Cts-Clinical and Translational Science最新文献

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.

Increasing antimicrobial resistance poses a serious challenge for the treatment of Shigella infections, and there is an urgent need for alternative antibacterial treatments. We conducted a clinical trial to investigate the efficacy of oral tebipenem pivoxil, compared to intravenous ceftriaxone, in Bangladeshi children with shigellosis. Using demographic data of 2249 Bangladeshi children with suspected shigellosis, population pharmacokinetic (PK) simulations were conducted to simulate tebipenem PK profiles in children with the proposed dosing regimen. Subsequently, the model predictions estimated each virtual participant's fraction of time over the 3-day treatment period during which simulated free tebipenem plasma concentration was above the minimum inhibitory concentration (fT > MIC). Variability associated with the prevalence of different Shigella species in Bangladeshi children and the MIC distributions were incorporated. Shigella treatment effect was assumed for participants that had fT > MIC for at least 40% of the 3-day treatment period (40% fT > MIC). The probability of achieving 40% fT > MIC was 86.4% for 4 mg/kg tebipenem pivoxil three times daily (TID) dosing and 92.4% with 3 mg/kg tebipenem pivoxil four times daily (QID) dosing. Lastly, the probability of tebipenem pivoxil being non-inferior to ceftriaxone, in a clinical trial containing 66 participants per arm, was evaluated for two dosing regimens. Three levels of ceftriaxone resistance were simulated to examine how dynamic ceftriaxone resistance may impact the trial outcome. Our findings suggest that more frequent tebipenem pivoxil dosing may increase the chance of producing treatment effects, contribute valuable insights to inform dosing strategy selection, and demonstrate a workflow that can be adapted to other drugs and diseases.

Funding freezes can strike active clinical trials without warning. Participants still need care. Science still needs integrity. This paper offers a practical, seven-day playbook for safely pausing active clinical trials when funding stops.

Cannabidiol (CBD) use has increased in America due to its widespread availability. Cannabidiol is metabolized by multiple polymorphic enzymes including CYP3A, CYP2C9, and CYP2C19. We sought to evaluate the genotype-specific adverse events and pharmacokinetic profiles of cannabidiol, 7-OH cannabidiol (an active metabolite), and 7-COOH cannabidiol. We completed a secondary analysis of an open-label, fixed-sequence, single-center study of cannabidiol in 33 healthy subjects. Patients first received a single dose of cannabidiol 5 mg/kg orally with serial plasma concentrations measured. Later, patients were titrated to 5 mg/kg twice daily for 14 days to reach steady state with serial plasma concentrations measured. CYP3A, CYP2C9, and CYP2C19 genotypes were assessed. Pharmacokinetic parameters were calculated by noncompartmental analysis. Diarrhea was observed more frequently in individuals with both CYP3A5 poor metabolism and CYP2C19 intermediate/normal metabolism (39%) compared to individuals with other genotypes (7%, p = 0.0463). Individuals with both CYP3A5 poor metabolism and CYP2C19 intermediate/normal metabolism had increased 7-OH cannabidiol and 7-COOH cannabidiol exposure at steady state. Cannabidiol parent drug exposure varied by CYP2C19 metabolizer status, with lower cannabidiol exposure and parent to metabolite ratios in intermediate metabolizers after single dose (p = 0.014) and at steady state (p = 0.0033). Similar CYP2C19 genotype-specific exposure was observed in an external validation cohort. Minor differences in exposure of cannabidiol and its metabolites were observed between CYP3A5 and CYP2C9 genotype groups. Significant changes in pharmacokinetics were observed between CYP2C9, CYP2C19, and CYP3A5 genotype groups. Future studies should assess whether pharmacogenomics can predict intestinal concentrations of CBD, its metabolites, and diarrhea.