Cts-Clinical and Translational Science最新文献

Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate (ADC) composed of the DM4 payload conjugated to a folate receptor α (FRα)-targeting antibody via the cleavable sulfo-SPDB linker. MIRV targets and binds to FRα with high affinity and specificity, releasing the DM4 payload intracellularly following MIRV-FRα complex internalization and degradation. DM4 and its metabolite S-methyl-DM4 suppress microtubule dynamic instability, which triggers cell cycle arrest and apoptosis. Selective FRα-overexpression in ≥ 90% of epithelial ovarian tumor cells and its ability to internalize large molecules make it a highly attractive ADC target for epithelial ovarian cancers (including primary peritoneal and fallopian tube cancers). Although up to 80% of patients initially respond to platinum-based therapies, the majority of tumors will recur and become platinum-resistant. Unfortunately, platinum-resistant ovarian cancer (PROC) carries a poor prognosis with an overall survival of 12–14 months from the time of platinum-resistance, and prior to MIRV approval in 2022, little had changed in treatment options for decades. The MIRV Phase 3 registrational trial (MIRASOL) showed superiority of MIRV vs. chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan) in patients with high (≥ 75%) FRα-expression PROC, showing an objective response rate of 42% versus 16%, a median progression-free survival of 5.6 versus 4.0 months, and an overall survival of 16.5 versus 12.8 months. Here, we briefly review MIRV mechanism of action, pharmacokinetics, pharmacodynamics, and key clinical efficacy and safety data.

Poisoning among older adults poses unique challenges due to age-related physiological changes, polypharmacy, and comorbidities. As Thailand transitions to a super-aged society, this study characterizes poisoning patterns in Thai older adults to inform prevention strategies. This retrospective, cross-sectional study analyzed poisoning cases involving patients ≥ 60 years reported to the Siriraj Poison Control Center from 2020 to 2023. Data included demographics, comorbidities, exposure characteristics, clinical features, and outcomes. Among 5146 poisoning cases, 682 (13.3%) involved older adults (median age: 68.5 years). Females accounted for 50.4%, and the 60–69 age group was most affected (53.8%). Comorbidities, primarily cardiovascular diseases, were present in 58.9% of patients. Most exposures were unintentional (74.6%), with nonpharmaceutical agents (54.2%) slightly exceeding pharmaceuticals (45.8%). Common nonpharmaceutical exposures included venomous animals (15.8%), household products (10.2%), and insecticides or rodenticides (7.4%). The most common scenario for unintentional exposure to nonpharmaceuticals was “accidental ingestion of nonedible substances” (41%). Among pharmaceutical exposures, antipsychotics (12.5%), analgesics (8.4%), and cardiovascular agents (5.3%) were most frequent. Unintentional pharmaceutical poisonings (73%) often resulted from adverse drug reactions or interactions (56.8%) or wrong administration route (20.8%). The proportion of fatal cases declined from 2020 to 2023; however, this trend should be interpreted cautiously due to potential confounding factors. Overall, poisoning in Thai older adults is primarily unintentional and often linked to complex medication use and comorbid conditions. These descriptive findings provide baseline information to support future efforts in medication safety, environmental awareness, and mental health promotion for Thailand's aging population.

D-2570 selectively binds to the pseudokinase domain of tyrosine kinase 2, which mediates the downstream cytokine signaling pathways involved in immune regulation. The safety, tolerability, pharmacokinetics, and pharmacodynamics of D-2570 were evaluated in a randomized, double-blind, placebo-controlled phase I study conducted in healthy Chinese subjects. The study consisted of three parts: single ascending dose (D-2570: 3–48 mg once daily) study, multiple ascending dose (D-2570: 6–36 mg once daily for 10 days) study, and food effect (D-2570: 9 mg) study. D-2570 was rapidly absorbed, with peak plasma concentration at around 4 h and exposure increased sub-proportional across the dose groups. Following multiple dosing, mean terminal elimination half-lives at steady state ranged from 22.22 to 33.86 h, with modest area under curve accumulation (1.74- to 2.08-fold) showing no dose dependence. A high-fat meal increased area under the concentration time curve from time zero extrapolated to infinite time and maximum plasma concentration by 33% and 15% for the 9-mg dose, with no significant effect on median time to maximum concentration. The inhibitory effect of D-2570 on the release of interferon-gamma induced by interleukin-12/interleukin-18 increased dose-dependently in the range of 6–36 mg. No deaths or serious treatment-emergent adverse events occurred, and all the adverse events were Grade 1 or 2 in severity. D-2570 was well tolerated in healthy Chinese subjects, and its pharmacokinetic profile was characterized. These results provide the rationale for dose selection in future clinical trials and support advancing D-2570 as a potential treatment option for autoimmune diseases mediated by tyrosine kinase 2.

Trial Registration: Chinadrugtrials.org.cn (CTR20222168)

Clinical genomics and pharmacogenomics have largely remained separate fields, though some genetic variants have overlapping disease risk and drug implications. However, the extent of this overlap is not well studied. To explore this gap, we cross-referenced genes from the American College of Medical Genetics Secondary Findings v3.2 list with genomic databases and drug labeling to identify gene-phenotype pairs with overlapping clinical genomics and pharmacogenomic implications. We searched GeneReviews and PharmGKB (now called ClinPGx) for each gene-phenotype pair and reviewed the FDALabel database contraindications or warnings. Targeted therapies for specific germline/somatic variants were excluded. PGx-trained pharmacists and a genetic counselor classified gene-phenotype pairs into three levels: Level 1 (Food and Drug Administration's or guideline-driven recommendations), Level 2 (potential pharmacotherapy implication), and Level 3 (no/weak interactions). Among 97 gene-phenotype pairs reviewed, 22 (23%) were Level 1, 31 (32%) were Level 2, and 44 (45%) were Level 3. Pharmacotherapy implications included risks inferred by disease pathology (e.g., anticoagulants and hereditary hemorrhagic telangiectasia) and less obvious associations (e.g., Marfan syndrome and fluoroquinolones). Unrecognized medication implications may pose patient safety risks. Greater research, information consolidation and dissemination, and multidisciplinary collaboration among clinical genomics specialists, pharmacogenomic specialists, and other practitioners are essential as genetic testing becomes routine in clinical care.

The aim of this study was to describe self-reported use of medications with established pharmacogenetic guidance in the Our Future Health (OFH) cohort. We examined four key pharmacogenes—CYP2C19, CYP2C9, CYP2D6, and SLCO1B1—and medications supported by strong evidence for clinical actionability according to the Clinical Pharmacogenetics Implementation Consortium (CPIC). Self-reported medication use was summarized, concurrent use assessed, and findings stratified by age, sex, and ethnicity. We studied these data in 1.78 million OFH participants included in the June 2025 release. The cohort was 57.3% female, aged 18–95 years (mean 53.1 years), with 90.2% self-identifying as “White.” Eighteen medication groups were explicitly listed in the baseline questionnaire, enabling identification of exposure at group level rather than for individual drugs. Medication groups with pharmacogenetic relevance included antidepressants (selective serotonin reuptake inhibitors and tricyclics), statins, proton pump inhibitors, ibuprofen, opioids, clopidogrel, and warfarin. Overall, 25.2% of participants (N = 449,641) reported use of at least one such group. These users tended to be older, more frequently female, and reported more comorbidities than non-users. Concurrent exposure to two or more pharmacogenetically actionable medications metabolized by different genes was common, occurring in 37% of users. A substantial proportion of the OFH cohort therefore reported exposure to medications with pharmacogenetic guidance. Use was observed across all ages, with prevalence increasing with age. With continued expansion of the cohort and future linkage to prescribing records, OFH will provide a critical resource for population-scale pharmacogenetic research.

Amyloid-beta (Aβ) plaque brain clearance is one of the promising disease-modifying treatment approaches to slow cognitive decline in Alzheimer's disease (AD). ABBV-916, an anti-amyloid antibody, was being developed as an early AD disease-modifying treatment. A phase 1, randomized double-blind, placebo-controlled single ascending dose (SAD) study investigated the safety, tolerability, pharmacokinetics (PK), and immunogenicity of ABBV-916 in healthy participants. Five groups of participants were enrolled and randomized 6:2 to receive ABBV-916 (100, 300, 1000, or 3000 mg) or placebo by intravenous (IV) infusion or subcutaneous (SC) injection (300-mg dose only). After dosing, participants were followed for 20 weeks for assessments. Cerebrospinal fluid (CSF) samples were collected after dosing 1000 mg IV for determination of ABBV-916 levels in the CSF. ABBV-916 single doses up to 3000 mg were well tolerated in healthy participants. No clinically significant laboratory findings, amyloid-related imaging abnormalities, or serious adverse events were reported. The ABBV-916 PK profile exhibited dose-related increases in maximum concentration and area under the plasma concentration-time curve with terminal elimination half-life ranging from 29 to 40 days across the cohorts. The estimated absolute bioavailability after SC dosing was 51%. The average CSF-to-serum partition ratio was 0.12% (range 0.10%–0.21%). Positive anti-drug antibody was detected in < 7% of participants, which was transient, at low titer, and did not affect ABBV-916 PK. This study demonstrated desirable safety, tolerability, and PK profile of ABBV-916 after single-dose administration in healthy participants. The data supported further evaluation of ABBV-916 multiple IV and SC doses in patients with AD.

Recent updates in clinical guidelines and health authority guidance documents have aimed to standardize best practices for assessing renal function; however, it remains unclear whether the pharmaceutical industry has fully adopted these recommendations. This analysis aims to describe the current methodologies used to evaluate the impact of renal impairment (RI) on drug exposure and to inform dosing recommendations for patients with RI, providing insight into current industry practices and identifying potential areas for improvement. A list of new molecular entities (NMEs) approved by the US Food and Drug Administration between 2018 and 2024 was compiled, and the clinical development strategies for assessing the impact of RI on the pharmacokinetics and safety of these NMEs were reviewed. We reviewed 192 NMEs. In dedicated renal impairment studies, renal function was assessed by the estimated glomerular filtration rate (eGFR) in 60 studies, measured GFR in 1 study, and creatinine clearance in 31 studies. We also found that 6 NMEs—5 out of 162 NMEs with non-substantial renal excretion (RE) and 1 out of 30 NMEs with substantial RE required an actionable dosing recommendation for patients with mild RI. In contrast, for severe RI, we found that 47 NMEs—30 out of 162 NMEs with non-substantial RE and 17 out of 30 NMEs with substantial RE required an actionable dosing recommendation. The findings suggest that excluding mild RI patients from phase 2 and 3 studies is not required and highlight that industry must continue efforts to harmonize drug development with clinical guidelines.

Pharmacogenetics (PGx) applies knowledge of drug-gene interactions to maximize effectiveness and reduce toxicity of medications. PGx impacts the dosing of chemotherapy for gastrointestinal cancer, including fluoropyrimidines and irinotecan. However, pretreatment PGx testing is not routinely implemented due to barriers, including insufficient data surrounding counseling practices. This study assessed genetics knowledge and PGx attitudes in patients with gastrointestinal cancers. A survey was distributed to Penn Medicine Biobank and IMPACT-GI participants. Multivariable analysis was conducted to assess the influence of genetics knowledge and patient characteristics on attitudes toward PGx. 132 participants completed the survey, 69 (52%) female, 22 (17%) non-White, 50 (38%) colorectal and 40 (30%) pancreatic cancers. The mean genetics knowledge score was 2.67 ± 1.14 correct responses out of 4. Willingness to undergo pharmacogenetic testing was associated with higher genetics knowledge (β = 0.6, 95% CI [0.1, 1.0], p = 0.0132), being female (β = 1.1, 95% CI [0.0, 2.2], p = 0.0435), and higher self-reported health literacy (β = 2.2, 95% CI [0.9, 3.5], p < 0.001). Participants were less willing to undergo testing if they had health insurance concerns (β = −3.7, 95% CI [−5.8, −1.7], p < 0.001) or did not complete secondary education (β = −2.0, 95% CI [−3.5, −0.6], p = 0.006). Patients preferred providers to obtain consent and explain PGx's utility before testing. These findings provide initial patient-informed guidance for the implementation of pharmacogenetic testing in gastrointestinal cancer care and identify targets for patient education. As all survey respondents were research-engaged and from a single institution, the study population may not be widely generalizable.

Japan has faced persistent challenges of “Drug Lag” and “Drug Loss”, partly due to the regulatory requirement for Japanese Phase I studies prior to global trial participation. However, recent regulatory reforms have introduced flexibility, creating new opportunities for Japan to strategically contribute to global drug development. This study redefined the value of Japanese Phase I by evaluating three options during the early development phase: the Japanese Phase I waiver, the first-in-human study conducted in Japan, and multifunctional Japanese Phase I studies. We analyzed 12 internal cases of Japanese Phase I waiver consultations and conducted a nationwide survey at early phase clinical trial sites. Our findings highlight Japan's robust clinical trial infrastructure for early phase trials. Japanese clinical trial sites have not only accumulated extensive experience in early phase trials but have also conducted specialized evaluations and enrolled diverse populations (e.g., non-Japanese Asians, Caucasians, and patients). The cycle time analysis showed that trials in Japan could be initiated within globally competitive timelines, often faster than those in the EU. These strengths position Japan as a key location for first-in-human and early phase trials, enabling earlier access to investigational therapies and supporting global development strategies. We propose a flexible, case-by-case approach that leverages Japan's clinical research capabilities. This strategy not only preserves Japan's clinical trial infrastructure but also aligns with national initiatives to strengthen the “Drug-Discovery Ecosystem”. By integrating Japan into early phase development, pharmaceutical companies can accelerate global innovation while improving access to Japanese patients.

In clinical pharmacology trials, pharmacokinetic samples are typically collected via venipuncture by trained staff. However, recent advances in blood collection devices have enabled participant self-collection of samples. Here, we describe the feasibility of collecting dried blood from healthy volunteers using a microsampling device by comparing centanafadine concentrations from self-collected microsamples with those collected via venipuncture by phlebotomists in an exploratory phase 1 pharmacokinetic trial. High-performance liquid chromatography with tandem mass spectrometric (HPLC-MS/MS) bioanalytical methods were validated for both dried blood collected via microsampling and plasma, with all validation criteria successfully met. Concordance between venous and microsamples was evaluated using graphical analysis and Deming regression, based on data from two conventional phase 1 trials (samples collected by clinical staff) and an exploratory pharmacokinetic trial comparing staff-collected venous samples (visits 1 and 2) with microsamples collected by staff (visit 1) or self-collected by participants (visits 2 and 4). Deming regression revealed significant linear relationships between centanafadine concentrations from venous and dried blood samples in conventional trials, and between microsamples at visits 2 and 4 versus visit 1 in the exploratory pharmacokinetic trial (visit 2: self-collected under supervision, slope = 1.135; visit 4: self-collected at home, slope = 0.967). The bioanalytical method used for the measurement of centanafadine concentrations in dried blood collected by the microsampling device was successfully validated, and feasibility assessments resulted in concordance suggesting that it is suitable to collect centanafadine pharmacokinetic samples at home during the conduct of self-collection phase 1 pharmacokinetic trials.