly for data collection and study follow-up (n = 90–92), followed by patient recruitment (n = 56–61), and randomization (n = 28–38), with varying levels of transparency in reporting. We collated author-reported constraints related to the used registries into four overarching themes, that is, data availability and completeness, data quality, representativeness, and registry infrastructure and accessibility. This review shows that RRCTs are already used in different domains and geographic regions. Guidelines on structured and transparent reporting of RRCT methods and the optimal use are, however, needed to inform decision-making by health authorities and to reach their full potential.

TQS-168, a first-in-class small-molecule inducer of peroxisome proliferator-activated receptor gamma coactivator 1-alpha gene expression, is in development for the treatment of amyotrophic lateral sclerosis. A single-ascending-dose (SAD) and multiple-ascending-dose (MAD) study of TQS-168 was carried out in healthy male subjects to investigate safety, tolerability, pharmacokinetics (PK), food effect, and preliminary pharmacodynamic effects (PD). Since solubility enhancement could be beneficial, assessment of three formulations was incorporated into the study using an integrated rapid manufacturing and clinical testing approach. Dosing in the SAD part was initiated with a crystalline methylcellulose (MC) suspension, and then spray-dried dispersion (SDD) and hot-melt extrusion (HME) suspensions were evaluated. The HME and SDD formulations showed two and fourfold higher exposure than the MC suspension, respectively, and the SDD formulation was selected for progression to subsequent SAD and MAD cohorts, in which there was further investigation of the food effect on exposure in addition to assessments of safety, tolerability, PK, and PD. C_max and AUC plasma exposures of TQS-168 were supra-proportional at higher doses, irrespective of formulation. Median T_max for TQS-168 occurred between 0.5 and 4.0 h post-dose and occurred later with higher doses. Geometric mean half-lives (T_1/2) for TQS-168 were independent of formulation and food, ranging from 3.2 to 10.5 h following single doses and 4.1 to 7.3 h following multiple doses. Food blunted TQS-168 C_max but had minimal impact on AUC. TQS-168 was considered to be safe and generally well tolerated following single and multiple oral doses. The SDD formulation was selected for future patient studies.

Quizartinib prolongs QT interval through inhibition of the slow delayed rectifier potassium current (I_Ks). We used non-linear mixed-effects modeling to explore the relationship between quizartinib and its pharmacologically active metabolite AC886 and the Fridericia-corrected QT interval (QTcF) in newly diagnosed acute myeloid leukemia (AML) patients. We evaluated linear and non-linear drug effect models, using triplicate QTcF measurements with available time-matched pharmacokinetic samples from the Phase 3 QuANTUM-First trial. The effect of intrinsic and extrinsic factors on model parameters was tested using stepwise covariate model building. Simulations were conducted to predict the change from baseline in QTcF (ΔQTcF) at the maximum concentration at steady-state (C_max,ss) for quizartinib maintenance daily doses of 30 and 60 mg. The concentration-QTcF (C-QTcF) relationship was best described by a sigmoidal maximum effect model. After accounting for the effect of quizartinib, including AC886 concentrations did not further explain changes in QTcF. Circadian variations in QTcF were described using an empirical change from baseline based on clock times. Age and hypokalaemia were identified as statistically significant covariates on baseline QTcF; no covariates were found to impact the C-QTcF relationship. The median model-predicted ΔQTcF at C_max,ss was 18.4 ms (90% confidence interval (CI): 16.3–20.5) at 30 mg and 24.1 ms (90% CI: 21.4–26.6) at 60 mg. In conclusion, in newly diagnosed AML patients, ΔQTcF increased non-linearly with increasing quizartinib concentrations. The predicted ΔQTcF increase at C_max,ss supports the proposed dose adaptation based on observed QTcF and the dose reduction in case of strong cytochrome P450 3A (CYP3A) inhibitors coadministration.