Eltrombopag is an orally active thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia. The purpose of this randomized study is to evaluate the bioequivalence of test and reference eltrombopag olamine tablets in healthy Chinese subjects after consuming a low-calcium, high-fat, high-calorie breakfast. This was a single-center, randomized, open-label, two-sequence, two-period crossover study. Enrolled subjects were randomly divided into two groups at a 1:1 ratio, with each group randomly receiving either the test or reference eltrombopag olamine tablets per period. The washout period was set to 14 days. The concentration of eltrombopag in plasma was quantified using validated liquid chromatography-tandem mass spectrometry. Safety assessments were conducted throughout the entire trial. This study ultimately included 36 healthy subjects. The geometric mean ratio for maximum plasma concentration between the test or reference eltrombopag olamine tablets was 92.68%; the geometric mean ratio for the area under the concentration-time curve from the time zero to the last measurable concentration was 97.15%; for the area under the concentration-time curve from the time zero to infinity, the geometric mean ratio was 97.30%. The geometric mean ratios and their 90% confidence intervals for the key pharmacokinetic parameters fell within the range of 80.00-125.00%. Within the safety data set of 36 subjects, adverse events were reported in nine subjects, totaling 14 occurrences. All reported adverse events were Grade 1, and no serious adverse events occurred. These findings indicate that a single oral administration of the test eltrombopag is bioequivalent to the reference eltrombopag in healthy subjects after consuming a low-calcium, high-fat, high-calorie breakfast, with both formulations exhibiting a favorable safety profile. These results support the therapeutic interchangeability of the test formulation with the reference product, offering a reliable alternative for clinical use. This trial was registered at the Drug Clinical Trial Registration and Information Disclosure Platform ( http://www.chinadrugtrials.org.cn , CTR20230598) and ClinicalTrials.gov ( https://clinicaltrials.gov , NCT06768619).

This study evaluated the pharmacokinetics (PK), safety, and tolerability of TV-44749 in patients with schizophrenia or schizoaffective disorder. TV-44749 is a novel, long-acting, subcutaneous (SC) olanzapine injection designed to leverage the benefits of long-acting injectable treatment, reduce the risk for post-injection delirium/sedation syndrome (PDSS), and maintain the efficacy of olanzapine. In this open-label phase I study, patients completed an oral olanzapine treatment period followed by administration of TV-44749 single doses (SD cohort; 318 mg, 425 mg, or 531 mg) or multiple doses (MD cohort; three consecutive monthly doses of 283 mg or 566 mg). For the SD cohort, the follow-up period was up to 84 days (i.e., day 85) after TV-44749 administration. Patients in the MD cohort received TV-44749 on days 1, 29, and 57 over an 84-day treatment period and were followed until the end of the study. Evaluations included PK, adverse events (AEs), clinical assessments, and injection-site pain. A total of 71 (SD, 42; MD, 29) patients each received ≥ 1 dose of TV-44749. Both cohorts had overall similar baseline characteristics. Following subcutaneous administration, TV-44749 reached clinically relevant plasma concentrations (≥ 10 ng/mL) within 1-2 days, with a maximum observed plasma drug concentration (Cmax) within 11-14 days, followed by a sustained release profile over the dosing period of 1 month. The mean beta half-life values ranged from 5 to 10 days, and the mean apparent terminal half-life range was 11-17 days. The systemic exposure (Cmax and area under the plasma concentration-time curve (AUC)) of olanzapine and its two major metabolites, 10N‑glucuronide and N-desmethyl olanzapine, increased in an approximate dose-proportional manner over the clinically relevant dose range of 283 mg through 566 mg. The relative bioavailability of TV-44749 SD and MD compared with oral olanzapine after single or multiple doses was 112% (90% confidence interval (CI) 97, 129%) and 95% (90% CI 86, 106%), respectively. There were no grade ≥3 adverse events, no serious treatment-related adverse events, no suspected or confirmed post-injection delirium/sedation syndrome events, and no deaths. TV-44749 administration resulted in a sustainedrelease profile and comparable exposure to daily therapeutic doses of oral olanzapine over a monthly dosing interval. The TV-44749 systemic safety profile was consistent with approved oral olanzapine. The local tolerability was acceptable, and there were no PDSS events. These results contributed to the dose selection of TV-44749 in a phase III study evaluating its efficacy and safety in adults with schizophrenia (SOLARIS; NCT05693935).

Osteoporosis, a common condition of low bone mineral density (BMD), significantly increases fracture risk. Denosumab and alendronate are both established anti-resorptive therapies, yet their comparative effectiveness remains inconsistent across studies. The aim of this meta-analysis was to systematically evaluate the efficacy of denosumab versus alendronate for improving BMD at multiple skeletal sites in osteoporosis patients, aiming to provide evidence for clinical decision making. Multiple databases were searched for relevant randomised controlled trials published in English (as of November 2024). The primary outcomes were mean change of BMD at different skeletal sites. Data were pooled using fixed- or random-effects models to determine the mean differences (MDs) and 95% confidence intervals (CIs) for various BMD in patients treated with denosumab in comparison to patients treated with alendronate. This meta-analysis included thirteen randomized controlled trials (RCTs) with a total of 3364 patients and follow-up periods ranging from 6 to 24 months, and the overall quality of the studies was relatively high. The results demonstrated that denosumab was more effective than alendronate in increasing BMD at the lumbar spine (LS), femoral neck (FN), distal radius (DR), and total hip (TH) in osteoporosis patients and high-risk populations. Subgroup analysis revealed that postmenopausal women experienced greater improvements in BMD at the LS (p < 0.001) at 6 months, and at the FN (p < 0.001) at 24 months, comparedwith non-postmenopausal subjects. Denosumab was more effective than alendronate in increasing BMD. However, all the included randomised controlled trials (RCTs) carried a risk of bias, and the patient sample sizes were relatively small. Therefore, further studies with larger sample sizes and better methodological rigor are needed to confirm these findings. CRD420250655676.

This analysis aimed to evaluate the efficacy of brexpiprazole 2 or 3 mg/day for the treatment of agitation associated with dementia due to Alzheimer's disease, on the basis of pooled clinical trial data. Data were pooled from two similarly designed, phase 3, 12-week, multicenter, randomized, double-blind, placebo-controlled trials of fixed-dose brexpiprazole in participants in care facilities or community-based settings who had agitation associated with dementia due to Alzheimer's disease. Efficacy outcomes included Cohen-Mansfield Agitation Inventory (CMAI) total score (which measures the frequency of 29 different agitation symptoms), Clinical Global Impression-Severity of illness (CGI-S) score, CMAI factor scores (aggressive behaviors, physically nonaggressive behaviors, and verbally agitated behaviors), and response rates. A sensitivity analysis included a third trial with flexible dosing. In total, 621 participants were randomized (brexpiprazole, 368; placebo, 253), and completion rates were 320/368 (87.0%) and 225/253 (88.9%), respectively. Mean (SD) baseline CMAI total scores were: brexpiprazole 76.9 (17.2) points and placebo 75.5 (18.0) points. Over 12 weeks, CMAI total scores improved by least squares mean (SE) - 22.8 (0.8) points for brexpiprazole and - 18.3 (1.0) points for placebo, with a least squares mean difference between treatment arms of - 4.50 points (95% CI - 6.90 to - 2.10; p < 0.001; Cohen's d 0.30). CGI-S, CMAI factor, and response analyses also showed greater improvement with brexpiprazole versus placebo. The sensitivity analysis was supportive. Brexpiprazole 2 or 3 mg/day reduced agitation symptoms compared with placebo over 12 weeks in this large, pooled sample of participants with dementia due to Alzheimer's disease. ClinicalTrials.gov identifiers: NCT01862640, NCT03548584, and NCT01922258.

Insulin aspart-szjj (MERILOG™) is a biosimilar of the reference rapid-acting insulin analog, insulin aspart, and is approved for the same indication as reference insulin aspart: to improve glycemic control in adult and pediatric patients with diabetes mellitus. The physicochemical characteristics of insulin aspart-szjj were similar to reference insulin aspart, and the pharmacodynamic and pharmacokinetic equivalence of the agents has been shown in patients with type1 diabetes. Insulin aspart-szjj demonstrated clinical efficacy similar to that of reference insulin aspart in patients with type1 or type2 diabetes and was generally well tolerated in this population. The tolerability, safety, and immunogenicity profiles of insulin aspart-szjj were similar to those of reference insulin aspart. The role of insulin aspart in the management of diabetes mellitus is well established, and insulin aspart-szjj provides an effective biosimilar alternative for patients with diabetes mellitus requiring reference insulin aspart.

Discrete choice experiment (DCE) is increasingly recognized for its utility to elicit patient preferences in benefit-risk (BR) evaluation, particularly when options entail complex tradeoffs. This rimonabant case study focused on the methodology and versatility of DCE to elicit patient preferences for anti-obesity drugs. This study aimed to demonstrate the application of DCE as a tool to capture patient preferences concerning the BR profile of rimonabant, focusing on attribute-based choices, preference elicitation, experimental design, quantitative analysis, and practical application. A DCE was conducted involving standard steps: identifying attributes and levels, constructing choice sets, designing the questionnaire, and analyzing responses. Two benefit and three risk attributes important to theBR profile of anti-obesity drugs were selected basedon their significance to patients from published literature. Responses were analyzed using probit regression to quantify the preference for each attribute. Preference weights, derived from DCE, were combined with efficacy and safety data from clinical trials to estimate the utility function and probability of treatment selection. Lastly, the generated marginal rates of substitution (MRS) were used to present the extent to which patients were willing to trade off benefits to avoid risks. The coefficients from the probit model indicated that psychiatric conditions (i.e., mild anxiety to severe depression) significantly impacted treatment preference, followed by cardiovascular conditions, weight loss, and gastrointestinal conditions. On average, rimonabant was preferred over placebo 67% of the time. On the basis of MRS, to avoid a 1% increase of psychiatric condition, patients would be willing to forgo a 3.9% reduction in number of people achieving 10% weight loss, or a 0.44 level of improvement in high-density lipoprotein cholesterol, which elucidates how patients value benefits and risks when deciding on a treatment. This case study reaffirmed the utility of DCE as a valuable tool for BR evaluations, which aligned with what patients deemed important. The case study demonstrated essential attributes for anti-obesity medications. The methodological rigor and flexibility of DCE provided a robust framework for understanding, quantifying and analyzing preferences. The integration of elicited patient preferences, utility functions, and relevant clinical data offered quantitative insights into the structured BR assessment for regulatory decision-making and beyond.

The PROVENT study demonstrated the efficacy and safety of a single 300-mg dose of AZD7442 (tixagevimab/cilgavimab) for pre-exposure prophylaxis of COVID-19 in at-risk individuals. Here we report an analysis of repeat dosing of intramuscular AZD7442 300and 600mg from the PROVENT sub-study. The sub-study enrolled eligible participants from the parent study, creating four sub-study groups. Group 1 received AZD7442 300 mg in PROVENT followed by one 300-mg dose in the sub-study (10-14 months apart). Group 2 received placebo in PROVENT followed by two AZD7442 300-mg doses 6 months apart in the sub-study. Group 3a received AZD7442 300 mg in PROVENT followed by one 300-mg dose and two 600-mg doses 6months apart in the sub-study. Group 3b received placebo in PROVENT followed by one 300-mg dose and two 600-mg doses 6 months apart in the sub-study. The primary endpoint was safety. Secondary endpoints included pharmacokinetics and anti-drug antibody (ADA) responses. Adverse events (AEs) and serious AEs (SAEs) were reported in 75.7-81.5% and 13.2-16.8% of participants, respectively. AZD7442-related AEs, SAEs, and AEs of special interest occurred in 1.4-5.3%, 0-0.2%, and 0-5.3% of participants, respectively, and 3.9-6.7% experienced ≥ 1 cardiac and/or thromboembolic SAE. AZD7442 serum concentrations were dose-dependent with minimal accumulation following redosing, and 4.1-10.7% had treatment-emergent ADAs to AZD7442. AZD7442 safety, pharmacokinetic, and ADA response profiles were similar regardless of repeat dosing schedule, and consistent with single-dose study data. These results may support future use of long-acting antibodies. NCT04625725.

Using valproate during pregnancy carries risks of major congenital malformations and neurodevelopment disorders. Women with epilepsy and pregnancy plans should switch to an alternative and safe epilepsy management strategy. The present healthcare database study aimed at identifying treatment patterns that lead to successful epilepsy management and their associated factors, in females of childbearing potential (FCBP) after valproate discontinuation. FCBP who had been using valproate for epilepsy and discontinued its use (index date) between 2014 and 2017 were identified in the French and UK databases, Système National des Données de Santé/ Clinical Practice Research Datalink (SNDS/CPRD) and followed-up for 1 year. Clusters that most likely reflected a 'success' in epilepsy management were identified using a partition-around-medoids clustering algorithm. Success was defined on the basis of a combined approach including no valproate reintroduction and no negative medical parameters during follow-up. Baseline factors associated with successful/unsuccessful clusters were assessed in SNDS. A total of 7345/358 (SNDS/CPRD)FCBP diagnosed with epilepsy were included, of whom 67.3%/49.4% identified in successful clusters. The three most frequent clusters were 'predominantly no antiseizure medication (ASM)' (27.7%/20.9%), "predominantly monotherapy with another ASM' typically lamotrigine or levetiracetam (25.5%/20.7%), and 'predominantly return to valproate monotherapy' (17.5%/24.0%). Factors most strongly associated with no reintroduction of valproate were closer medical supervision (OR = 2.30), valproate dose-tapering prior discontinuation (OR = 2.40), pregnancy at index date (OR = 1.96), levetiracetam or lamotrigine delivery in the 90-days pre-index date (OR = 1.81, OR = 1.54). Factors most strongly associated with reintroduction of valproate included: older age (OR = 0.49 for [40-49] versus [13-29] year old), longer duration of epilepsy (OR = 0.63 for ≥ 5 versus < 1 year of history). Around half of women discontinued valproate successfully, especially if young, with a stabilised disease, with one quarter switching to monotherapy with another ASM, mainly lamotrigine or levetiracetam. Risk factors for unsuccessful discontinuation were identified, which may be useful as 'warning signs' to identify patients who need close follow-up during valproate discontinuation.

SCT510 is a proposed biosimilar of bevacizumab (Avastin®), a monoclonal antibody that targets vascular endothelial growth factor. This analysis aimed to characterize the population pharmacokinetics of SCT510, a bevacizumab biosimilar, and its reference product(Avastin®) in healthy subjects and patients with advanced non-squamous non-small cell lung cancer. Secondary objectives were to evaluate the pharmacokinetic similarity between the two drugs and to investigate the effects of factors, including alanine transaminase, creatinine clearance, and age, on their pharmacokinetic profiles. The population pharmacokinetic model was developed by pooling intensive pharmacokinetic data from a phase I trial in healthy male subjects with sparse pharmacokinetic data from a phase III trial in patients with non-squamous non-small cell lung cancer, utilizing a non-linear mixed-effects modeling (NONMEM) approach. A total of 2647 serum concentration data from 399 subjects were included in the population pharmacokinetic analysis. A two-compartment model with linear elimination adequately described the pharmacokinetic data for both SCT510 and Avastin®. The final model identified albumin, body weight, creatinine clearance, sex, study drug (SCT510 vs Avastin®), and subject type (healthy vs patient) as statistically significant covariates. Furthermore, the analysis confirmed the pharmacokinetic similarity of SCT510 and Avastin®, as no substantial differences in exposure were observed after single or multiple doses in either healthy subjects or patients. Finally, covariates such as alanine transaminase, creatinine clearance, and age were found to have no clinically relevant impact on the pharmacokinetics of either drug. SCT510 and Avastin® demonstrated comparable population pharmacokinetic profiles, supporting the biosimilarity of SCT510 to its reference product. The analysis also indicated that no clinically relevant differences in exposure were observed for either agent across a wide range of hepatic or renal function, or age. These findings collectively support that no dose adjustment is necessary for these factors. NCT05113511, NCT03792074.