Cts-Clinical and Translational Science最新文献

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.

Oxaliplatin-induced peripheral neuropathy (OIPN) causes numbness and pain in the limbs, often leading to interruption of chemotherapy and representing a significant clinical problem. Previous basic studies have suggested that the dipeptidyl peptidase-4 (DPP-4) inhibitor alogliptin may prevent OIPN. To evaluate whether concomitant use of DPP-4 inhibitors could prevent the development of OIPN in clinical practice, we retrospectively analyzed data from 1180 patients who initiated oxaliplatin treatment at Kyushu University Hospital between January 1, 2009 and December 31, 2019. The primary endpoint was the occurrence of OIPN of any grade. Kaplan-Meier analysis with cumulative doses demonstrated a significantly lower incidence of OIPN in the DPP-4 inhibitor group (p = 0.0422). After propensity score matching to adjust for patient backgrounds, the protective association remained significant (p = 0.0389). Furthermore, Cox proportional hazards analysis incorporating gender, age, regimen, and concomitant DPP-4 inhibitor use as covariates confirmed that DPP-4 inhibitor use was an independent protective factor for OIPN (HR = 0.690; 95% CI, 0.490-0.972; p = 0.034). These findings suggest that concomitant use of DPP-4 inhibitors may moderate the development of OIPN in patients receiving oxaliplatin.

Early-phase trials often struggle to detect treatment effects due to small sample sizes and substantial patient heterogeneity. While randomization is the standard for balancing treatment arms, many trials fail to account for key prognostic factors, potentially reducing statistical power and introducing bias. We surveyed 113 randomized oncology trials on ClinicalTrials.gov and found that established prognostic variables across cancer types, such as albumin, chloride, and Eastern Cooperative Oncology Group (ECOG) performance status, were frequently underutilized as randomization factors, despite being routinely collected at baseline. To address this, we evaluated a prognostic model-based randomization strategy using the Real-wOrld PROgnostic score (ROPRO), which integrates 27 baseline variables into a single continuous risk score across cancer indications. Using semi-synthetic simulations, we compared ROPRO-based randomization to ECOG randomization for detecting treatment effect across survival models, treatment effect sizes, and levels of patient heterogeneity. ROPRO consistently improved statistical power and reduced required sample sizes across treatment effect sizes (HR = 0.5, 0.6, 0.7) and survival models at different shapes. Power advantages ranged from +1 to +11 percentage points, with the greatest gains observed at moderate sample sizes. These findings support the use of prognostic model-informed randomization strategies in early-phase oncology trials, particularly in the context of FDA's Project Optimus, which emphasizes the need for finding optimal doses and regimens prior to registration trials.

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.

Clinical PGx practice guidelines (PGx guidelines) may have limited generalizability for "marginalized" groups. We proposed the five-step Real-World Data for Genome-Guided Prescribing (ReGGRx) framework and, using All of Us research program (AoU) data, examined its ability to estimate disparities in concordance with and benefit from PGx guidelines for CYP2C19 testing when choosing antiplatelet and antidepressant drugs. The selected measures were intended to identify disparities in avoiding drug failure independent of following PGx guidelines, the odds of avoiding drug failure with PGx concordant treatment, and the degree to which "marginalized" groups (i.e., groups underrepresented in biomedical research [UBR] and with indeterminate CYP2C19 phenotypes) benefit from PGx concordant treatment, when compared with "non-marginalized" groups (i.e., non-UBR and known CYP2C19 phenotypes). Our findings identified disparities in the antidepressant cohort with UBRs (32% of cohort) having a lower odds of avoiding drug failure. For both cohorts, a lower probability of avoiding drug failure was observed in the indeterminate phenotype group (1% of cohorts) than in the known phenotype group, indicating a need to better characterize rare or ancestry-specific risk alleles. With PGx concordant treatment, negative equal opportunity difference values suggested that the UBR group was less likely to avoid drug failure than the non-UBR group. Overall, our findings illustrate the promise of the ReGGRx framework to assess PGx guideline generalizability and produce evidence for use in drug policy decisions.

Denosumab is a monoclonal antibody targeting the receptor activator of nuclear factor kappa-b ligand widely used for the prevention of skeletal-related events in patients with bone metastases. This Phase 1 randomized, double-blind, two-arm, parallel-group study assessed the equivalence in pharmacokinetics (PK) and compared the pharmacodynamics (PD), safety, and immunogenicity of the proposed biosimilar RGB-14-X and reference denosumab in healthy males. Participants were randomized 1:1 to a single subcutaneous 60 mg dose of RGB-14-X or reference denosumab, with 252 days of follow-up. Primary PK endpoints were maximum observed serum concentration (C_max) and area under the concentration-time curve from time 0 to last quantifiable concentration (AUC_0-last) and extrapolated to infinity (AUC_0-inf). Secondary objectives were to compare additional PK parameters, safety and tolerability, PD and immunogenicity between groups. Of 165 participants randomized, 162 (98.2%) completed the study. The geometric mean ratios and corresponding 90% confidence intervals of RGB-14-X versus reference denosumab for C_max, AUC_0-last, and AUC_0-inf were within the pre-specified range of 0.80-1.25, demonstrating equivalence. No notable differences were observed in secondary PK or PD parameters between groups; maximum reduction in concentration of the bone resorption marker serum C-terminal telopeptide of type I collagen (CTX) and the extent and duration of reduction in CTX levels over time were similar. RGB-14-X was well tolerated with a similar safety profile to reference denosumab. No anti-drug or neutralizing antibodies were detected in either group. RGB-14-X demonstrated biosimilarity to reference denosumab, with equivalent PK and similar PD, safety, and immunogenicity outcomes in healthy males.

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.

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.

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.