Cts-Clinical and Translational Science最新文献

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection (LRTI) in infants worldwide. Nirsevimab, an extended half-life monoclonal antibody against RSV, is approved in China for the prevention of RSV lower respiratory tract disease in infants; however, global nirsevimab trials did not enroll Chinese infants. To inform the investigation of nirsevimab for the prevention of RSV LRTI in Chinese infants, this Phase I, randomized, placebo-controlled trial evaluated the pharmacokinetics (PK) and safety of nirsevimab in healthy Chinese adults. Participants were randomized 3:1 to a single 300 mg intramuscular dose of nirsevimab or placebo and were followed through 150 days post-dose. Serum nirsevimab concentrations were measured and PK parameters of maximum serum concentration (C_max), time to maximum concentration (t_max), and area under the concentration-time curve from time 0 to Day 150 (AUC_0–150) were estimated. Treatment emergent adverse events (AEs), clinical laboratory data, and vital signs were evaluated. Overall, 24 participants were randomized to nirsevimab (n = 18) or placebo (n = 6). Nirsevimab geometric mean (coefficient of variation [%CV]) C_max was 46.9 (21.7) μg/mL, median (range) t_max was 7.0 (4.9, 29.9) days, and geometric mean (%CV) AUC_0–150 was 4210.6 (13.6) μg·day/mL. Treatment-emergent AEs (all Grade 1 or Grade 2 in severity) were reported in 5/18 (27.8%) nirsevimab recipients and 2/6 (33.3%) placebo recipients. No serious AEs, new onset chronic disease, or deaths were reported. Overall, safety and PK outcomes were consistent with those observed in healthy adults in the USA, with no new safety concerns.

Electronic health records (EHRs), though they are maintained and utilized for clinical and billing purposes, may provide a wealth of information for research. Currently, sources are available that offer insight into the health histories of well over a quarter of a billion people. Their use, however, is fraught with hazards, including introduction or reinforcement of biases, clarity of disease definitions, protection of patient privacy, definitions of covariates or confounders, accuracy of medication usage compared with prescriptions, the need to introduce other data sources such as vaccination or death records and the ensuing potential for inaccuracy, duplicative records, and understanding and interpreting the outcomes of data queries. On the other hand, the possibility of study of rare disorders or the ability to link apparently disparate events are extremely valuable. Strategies for avoiding the worst pitfalls and hewing to conservative interpretations are essential. This article summarizes many of the approaches that have been used to avoid the most common pitfalls and extract the maximum information from aggregated, standardized, and de-identified EHR data. This article describes 26 topics broken into three major areas: (1) 14 topics related to design issues for observational study using EHR data, (2) 7 topics related to analysis issues when analyzing EHR data, and (3) 5 topics related to reporting studies using EHR data.

Despite the widespread use of currently available serum phosphate management options, elevated serum phosphate is common in patients with end-stage kidney disease on dialysis. Characteristics of currently available phosphate binders that lead to poor patient experiences such as large drug volume size of required daily medication (e.g., many large tablets) and adverse gastrointestinal effects may decrease compliance to labeled dosing instructions, thus decreasing their efficacy. Oxylanthanum carbonate is a new molecule yielding the same phosphate-binding capacity as lanthanum carbonate, but in a much smaller drug volume and tablet size. It is formulated as small tablets that can be easily swallowed. In a double-blind dose-escalation phase 1 study, healthy volunteers (n = 32) were randomly divided into four treatment arms and randomly assigned to receive oxylanthanum carbonate tablets or a placebo over a period of 4 days to evaluate safety, urinary and fecal excretion of phosphorus, and pharmacokinetics. Each treatment arm evaluated a different dose of oxylanthanum carbonate: 500, 1000, 1500, or 2000 mg three times a day (TID). The study drug was well-tolerated. Oxylanthanum carbonate effectively decreased dietary phosphorus absorption, demonstrated by decreased urinary phosphorus excretion and increased fecal phosphorus excretion. Systemic absorption of oxylanthanum carbonate was minimal, with lanthanum serum concentration values below the level of quantification (0.500 ng/mL) in all subjects receiving 500 mg TID and did not exceed 0.7 ng/mL at other doses. Future studies should evaluate and confirm the ability of oxylanthanum carbonate to reduce pill burden and improve dose administration, patient tolerability, adherence, and treatment outcomes.

Trial Registration: ClinicalTrials.gov identifier: NCT01560884

Mycophenolic acid (MPA) is commonly used to treat autoimmune diseases in children, and therapeutic drug monitoring is recommended to ensure adequate drug exposure. However, multiple blood sampling is required to calculate the area under the plasma concentration-time curve (AUC), causing patient discomfort and waste of human and financial resources. This study aims to use machine learning and deep learning algorithms to develop a prediction model of MPA exposure for pediatric autoimmune diseases with optimizing sampling frequency. Pediatric autoimmune patients' data were collected at Nanfang Hospital between June 2018 and June 2023. Univariate analysis was applied for feature selection. Ten algorithms, including Random Forest, XGBoost, LightGBM, Gradient Boosting Decision Tree, CatBoost, Artificial Neural Network, Grandient Boosting Machine, Transformer, Wide&Deep, and TabNet, were employed for modeling based on two, three, or four concentrations of MPA. A total of 614 MPA AUC_0-12h samples from 209 patients were enrolled. Among the 10 models evaluated, the Wide&Deep model exhibited the best predictive performance. The predictive performance of the Wide&Deep model using four and three blood concentration points was similar (R ² ≈ 1 for four points; R ² = 0.95 for three points). No significant difference in accuracy within ±30% was observed between models utilizing three and four blood concentration points (p = 0.06). This study demonstrates that in the Wide&Deep model, MPA exposure can be accurately estimated with three sampling points in children with autoimmune diseases. This model could help reduce discomfort in pediatric patients without reducing the accuracy of MPA exposure estimates in clinical practice.

Iruplinalkib (WX-0593), a selective oral ALK/ROS1 tyrosine kinase inhibitor, was approved in China as first-line therapy for ALK-positive non-small-cell lung cancer (NSCLC) and for the treatment of locally advanced or metastatic ALK-positive NSCLC that has progressed following crizotinib therapy. Pharmacokinetics (PK) data of iruplinalkib have been collected in healthy subjects and patient populations in several studies. We developed a population PK (PopPK) model for describing iruplinalkib plasma concentrations and for evaluating whether dose adjustments are necessary based on demographic factors or disease characteristics. Plasma concentration–time data were collected from 392 participants (16 healthy volunteers and 372 patients with solid tumors) who received single or multiple doses of iruplinalkib in four trials. Data were analyzed using non-linear mixed-effects modeling. Iruplinalkib plasma concentrations were best described by a two-compartment model with first-order absorption and first-order elimination. Baseline body weight, time-varying albumin, time-varying creatinine clearance, and time-varying lactate dehydrogenase were significant covariates of apparent clearance from the central compartment (CL/F) while baseline body weight was a significant covariate of apparent volume of the central compartment (V1/F). Given the small or modest effect of all statistically significant covariates on iruplinalkib exposure at steady-state, no covariate was expected to have clinically meaningful effects on iruplinalkib exposure. Furthermore, iruplinalkib absorption was delayed 0.472 h after meal, and K_a was 58.8% of that under fasting. However, there was no difference in exposure of iruplinalkib between the fasted and fed states. In conclusion, the PopPK model adequately describes iruplinalkib PK properties in Chinese healthy subjects and patients with solid tumors. No covariate had a clinically meaningful impact on iruplinalkib exposure. These results indicate that dose adjustment of iruplinalkib is not necessary, based on the aforementioned covariates, for ALK-positive NSCLC patients.

The feasibility of conducting a fully remote, interventional, phase II decentralized clinical trial (DCT) was investigated in major depressive disorder (MDD). Key learnings were collated to improve future DCTs. A double-blind, placebo-controlled, parallel-group, DCT enrolled adult MDD patients with inadequate response to first-line antidepressant monotherapy (ongoing ≥8 weeks) and a Montgomery-Åsberg Depression Rating Scale total score (MADRS) ≥22 at screening. Patients were randomized 1:1 to BI 1358894 125 mg or placebo daily for 6 weeks remotely. Safety parameters, primary end point (change from baseline in MADRS at Week 6), and patient experience were assessed. The DCT was considered feasible if the trial protocol could be successfully executed. Overall, DCT procedures were successfully executed per protocol. However, despite achieving a vast patient outreach, the trial was terminated early due to deficient enrollment. Of the 136 patients who consented for enrollment and underwent screening, 45 were randomized and 43 received treatment (BI 1358894, n = 20; placebo, n = 23); 97.7% of patients completed the trial. Patients had a mean (SD) age of 42.2 (13.1) years and most (83.7%) were female. Adverse events were reported by 86.0% of patients (BI 1358894, 90.0%; placebo, 82.6%). Most patients (88%) reported a positive experience with the DCT. Key learnings related to the impact of stringent eligibility criteria, recruitment optimization strategies, plus the benefits and limitations of digital technologies. A fully remote, interventional DCT was feasible in MDD, and was well perceived by trial participants. Learnings related to recruitment optimization and trial design should be considered for future interventional DCTs.

Denosumab is a human IgG2 monoclonal antibody against receptor activator of nuclear factor kappa-B ligand (RANKL) for the treatment of osteoporosis and bone loss. HLX14 is a proposed biosimilar of denosumab. This randomized, parallel-group, two-part, phase I study aimed to compare the pharmacokinetics, pharmacodynamics, safety, and immunogenicity of HLX14 with reference denosumab in Chinese healthy adult male participants. In Part 1, participants were randomized 1:1 and given HLX14 or reference denosumab sourced from the European Union (EU). In double-blind Part 2, participants were randomized 1:1:1:1 to receive HLX14 or denosumab sourced from the United States, EU, or China. All study drugs were administered via subcutaneous injection at a single dose of 60 mg. The primary endpoints were area under the serum drug concentration–time curve from time 0 to the last concentration-quantifiable time t (AUC_0–t), maximum serum drug concentration (C_max), and area under the serum drug concentration–time curve from time 0 to infinity (AUC_0–inf). Twenty-four participants were randomized in Part 1 and 228 in Part 2. The 90% confidence intervals of geometric mean ratio of AUC_0–t, C_max, and AUC_0–inf between HLX14 and denosumab from different sources fell within the pre-specified similarity margins of 0.80–1.25 (AUC_0–t, 0.91–1.13; C_max, 0.91–1.13; AUC_0–inf, 0.91–1.12), demonstrating pharmacokinetic similarity. No notable difference was observed among treatment groups in pharmacodynamics, safety, or immunogenicity. HLX14 demonstrated highly similar pharmacokinetic characteristics with comparable pharmacodynamics, safety, and immunogenicity to denosumab, supporting its further investigation as a potential denosumab biosimilar.

Autologous chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable response rates, yet its widespread implementation is hindered by logistical, financial, and physical constraints. Additionally, challenges such as poor persistence and allorejection are associated with allogeneic cell therapies. An innovative approach involves in vivo transduction of endogenous T-cells through the administration of CAR mRNA encapsulated in polymeric nanoparticles (NPs), resulting in transient CAR surface expression on circulating T-cells. This method presents a promising alternative, although the dose–exposure–response relationship of in vivo CAR-Ts remains poorly elucidated. The transient nature of CAR expression may necessitate repeated dosing, potentially introducing additional hurdles like cost and patient compliance. To address this issue, we have devised a translational pharmacokinetic–pharmacodynamic (PK–PD) model that characterizes the transient surface CAR expression following mRNA-encapsulated NP administration, leveraging in vitro and in vivo data alongside critical binding kinetic parameters sourced from literature. Our model adequately captures the transient surface CAR expression in both settings, while incorporating known physiological parameter values and exhibiting precise estimation of unknown parameters (coefficient of variation < 30%). Global sensitivity analyses underscore the significance of intracellular mRNA stability, highlighting the sensitivity of parameters linked to free intracellular mRNA concentration. Model-based simulations indicate that optimizing dose and dosing frequency can achieve sustained CAR expression, despite the transient protein expression characteristic of mRNA-based therapies. This mechanistic PK–PD model holds potential for integration into physiologically-based pharmacokinetic models, facilitating the translation of in vivo CAR-T-cell therapies from preclinical studies to human applications.

SGLT2 inhibitors show promise in reducing hospitalization for heart failure in diabetics, but their long-term effects and time-dependency remain unclear. We conducted a retrospective nested case–control study within a large type 2 diabetic cohort (n = 11,209) using electronic health records. Cases (heart failure hospitalization, n = 352) were matched to controls (n = 1372) based on age, sex, cohort entry date, and diabetes duration. Matched-set conditional logistic regression was used to estimate hazard ratios (HRs) for antidiabetic drug class and heart failure hospitalization risk. SGLT2 inhibitors were associated with a significant reduction in heart failure hospitalization risk (adjusted HR 0.56, 95% CI 0.38–0.82, p = 0.028). This protective effect appeared more pronounced with a longer duration of treatment, suggesting a potential cumulative benefit. Time-varying analysis within propensity score-matched cohorts revealed a progressive decrease in hospitalization risk with continued SGLT2 inhibitor use, indicating a strengthening effect over time (greedy nearest neighbor: HR 0.52, CI 0.31–0.87, p = 0.015; optimal matching: HR 0.54, CI 0.34–0.85, p = 0.008). While promising, further investigation with larger datasets is warranted to definitively confirm these findings.

Recent reports suggest that plasma riboflavin may serve as a biomarker for BCRP inhibition in humans. However, the clinical data supporting this claim have been limited, with only two studies showing modest increases in riboflavin levels after administration of a BCRP inhibitor. We have recently demonstrated that co-administration of 375 mg once daily (q.d.) cedirogant, an in vitro BCRP inhibitor, significantly increased rosuvastatin (an OATP1B1/1B3 and BCRP substrate) exposures but did not change the levels of the OATP1B endogenous biomarker coproporphyrin-I, demonstrating that cedirogant is a clinical BCRP inhibitor. Samples from this same cedirogant clinical drug–drug interaction study were utilized to test the hypothesis that endogenous plasma riboflavin is a biomarker of BCRP inhibition. Plasma riboflavin levels in the absence of cedirogant ranged from 1 to 10 ng/mL across the 11 participants analyzed with minimal (<20%) intrasubject variability over a 24-hour interval. Contrary to expectations, 375 mg q.d. oral administration of cedirogant did not increase riboflavin levels. These data strongly suggest that endogenous plasma riboflavin is not a viable biomarker for BCRP inhibition in humans.