Clinical Drug Investigation最新文献

Background and objective: 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.

Methods: 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.

Results: 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.

Conclusion: TV-44749 administration resulted in a sustained release 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).

Bumetanide nasal spray (ENBUMYST^™) is a loop diuretic developed by Corstasis Therapeutics for the treatment of oedema. It is designed as a short-term therapeutic option, with absorption via the nasal mucosa potentially offering more consistent or predictable bioavailability than oral administration, particularly in patients with gastrointestinal impairment. Bumetanide nasal spray received its first approval on 12 September 2025 in the USA for the treatment of oedema associated with congestive heart failure (CHF), and hepatic and renal disease, including nephrotic syndrome in adults. This article summarizes the milestones in the development of bumetanide nasal spray leading to this first approval for the treatment of oedema.

Background and objectives: Zongertinib is an irreversible tyrosine kinase inhibitor that selectively inhibits human epidermal growth factor receptor 2 (HER2) while sparing epidermal growth factor receptor (EGFR), minimizing related toxicities. This non-randomized, open-label, Phase I study evaluated the absorption, distribution, metabolism and excretion (ADME) of zongertinib (Part A) and its absolute bioavailability (F) (Part B) in healthy male volunteers.

Methods: In Part A, eight subjects received a single oral 60 mg dose of zongertinib (C-14)-solution containing radiolabeled [¹⁴C]zongertinib [3.7 MBq] and unlabeled drug. In Part B, seven subjects received an oral unlabeled zongertinib 60-mg film-coated tablet after fasting, followed by a 15-min intravenous (IV) infusion of 100 μg zongertinib solution (C-14), consisting of 10 μg [¹⁴C]zongertinib [~ 0.03 MBq] and 90 μg unlabeled drug. Plasma pharmacokinetics, excretion pathways, metabolism, and bioavailability were assessed. Safety was evaluated in both study parts.

Results: After oral dosing in Part A, peak plasma concentration occurred at a median of 1-h post-dose (range 0.5‒2.0 h). Mean recovery of the radioactive dose was 93.8%, primarily in feces (92.5%) and minimally in urine (1.30%). Unchanged zongertinib accounted for most circulating radioactivity (74.6%) in plasma and was the most abundant component in feces (31.4% of the dose) and urine (0.18% of dose). In vitro metabolism involved oxidation (48-62%), glucuronidation (13-25%), and glutathione conjugation (13-25%). In part B, the mean F of the oral tablet was 76.2%. Following IV administration, zongertinib showed low plasma clearance (106 mL/min) and a moderate volume of distribution of 138 L. Zongertinib had a manageable safety profile in both study parts.

Conclusions: Zongertinib was rapidly absorbed with high absolute bioavailability. The unchanged zongertinib was the predominant form in plasma and excreta, with fecal excretion as the main elimination pathway. Metabolism occurred primarily through oxidation, with minor contributions from glucuronidation and glutathione conjugation.

Clinical trial registration: Registered under identifier NCT05879991 (25 May 2023).

Background: SCT510 is a proposed biosimilar of bevacizumab (Avastin^®), a monoclonal antibody that targets vascular endothelial growth factor.

Objective: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Clinical trial registration: NCT05113511, NCT03792074.

Background and objectives: 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 300 and 600 mg from the PROVENT sub-study.

Methods: 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 6 months 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.

Results: 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.

Conclusions: 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.

Clinicaltrials:

Gov registration: NCT04625725.

Background and objective: Fixed-dose combinations (FDCs) of amlodipine and telmisartan are widely used for hypertension management owing to their efficacy and improved adherence. This study aimed to characterize the pharmacokinetics (PKs) of both drugs after a single oral dose of a single-pill FDC of amlodipine 5 mg/telmisartan 80 mg in healthy Korean males.

Methods: A total of 681 amlodipine and 1500 telmisartan plasma concentrations from 32 healthy Korean males were retrospectively obtained from a bioequivalence study. Noncompartmental analysis and population analysis were conducted using WinNonLin™ (Pharsight Corp., Mountain View, CA, USA) and NONMEM^® (ICON Development Solutions, Hanover, MD, USA), respectively. A two-compartment model with first-order absorption and elimination was selected for both drugs. Covariate screening using a stepwise approach evaluated 38 demographic and clinical factors.

Results: Amlodipine exhibited a longer half-life and a larger apparent volume of distribution than telmisartan. Telmisartan PKs showed high interindividual (45.9% for absorption rate constant, 45.3% for apparent volume of distribution of the central compartment [V₁/F], and 40.9% for apparent clearance [CL/F]), interoccasion (53.7% for V₁/F), and residual (80.3%) variabilities. Preliminary covariate analysis suggested that body surface area and age potentially influenced V₁/F and CL/F for amlodipine, while height, smoking status, and total bilirubin levels were associated with telmisartan V₁/F and CL/F.

Conclusions: To our knowledge, this is the first population PK study to characterize the PKs of amlodipine and telmisartan co-administered as a single-pill FDC and to identify preliminary covariates that may influence their PK profiles.

Background and objectives: The H018 tablet is an orally administered selective inhibitor of Janus kinase 1 and has been specifically developed for the treatment of rheumatoid arthritis. To our knowledge, this study is the first to investigate the safety, pharmacokinetics, and pharmacodynamics of H018 tablets after single and repeated administrations.

Methods: This study was a phase I, randomized, double-blind, placebo/positive drug-controlled trial. In the single-dose part, 58 healthy subjects received a single oral dose of 10, 20, 40, 80, 120, or 160 mg. In the multiple-dose part, 60 healthy subjects received an oral dose of 80, 120, 160, or 200 mg of H018 once daily for 7 consecutive days; an oral dose of 200 mg of filgotinib once daily for 7 consecutive days; or an oral dose of 100 mg of H018 every 12 h, with a total of 13 doses administered. Pharmacokinetic parameters were determined from H018 plasma concentrations through a non-compartmental analysis. The dose proportionality of H018 after individual doses and its pharmacodynamic, safety, and tolerability profiles were evaluated.

Results: In the single-dose part, the area under the plasma concentration-time curve and maximum plasma concentration did not exhibit a typical dose-exposure proportional relationship at increasing doses. Urine and feces were not the main excretion routes for H018, M10, and M8. A total of 42 metabolites were identified in plasma, and the parent drug H018 accounted for the highest proportion (69.66%), followed by metabolite M10 (15.57%). The proportions of all other metabolites in plasma were less than 10%. The maximum inhibition rate of phosphorylated signal transducer and activator of transcription 1 was achieved at 1 h after H018 administration, and the inhibition rate increased with the administered dose and plasma drug concentration. The plasma concentrations of H018, its metabolites, or the positive control drug (filgotinib) were undetectable during the multiple-dose phase. Comparable to the maximum phosphorylated signal transducer and activator of transcription 1 inhibition rate of filgotinib, the phosphorylated signal transducer and activator of transcription 1 inhibition rate was essentially reached or very close to the maximum value approximately 1 h after the first and last administrations of H018 tablets, and H018 showed favorable safety and tolerability profiles.

Conclusions: H018 tablets exhibited a rapid onset of action upon oral administration, and the peak inhibition rate was attained approximately 1 h after administration. H018 demonstrated favorable safety and tolerability profiles within the tested dose range, showing potential as a therapeutic option for rheumatoid arthritis treatment.

Background and objectives: 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.

Methods: 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.

Results: 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).

Conclusions: 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.