Cts-Clinical and Translational Science最新文献

Broadly neutralizing antibodies (BNAb) are capable of neutralizing multiple HIV-1 strains through the targeting of conserved epitopes. This study's objective was to quantify the pharmacokinetic (PK) parameters describing the distribution and elimination of the BNAb VRC07-523-LS in people with HIV (PWH), and to identify the influence of viral load on VRC07-523-LS elimination. The PK of VRC07-523-LS was assessed in participants with and without HIV after intravenous or subcutaneous administration. A Bayesian strategy was utilized to estimate VRC07-523-LS PK parameters, leveraging a previously published study in adults without HIV. The effects of static viral loads on VRC07-523-LS exposure and time to a target trough serum concentration of 1 mg/L was then evaluated using clinical trial simulations. VRC07-523-LS serum concentrations were described by a two-compartment model with first order absorption from the subcutaneous site. Typical clearance was estimated as 99.3 mL/day, which increased to a maximum of 6.46-fold higher with viremia. Clinical trial simulations without viremia showed that a 700-2100 mg dose of VRC07-523-LS is expected to remain above the IC₅₀ of 0.055 mg/L beyond 52 weeks. With a viral load of 30,000 copies/mL, a 2100 mg dose of VRC07-523-LS is expected to result in 90% of participants having a concentration below 1 mg/L by 18.6 weeks, a decrease of 42 weeks compared to aviremic patients. Mechanistic modeling offers the ability to identify HIV viral load effects on BNAb PK and can improve BNAb dosing, especially with consideration of acute versus maintenance treatment.

Pharmacokinetics (PK) has long been differentiated from pharmacodynamics (PD) and biomarkers, yet this distinction undervalues PK's translational relevance. In this Perspective, we propose that PK itself functions as a biomarker that bridges dose, exposure, and response. Using examples from target-mediated drug disposition, antidrug antibodies, cerebrospinal fluid PK, high-dose methotrexate therapy, and anti-infective pharmacology, we illustrate how PK serves as a measurable, predictive, and actionable biomarker that informs drug development, guides decisions, and advances precision medicine.

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.

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.

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.

Paclitaxel (Taxol) is a widely used anticancer agent that undergoes extensive hepatic metabolism and that causes a debilitating, dose-limiting peripheral neurotoxicity. We previously reported that the uptake of paclitaxel in hepatocytes and dorsal root ganglion neurons, the site of injury within the nervous system, is mediated by the organic anion transporting polypeptides OATP1B1 and OATP1B3 (Oatp1b2 in rodents), transporters that are highly sensitive to pharmacological inhibition. To facilitate future screens of chemical libraries to identify modulators and imaging-based drug distribution studies, we explored the utility of PB-Gly-Taxol and PB-GABA-Taxol, derivatives of paclitaxel linked to the coumarin-derived fluorophore Pacific Blue, as in vitro and in vivo substitute biomarker probes of paclitaxel. Transport studies in transfected HEK293 cells revealed efficient uptake of these PB-taxoids by human and murine OATP1B/Oatp1b-type transporters, with up to 100-fold increases in uptake relative to values observed in vector control cells, and inhibition of this transport by known inhibitors. Although cell viability assays demonstrated lower cytotoxicity of both PB-taxoids (IC₅₀: 13~80 nM) against a panel of breast cancer cell lines, ensuing investigations confirmed their ability to induce peripheral neurotoxicity phenotypes in mice (p < 0.05), in an Oatp1b2-dependent manner, to the same extent as paclitaxel. These findings imply that PB-taxoids mimic the transport and toxicokinetic features of paclitaxel, and these agents thus offer potential as fluorescent imaging tools for exploring drug-drug interaction liabilities and paclitaxel-related toxicity profiles that involve OATP1B/Oatp1b-type transporters.

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.

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.

The Ministerial Ordinance on Good Post-Marketing Study Practice for Drugs was amended by the Ministry of Health, Labour and Welfare (MHLW) in 2018 to clearly define post-marketing database studies (DBS) as a measure of pharmacovigilance activities for approved medical products in Japan. This review describes and characterizes DBS in the landscape of post-marketing safety/effectiveness investigations of approved medical products in Japan for the past 6 years. New drugs and regenerative medical products approved by MHLW between January 1, 2019, and December 31, 2024, were included (N = 697). Of the total 572 planned post-marketing surveillances, 91 (15.9%) DBS were identified. The percentage of DBS initially decreased from 2019 to 2021 and then increased to 18.9% by 2024. Compared with other drugs, DBS were less likely planned for orphan (10.5%) and pediatric (7.4%) drugs. Control arms were used in 71.4% of DBS. The safety specifications evaluated in DBS using administrative data tended to focus on specific types of conditions, such as those related to the circulatory system. The findings suggest that DBS has begun to increase in recent years while highlighting challenges in accessing fit-for-purpose data and the need for appropriate pharmacoepidemiologic methods to support comparative evaluations. Access to large sample sizes provides DBS several advantages, including utility for evaluation of rare adverse events and the ability to establish a control group. Multi-sector and multi-stakeholder efforts may have the potential to further advance the utilization of real-world data in post-marketing benefit/risk investigations of medical products.

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.