Cts-Clinical and Translational Science最新文献

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.

Pre-therapeutic UGT1A1 genotyping is increasingly performed in patients receiving irinotecan, as its active metabolite SN-38 is primarily cleared through UGT1A1-mediated glucuronidation. Patients with the UGT1A1*28/*28 genotype exhibit reduced UGT1A1 activity, leading to increased SN-38 exposure and a higher risk of adverse events such as neutropenia and diarrhea. Although sacituzumab govitecan contains the same active metabolite as irinotecan, routine UGT1A1 genotyping prior to treatment with this drug is not yet standard practice and is not included in its product information. The aim of this study was to assess whether pre-therapeutic UGT1A1 genotyping may also benefit patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative and triple-negative breast cancer who are treated with sacituzumab govitecan. A literature search was conducted to identify relevant studies assessing the impact of UGT1A1 genotyping on the safety and efficacy of sacituzumab govitecan treatment. A meta-analysis was performed on selected studies. Additionally, a pharmacological analysis was performed using public data comparing SN-38 levels in patients treated with sacituzumab govitecan to those receiving irinotecan. The meta-analysis shows that grade ≥ 3 adverse events, including neutropenia, febrile neutropenia, and diarrhea, occurred more frequently in patients with the *28/*28 genotype. Furthermore, a statistically significant increased risk was found for developing grade ≥ 3 diarrhea or febrile neutropenia in this group. Although the meta-analysis was underpowered due to small sample sizes, the pharmacological analysis demonstrated higher SN-38 levels in patients treated with sacituzumab govitecan, supporting the rationale for UGT1A1 genotyping in this context.

Irinotecan (CPT-11) is a prodrug of the topoisomerase I inhibitor SN-38 used in the treatment of metastatic carcinomas of the colon or rectum. The clinical utility of this drug is hindered by debilitating side effects, most notably, severe gastrointestinal toxicity, which affects up to 40% of patients. Although the accumulation of SN-38 in intestinal enterocytes, following biliary secretion and microbial metabolism of its glucuronide metabolite, is believed to be a critical preceding event to CPT-11-induced toxicity, the transport mechanism involved in this process remains incompletely understood. Here, we tested the hypothesis that the organic anion transporting polypeptide OATP2B1 is an intestinal uptake transporter of SN-38 and a critical determinant of CPT-11-induced toxicity. Mice with Oatp2b1 deficiency experienced milder diarrhea and reduced changes in their intestine length, a known injury marker, compared to wild-type mice when subjected to CPT-11 treatment. These observations were confirmed by a histological examination indicating that damage to intestinal enterocytes was more severe in wild-type mice. The phenotypic alterations in Oatp2b1-deficient mice occurred without substantial changes in measures of systemic exposure to the parent drug, SN-38, or its glucuronide conjugate. Collectively, our study indicates that plasma concentrations of SN-38 are a poor predictive biomarker of CPT-11-induced gastrointestinal toxicity and provides an incentive for the future development of intervention strategies aimed at increasing the tolerance to this clinically important drug with the use of OATP2B1 inhibitors.

Fluoropyrimidines are a vital component of chemotherapy regimens. Deleterious DPYD variants reduce activity of dihydropyrimidine dehydrogenase, the rate-limiting enzyme of fluoropyrimidine catabolism, resulting in reduced fluoropyrimidine clearance and elevated risk of life-threatening toxicities. DPYD genotype-guided fluoropyrimidine therapy can mitigate the risk of severe life-threatening toxicities, but adoption of testing globally has been limited. We developed a 91-item survey investigating global DPYD implementation strategies to gain insight into common practices and successful strategies. The survey was disseminated to Pharmacogenomics Global Research Network Implementation Working Group members consisting of 54 health care sites across 15 countries. Survey responses were received from 28 sites (52%) across 9 countries. Over 80% of sites implemented, or planned to implement, a preemptive testing strategy (i.e., before a fluoropyrimidine is administered) leveraging the electronic health record (EHR) to disseminate DPYD results to providers. All sites created infrastructure to support DPYD testing (e.g., order sets, EHR decision support), but 70% of sites indicated reliance on clinicians to remember test ordering. Only 2 sites reported high DPYD testing rates (> 75%) among patients planned to receive a fluoropyrimidine. Most sites (57%) used in-house clinical laboratories that tested for the majority of DPYD Tier 1 variants. Among sites that had implemented DPYD testing, the median turnaround time was 10 days. Few sites indicated that a high percentage (> 75%) of DPYD results were returned before fluoropyrimidine administration. Our results suggest that additional implementation strategies are needed, addressing barriers and facilitators of DPYD testing.

Pharmacogenomics (PGx) is a rapidly evolving field that aims to personalize medicine by identifying genetic variations that influence drug response. While next-generation sequencing (NGS)–based applications are not yet widely adopted in clinical routine, this study aimed to validate 9 genes of the NGS-based Ion AmpliSeq Pharmacogenomics Panel on 28 samples with known diplotypes for routine clinical implementation at Bumrungrad International Hospital (BIH). The panel was evaluated for accuracy (> 96.77%), sensitivity (100%), specificity (> 95.31%), positive predictive value (PPV; > 90.63%), negative predictive value (NPV; 100%), and reproducibility (> 99.85%). A novel bioinformatics pipeline, BIH-protocol, was specifically developed and designed to mitigate errors across all measurement metrics, ensuring reliability and accuracy of test results, even in individuals with complex genetic backgrounds. These results demonstrate 100% precision and reliability of the Ion AmpliSeq Pharmacogenomics Panel together with BIH-protocol for genetic variation detection. These findings demonstrate the panel's suitability for integration into routine clinical practice and its potential to advance personalized medicine.

While the subcutaneous (SC) route of administration (RoA) is more patient-centric and cost-effective than the intravenous (IV) RoA, the Switch-to-SC paradigm has been employed in oncology antibody drug development. T cell engagers (TCEs) are typically highly potent and efficacious at low doses, supporting their suitability for the Direct-to-SC in FIH paradigm. This perspective discusses anticipated clinical pharmacology challenges associated with the Direct-to-SC in FIH paradigm and provides potential solutions to address the challenges.