Corticosteroids are effective anti-cancer agents for treating hematologic malignancies in children. However, avascular necrosis (AVN) is a common and debilitating adverse effect, leading to bone death and impacting long-term quality of life. This study aimed to uncover the genetic factors contributing to corticosteroid-induced AVN in a well-characterized cohort of pediatric cancer patients. We conducted a genome-wide association study (GWAS) on 972 patients, including 108 with AVN grade ≥2 and 864 dose-matched controls. The GWAS of 6.4 million genetic markers identified four significant AVN-associated loci (P < 5 × 10−8): WNT7B (OR = 9.2; 95% CI, 3.8-22.0), POGK (OR = 8.4; 95% CI, 3.6-19.5), ZNF37A (OR = 6.0; 95% CI, 2.9-12.5), and a synonymous variant in FAM240C (OR = 5.0; 95% CI, 2.6-9.5). A multi-marker predictive model combining single nucleotide polymorphisms (SNPs) and clinical factors showed an area under the ROC curve (AUC) of 78.7%, outperforming SNP-only (67.8%) and clinical-only (68.4%) models. The osteogenic processes regulated by WNT7B, part of the Wnt signaling pathway, may contribute to AVN-related disrupted bone development and repair. Similarly, POGK and ZNF37A, both containing the KRAB domain, are hypothesized to affect osteoblast differentiation and skeletal development in AVN. Developing a predictive model for individual susceptibility to corticosteroid-induced AVN will enhance the monitoring and management of corticosteroid use in children with cancer.
Dapagliflozin has demonstrated multiple benefits in clinical trials for heart failure with reduced ejection fraction (HFrEF), but older patients with multiple comorbidities were often excluded. This study aimed to evaluate the effectiveness and safety of dapagliflozin in a real-world population of HFrEF patients. This retrospective study included HFrEF patients from a tertiary hospital, who initiated dapagliflozin between January 202 and December 2022. The mean follow-up was 15.3 ± 8.3 months. Each patient served as their own control to compare left ventricular ejection fraction (LVEF), laboratory parameters, and time-dependent events, such as heart failure (HF) readmissions. A total of 155 HFrEF patients (mean age 68.5 ± 14.5 years; 75.5% male) were included. Of these, 47.1% had non-ischemic heart disease, 49.0% had type 2 diabetes mellitus, and most were on beta-blockers, loop diuretics and angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, or angiotensin receptor neprilysin inhibitor. LVEF improved from 29.2% to 34.3% (P < .001), with significant reductions in body weight and heart rate (P < .001). HF-related emergency room visits decreased (0.68 ± 1.06 to 0.58 ± 0.96; P = .329). Renal function declined, with glomerular filtration rate decreasing from 67.6 ± 25.2 to 55.2 ± 30.8 mL/min/1.73 m2 (P < .001), particularly in older patients (HR 1.033; 95% CI: 1.004-1.063) and those with higher baseline heart rate (HR 1.028; 95% CI: 1.011-1.045). Severe adverse drug reactions occurred in 3.9% of patients, with hypotension (12.9%) being the most common. In conclusion, dapagliflozin demonstrated a favorable safety profile and significant hemodynamic benefits, improving LVEF and stabilizing HF progression in a real-world HFrEF population.
According to the FDA Guidance for Industry on Clinical Drug Interaction (DDI) Studies with Combined Oral Contraceptives (COCs), sponsors are expected to conduct dedicated clinical DDI studies if in vitro findings suggest weak or moderate CYP3A induction, while concomitant use of COCs with strong inducers should be avoided. The guidance further suggests that a negative DDI result for drospirenone (DRSP) may be extrapolated to other progestins that are less sensitive to CYP3A modulation, such as levonorgestrel (LNG). This approach assumes that DDI-mediated changes in exposure directly translate into clinical efficacy across progestins. To evaluate the validity of this assumption, we established a quantitative link between dose, exposure, and response (Pearl Index [PI] and ovulation rate [OR]) via an integrated model-based meta-analysis, physiologically based pharmacokinetic, and pharmacokinetic/pharmacodynamic (PK/PD) modeling and simulation approach using data from 51 clinical studies in 36,040 women receiving LNG or DRSP. COCs containing LNG and DRSP were selected because they represent clinically relevant progestins at the lower and the upper end of the fraction metabolized via CYP3A4. The results of our analysis show a moderate correlation (Pearson's r = 0.52, 95% CI 0.46-0.58, P < 0.001) between PI and OR, which enables the use of OR as an ethically measurable endpoint, even at subtherapeutic doses/exposures, to predict efficacy outcomes. They further show that DDI-induced changes in exposure do not directly translate into clinical response. Therefore, DDIs with COCs should be interpreted in a PK/PD rather than a PK-only context. The quantitative framework developed in this study can serve as the scientific basis to do so.
Quetiapine, an atypical antipsychotic primarily metabolized by CYP3A4, exhibits altered pharmacokinetics (PK) in patients with liver cirrhosis and individuals with CYP3A4 polymorphisms. This study aimed to develop and validate a physiologically based pharmacokinetic (PBPK) model to predict the effects of hepatic impairment and CYP3A4*22 variants on quetiapine PK. A model was developed using data from healthy individuals administered a single 25 mg dose and validated against 19 independent clinical datasets. Subsequently, the model was adapted to simulate PK in patients with liver cirrhosis (Child-Pugh A, B, and C) and those with CYP3A4*1/*22 and *22/*22 genotypes. Simulation results showed a significant increase in systemic exposure and a corresponding decrease in apparent clearance as hepatic impairment worsened or in the presence of CYP3A4*22 alleles. Model-based dose adjustments were proposed and validated, effectively aligning drug exposure levels in specific populations with those observed in healthy controls. In severe cases (Child-Pugh C with CYP3A4*22/*22), only 5% of the standard dose was required to achieve reference exposure levels. This study demonstrates that PBPK modeling is a valuable tool for optimizing individualized dosing in patients with hepatic impairment or genetic variability. These findings offer clinically relevant insights for safer and more effective quetiapine therapy through evidence-based dose adjustments.
Cyclosporine (cyclosporin A or CsA), a clinically relevant but nonspecific inhibitor of hepatic organic anion transporting polypeptides (OATPs), is used for assessing transporter-mediated drug–drug interactions (DDIs) at varying dosing regimens. We developed a physiologically based pharmacokinetic model to reproduce CsA pharmacokinetics (PK) and effect of CsA on substrates of OATPs and cytochrome P450 (CYP)3A4. The model was built using intravenous and oral CsA clinical PK and DDI data in healthy volunteers. The model reproduces single- and multiple-dose clinical CsA PK from numerous studies with simulated/observed AUC and Cmax within 0.59-1.75 following oral CsA dosing. As an object of CYP3A4, the model reproduces the observed effect of ketoconazole and grapefruit juice on CsA PK. CsA inhibition constants against CYP3A4 and hepatic OATPs were estimated to reproduce clinical DDIs with CYP3A index substrate midazolam (MDZ) and OATP1B biomarker coproporphyrin-I, and confirmed with felodipine and pitavastatin, verifying the model for inhibition of hepatic CYP3A4 and OATPs in healthy volunteers. A review of clinical data herein indicates that most clinical DDI studies utilize a single dose of CsA and for certain clinical substrates, a counterintuitive decrease in half-life following CsA administration has been observed (similar to single-dose rifampin DDIs). Using the currently developed CsA model, we predicted the effect of various single- and multiple-dose CsA regimens against OATP1B substrate and MDZ models. Depending on the OATP1B substrate characteristics, 200 mg CsA twice daily or a single 600 mg dose reasonably mimic simulated continuous OATP1B inhibition and single-dose rifampin, albeit with predicted weak-to-moderate CYP3A4 inhibition.
Idecabtagene vicleucel (ide-cel, ABECMA) is an autologous, B-cell maturation antigen-directed, chimeric antigen receptor (CAR) T-cell therapy, which has demonstrated significantly improved progression-free survival (PFS) and overall response rate (ORR) in patients with triple-class-exposed relapsed/refractory multiple myeloma (TCE RRMM). Here, we characterize cellular expansion of ide-cel in vivo and further evaluate associations between cellular expansion and clinical efficacy and safety endpoints. The exposure parameters of ide-cel were evaluated through non-compartmental analysis methods using the time course data of CAR transgene copy numbers collected from the ide-cel arm of Study KarMMa-3 (NCT03651128). Multivariable regression analyses were conducted between the exposure parameters and clinical responses to characterize relationships between cellular expansion in vivo and clinical outcomes and to evaluate potential effects of covariates on the exposure–response (E-R) relationships. There appears to be lack of a strong association between actual ide-cel dose and cellular expansion at the dose range evaluated in Study KarMMa-3. The multivariable E-R regression models suggest positive relationships between cellular expansion and clinical efficacy and safety endpoints, with higher exposure associated with longer PFS, higher ORR, and higher rates of cytokine release syndrome requiring tocilizumab or corticosteroids. The current analyses do not identify any clinically relevant covariate effects on the E-R relationships. The positive exposure–response relationships were found to be overall similar between KarMMa-3 and a previous study KarMMa. The modeling analyses, paired with clinical data, support extending the dose range from previously approved 300-460 × 106 CAR+ T cells to 300-510 × 106 CAR+ T cells for TCE RRMM patients.
The neurokinin 3 receptor antagonist fezolinetant is an approved treatment for vasomotor symptoms due to menopause. The impacts of hepatic and renal impairment on the pharmacokinetics and safety of a single oral dose of fezolinetant 30 mg were investigated in two independent studies. The studies enrolled healthy women and women with mild or moderate hepatic impairment (defined by Child–Pugh classification) or mild to severe renal impairment (categorized by estimated glomerular filtration rate). Blood samples for fezolinetant and its metabolite, ES259564, were collected predose and up to 96 h postdose. Safety was assessed using treatment-emergent adverse events (TEAEs). Overall, 26 and 27 women were enrolled in the hepatic and renal studies. Fezolinetant exposure (area under the concentration–time curve from time of dosing to infinity [AUCinf]) was higher in those with hepatic impairment than women with normal function (geometric mean ratios [90% confidence interval]: mild/healthy control: 155.89% [108.04%-224.92%], moderate/healthy control: 196.11% [131.64%-292.15%]). The AUCinf results for ES259564 were similar between women who were hepatically impaired and of normal functioning. Renal impairment did not substantially increase the exposure of fezolinetant. However, those with moderate or severe renal impairment had higher AUClast (from time of dosing to last measurable concentration) results for ES259564 than healthy women (moderate/healthy control: 177.14 [120.02-261.44], severe/healthy control: 478.56 [347.93-658.22]). No serious TEAEs were reported in either study. In conclusion, hepatic impairment affects the metabolism of fezolinetant as shown by progressive increases in systemic exposure. Marginal impacts were noted in women with renal impairment.
Recognition of benefits and adverse effects of therapies in earlier clinical trial phases could improve the safety, efficiency, and cost of clinical trials. Using four clinical trials representing a diverse set of diseases and drug classes (EXSCEL: exenatide/GLP-1 RA, SUGAR-DM-HF: empagliflozin/SGLT2i, PRADA: epirubicin/anthracycline, and AMPLE: abatacept/immunomodulator and adalimumab/TNF inhibitor), we hypothesized that previously validated proteomic measures for cardiometabolic outcomes could enable the detection of beneficial and adverse drug effects in fewer participants over a shorter follow-up period. Changes in SomaSignalTM proteomic tests over time in response to treatment were assessed in the EXSCEL (baseline vs 1 year; once-weekly exenatide (EQW) (n) = 1812 vs control (n) = 1787), SUGAR-DM-HF (baseline vs 12 weeks and 36 weeks; empagliflozin (n) = 45 vs control (n) = 52), AMPLE (baseline vs 85 days and 1 year; abatacept (n) = 210, adalimumab (n) = 222), and PRADA (baseline vs 7-10 days and 3 months, n = 120) trial. Improvement of cardiovascular risk and cardiometabolic traits with EQW was detectable within 1 year (P = .002) in sample sizes significantly smaller than the original study. Cardio- and kidney-protective (P = .06, P = .037) effects of empagliflozin were detectable within 36 weeks in a small sample size (n ∼ 50). Abatacept and adalimumab treatment demonstrated significant improvements in cardiovascular risk (P ≤ .001, P ≤ .001) and cardiorespiratory fitness (P ≤ .001, P ≤ .001) within 85 days. In contrast, anthracycline treatment led to significant increases in heart failure mortality risk (P ≤ 0.001) and cardiovascular risk (P = .004) after the first cycle of chemotherapy treatment. These findings provide preliminary evidence that proteomics may provide a powerful tool for optimizing drug pipelines by predicting the effects of novel therapeutics in smaller, shorter trials.
The research aimed to develop a validated model for predicting the risk of linezolid-induced thrombocytopenia (LIT). An XGBoost model and SelectFromModel method were used to screen the important factors. Based on the selected features, five models—Logistic Regression, XGBoost, Random Forest, Naive Bayes, and Support Vector Machine—were established. Finally, the model results were interpreted using SHAP. In this retrospective study, 187 patients were enrolled, and the incidence of LIT was 35.8%. An XGBoost model was established with good performance, in which the AUCs of the training set and validation set were all 0.9. The duration of linezolid treatment, ICU admission time, low baseline platelet level, shock, and concomitant use of piperacillin-tazobactam were significant risk factors for LIT. A moderately raised level of platelet-large cell ratio, total bilirubin, and weight may help reduce the incidence of LIT.
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