Cts-Clinical and Translational Science最新文献

Ecopipam, a selective dopamine D1 receptor antagonist in development for Tourette syndrome, is primarily converted by uridine diphosphate-glucuronosyltransferase (UGT)1A9 to ecopipam glucuronide, with a minor metabolic pathway by cytochrome P450 3A4 forming EBS-101-40853 (also referred to as N-desmethylecopipam or SCH 40853; also glucuronidated by UGT1A9). This open-label, fixed-sequence study evaluated the effect of mefenamic acid (UGT1A9 inhibitor) and divalproex sodium extended release (ER; general UGT inhibitor) on the pharmacokinetics (PK) of ecopipam and its metabolites. Ecopipam 179.2 mg was administered on Day 1. Cohort A received mefenamic acid 250 mg every 6 h from Days 7 to 13, with ecopipam 179.2 mg co-administered on Day 7. Cohort B received divalproex sodium ER 1250 mg once daily from Days 7 to 16, with ecopipam 179.2 mg co-administered on Day 10. A total of 38 healthy individuals (mean [SD] age, 38.2 [8.3] years; 81.6% male) had ≥ 1 post-dose safety or PK assessment, and 31 completed the study. Ecopipam alone or with UGT inhibitors was well tolerated. Mefenamic acid increased the C_max of ecopipam (21%) and EBS-101-40853 (12%) and AUC_inf of ecopipam (45%) and EBS-101-40853 (42%), but did not substantially alter the PK of ecopipam glucuronide or EBS-101-40853 glucuronide. Divalproex sodium ER increased the C_max (66%) and AUC_inf (2.1×) of ecopipam, increased the C_max (40%) and AUC_inf (86%) of EBS-101-40853, and decreased the C_max of ecopipam glucuronide and EBS-101-40853 glucuronide (23% and 32%, respectively). Inhibition of ecopipam metabolism indicated that ecopipam dose adjustments may be needed when administered with UGT inhibitors.

J. Etkins, G. C. So, J. B. L. Lu, et al., “Genotype–Specific Safety and Pharmacokinetics of Cannabidiol in Healthy Volunteers,” Clinical and Translational Science 19 (2026): e70455, https://doi.org/10.1111/cts.70455.

In the article cited above, Figures 4 (single dose) and 5 (steady state) were transposed. Figure 5 was published in the place of Figure 4 and vice versa.

The correct labeling is as follows:

Figure 4

Figure 5

Tuvusertib is an investigational, orally administered inhibitor of ATR protein kinase, currently in Phase II clinical development. Here, we present an integrated nonclinical and clinical assessment of the effect of tuvusertib on QTc interval. In vitro inhibition by tuvusertib of the hERG potassium channel was evaluated, and in vivo ECG assessments evaluated the effect on QTc in dogs. PK-matched triplicate ECGs in patients receiving tuvusertib in Part A1 of the Phase I DDRiver Solid Tumors 301 study (N = 55; dosing regimens: 5–270 mg QD, 180–220 mg QD 2 weeks on/1 week off, or 150 mg BID 4 days on/3 days off) contributed to concentration-QTc analyses via linear mixed-effects modeling. In vitro, tuvusertib inhibited hERG with an IC₅₀ of 2.83 μM, which is ~2.5 times its steady-state unbound C_max at the clinical RDE (180 mg QD 2 weeks on/1 week off). In vivo, tuvusertib did not affect QTc up to 5 mg/kg/day in dogs (unbound C_max comparable to that at clinical RDE). In patients with advanced solid tumors receiving tuvusertib at up to threefold higher plasma concentrations than at the RDE, the risk for clinically relevant QTc prolongation was assessed to be low (upper limit of 90% CI of model-predicted ΔQTcF < 20 ms). There was no relationship between tuvusertib plasma concentration and RR interval, suggesting no effect on HR. Early integrated concentration-QTc assessments of tuvusertib monotherapy in Phase I were crucial in informing the low risk for clinically relevant QTc prolongation, thereby facilitating efficient evaluation of investigational tuvusertib combination strategies in ongoing clinical development.

Artificial intelligence (AI)-powered chatbots have emerged as potentially effective tools for delivering personalized, interactive, and culturally sensitive health education. Avoidable factors majorly cause oral and oropharyngeal cancers, and usually present with confusable symptoms, often leading to delayed diagnoses and poorer outcomes. Traditional oral health education methods have limitations in addressing the unique accessibility needs of groups that are most impacted by these outcomes. The primary aim of this study was to evaluate the usability and accuracy of an AI-powered chatbot prototype as an approachable, trustworthy, and engaging educational resource to enhance oral cancer awareness. A mixed-methods evaluation was conducted with six experts in behavioral science, oncology, dentistry, and AI. Experts interacted with the chatbot via a web interface and provided feedback via surveys rating usability and accuracy. Qualitative insights were gathered through open-ended survey questions and analyzed using thematic analysis, and quantitative data were collected through REDCap. The experts provided positive and constructive feedback, recognizing the chatbot's potential as an educational tool aiming to improve oral cancer-related information. They particularly praised its ease of access and the reliability of the information provided. However, experts identified areas for enhancement, including user interface changes, simplifying medical terminology, providing clearer initial guidance for users, and improving visual accessibility. Additionally, recommendations included integrating supplementary educational resources and clearer medical definitions to support deeper understanding and user engagement. This expert evaluation will guide the refinement for broader implementation in the project's next phase, evaluating acceptability and efficacy among non-expert users.

Inflammation and infection remain unmet challenges in wounds of various etiologies, delaying healing, impacting quality of life, and increasing healthcare costs. The thrombin-derived C-terminal peptide TCP-25 has demonstrated dual anti-inflammatory and antibacterial activities in animal wound infection models, thereby promoting healing, highlighting its therapeutic potential as a wound treatment. This first-in-human, double-blind, randomized, within-person and placebo-controlled clinical trial (NCT05378997) evaluated the safety, tolerability, and pharmacokinetics of topical TCP-25 in healthy volunteers. Twenty-four participants each received four suction blister wounds (two per thigh), with two wounds treated with TCP-25 (either 0.86, 2.9, or 8.6 mg/mL) and two with placebo gel, 5 times over 8 days. For the primary safety endpoint, no serious or significant adverse events or withdrawals due to adverse events were reported. Twenty-one participants (88%) reported at least 1 adverse event; all were mild or moderate and judged to be unlikely related to TCP-25 treatment. No abnormal local reactions occurred and no clinically relevant changes in electrocardiogram, vital signs, laboratory parameters, or physical examination findings were observed between baseline and end of treatment. For the secondary endpoint, TCP-25 was undetectable (< 90 nmol/L) in all plasma samples at all timepoints. Thus, topical TCP-25 gel was safe and well tolerated by healthy volunteers with epidermal wounds, with no evidence of measurable systemic exposure. Exploratory analyses indicated reduced wound exudation with TCP-25 treatment, particularly at 2.9 and 8.6 mg/mL. Taken together, these findings support further clinical evaluation of TCP-25 in relevant patient populations.

In 2020, COVID-19 caused a global health crisis, prompting research efforts and accelerating drug development. As part of this response, we conducted a phase 2b, multicentre, open-label, randomized (1:1) clinical trial to compare the effects of siltuximab versus corticosteroids on disease progression in hospitalized adults with COVID-19 pneumonia. Between April 2020 and January 2021, 82 patients were randomized to receive siltuximab and 80 corticosteroids (20 methylprednisolone and 60 dexamethasone). Median (IQR) age was 61 years (50–72). Nineteen patients allocated to siltuximab were admitted to the intensive care unit compared to eight receiving corticosteroids (p = 0.025). Corticosteroid treatment was independently associated with a higher risk of avoiding intensive care unit admission (2.7; 95% CI, 1.11–6.62), lower risk of requiring mechanical ventilation (0.43; 95% CI, 0.20–0.93) and shorter hospitalization duration (p = 0.008). Mortality was similar between arms (p = 0.675). Twenty-eight patients receiving siltuximab required rescue therapy while only 5 receiving corticosteroids (p < 0.001). Furthermore, patients receiving corticosteroids had a 53% lower risk of confirmed bacterial or fungal invasive infections (RR 0.47; 95% CI, 0.23–0.95; p = 0.0096). Our results show that initial treatment with corticosteroids was more effective than siltuximab in preventing disease progression, reducing intensive care unit admission, mechanical ventilation, with shorter hospital stays, and fewer infection in COVID-19 pneumonia. Despite numerous challenges, these findings provide valuable insights into optimizing therapeutic strategies, supporting corticosteroids as a preferred treatment over siltuximab in this setting.

Ecopipam is a first-in-class dopamine D1 receptor antagonist under investigation for the treatment of Tourette syndrome. This open-label, fixed-sequence, three-cohort study evaluated whether ecopipam induces or inhibits cytochrome P450 (CYP) 1A2, CYP2B6, CYP2C19, CYP2D6, CYP3A4, organic anion-transporting polypeptide (OATP) 1B1, and p-glycoprotein (P-gp). Probe substrates were administered alone and after single or steady-state dosing of ecopipam (1.8 mg/kg/day). Cohort 1 received standard doses of omeprazole (CYP2C19), caffeine (CYP1A2), and dextromethorphan (CYP2D6) orally, and a microdose of midazolam (CYP3A4) intravenously. Cohort 2 received a standard dose of bupropion (CYP2B6) orally. Cohort 3 received an oral solution containing microdoses of dabigatran (P-gp), pitavastatin (OATP1B1), rosuvastatin (BCRP, OATP, and P-gp), atorvastatin (BCRP, OATP, P-gp, and CYP3A4), and midazolam. A total of 56 healthy individuals (median [range] age, 36.5 [19–54] years; 85.7% male) were enrolled, and 48 completed the study. Ecopipam was well tolerated in the presence and absence of probe substrates. Steady-state ecopipam administration increased dextromethorphan exposure (> 100-fold); decreased the AUC_inf of midazolam, omeprazole, and dabigatran by 44.2%, 44.1%, and 37.9%, respectively; and decreased unconjugated bilirubin (UGT1A1) by 19.5%. Single-dose ecopipam increased atorvastatin C_max by 95% and rosuvastatin C_max by 11%, whereas steady-state ecopipam decreased the AUC_inf of atorvastatin by 26.8% and rosuvastatin by 16.4%. There were no changes in caffeine, bupropion, or pitavastatin exposure. Ecopipam is a strong inhibitor of CYP2D6 and weak inducer of CYP3A4, CYP2C19, P-gp, and UGT1A1. Ecopipam did not inhibit CYP3A4, CYP2C19, CYP2B6, CYP1A2, UGT1A1, P-gp, or OATP1B1 and did not induce OATP1B1 or CYP2B6.

Dicloxacillin and flucloxacillin are β-lactamase-resistant penicillin antibiotics that have been in clinical use for over 50 years. While both antibiotics are known to induce cytochrome P450 enzymes, there is limited information available regarding their interactions with drug transporters. Here, we investigated the in vitro transport and inhibition of hepatic organic anion transporting polypeptides (OATPs) and renal organic anion transporters (OATs) by these antibiotics in recombinant transporter overexpressing HEK293 cells. We also investigated the transport of these antibiotics by efflux transporters, as well as their inhibition of breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) using a HEK293 membrane vesicle transport assay. Dicloxacillin and flucloxacillin inhibited rosuvastatin transport by OATP1B1, OATP1B3, and OATP2B1, and the inhibition was strongest for OATP1Bs with IC₅₀ values of 3.9 and 31 μM (OATP1B1) and 6.7 and 21 μM (OATP1B3) for dicloxacillin and flucloxacillin, respectively. Both antibiotics also inhibited BCRP-mediated rosuvastatin transport with IC₅₀ values of 166 μM (dicloxacillin) and 379 μM (flucloxacillin), while P-gp-mediated transport of N-methyl-quinidine was inhibited to a lesser extent. All OATPs and OATs transported dicloxacillin and flucloxacillin. Static model predictions indicated that the inhibition of OATPs, BCRP, and P-glycoprotein by both compounds may be clinically relevant. We further developed and verified physiologically based pharmacokinetic (PBPK) models for dicloxacillin and flucloxacillin. PBPK model simulations predicted no major change in rosuvastatin, a substrate for OATPs and BCRP, pharmacokinetics when co-administered with dicloxacillin or flucloxacillin. Simulations with dicloxacillin and P-gp substrates dabigatran or digoxin also predicted limited inhibition of P-gp transport.

Testing thiopurine methyltransferase (TPMT) enzyme activity or genotype prior to thiopurine prescribing is recommended to reduce the risk of moderate to severe—and potentially fatal—myelosuppression in poor or intermediate TPMT metabolizers. Despite this, only about one-third of individuals prescribed thiopurines in Australia currently receive TPMT testing. The budgetary implications of expanding testing to align with guidelines remain unclear. We conducted a budget impact analysis from the Australian healthcare system perspective, comparing costs under current versus increased TPMT testing uptake. Phenotype frequencies among thiopurine users were estimated using ancestry-stratified prescribing data from the Person Level Integrated Data Asset of the Australian Bureau of Statistics combined with published phenotype distribution by ancestry. A simulation model was developed, incorporating phenotype frequencies, phenotype-specific hospitalization risks, and costs of testing and hospitalizations. In a hypothetical cohort of 10,000 thiopurine users, current testing rates of 32.5%–39.8% identify approximately 296 poor or intermediate metabolizers, leaving 586 individuals at elevated risk undetected. Increasing testing uptake by 10 percentage points from baseline could prevent 16 hospitalizations and save AUD$88,113 in hospital costs, leading to a mean net saving of AUD$42,728 (95% CI: AUD$41,685—AUD$43,770). The number needed to test to prevent one hospitalization was approximately 63. As myelosuppression represents a serious and potentially life-threatening adverse drug reaction, expanding TPMT testing offers a cost-effective, high-yield strategy to enhance patient safety and reduce preventable healthcare burden. These findings support more systematic integration of pharmacogenomic testing into routine thiopurine prescribing in Australia.

Severe thalassemia remains a significant public health concern in Southeast Asia. Prenatal screening is an effective strategy for early detection and prevention. This study aimed to determine the prevalence of severe thalassemia and assess the performance of prenatal screening at the Siriraj Thalassemia Center, Siriraj Hospital, Thailand. A retrospective review was conducted using data from January 2018 to December 2023. A total of 18,976 pregnant women underwent initial screening with mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and hemoglobin (Hb) typing. Of these, 12,499 tested positive. Complete screening data from 6,698 male partners identified 18.3% of couples as high-risk. Deoxyribonucleic acid (DNA) analysis and prenatal diagnostic testing were performed for at-risk pregnancies. Among high-risk couples, 75.2% of fetuses were identified by DNA analysis as being at risk for severe thalassemia, and 34.2% were confirmed as affected. The distribution of severe thalassemia types included Hb Bart's Hydrops Fetalis (15.8%), homozygous β-thalassemia (1.6%), and β-thalassemia/Hb E disease (16.8%). The most frequent α-thalassemia genotype in Hb Bart's cases was homozygous α⁰-thalassemia (--^SEA/--^SEA; 96.3%). The most common β-thalassemia mutation was a 4-base pair deletion at codons 41/42 (-TTCT; 40.2%). DNA testing for α-thalassemia showed 100% specificity and positive predictive value (PPV). For β-thalassemia, the sensitivity, specificity, PPV, and negative predictive value (NPV) were 97.6%, 98.9%, 96.1%, and 99.3%, respectively. The findings underscore the effectiveness of prenatal screening and diagnosis in identifying severe thalassemia, highlighting their importance for informing prevention strategies and guiding public health planning in high-prevalence settings.