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.

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. 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. 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. 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.

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. 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. 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. 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.

Fexinidazole, a nitroimidazole antiparasitic, has been approved to treat human African trypanosomiasis (HAT) worldwide. In vitro studies have shown that fexinidazole inhibits and weakly induces CYP3A4/5. In silico predictions indicated that fexinidazole, which has a significant intestinal and liver first-pass metabolism, could increase the exposure of a sensitive probe substrate of CYP3A4 by two-fold. Therefore, this study investigated the potential clinical drug-drug interactions (DDIs) of fexinidazole with CYP3A4 substrates. To assess the effect of fexinidazole on the pharmacokinetics of midazolam, a well-recognised sensitive CYP3A4 substrate (and its metabolites 1-hydroxy-midazolam and N-glucuronide-midazolam) in humans and to elucidate the underlying mechanism of the in vivo DDI. This was a phase I, open-label, single-centre, non-randomised, single-sequence, two-period, two-treatment crossover study. The study population consisted of 12 healthy male and female participants. The two treatment periods included Period 1, wherein a single midazolam dose was administered on Day 1, and Period 2, wherein fexinidazole was administered once daily from Day 1 to Day 5, with a single midazolam dose co-administered on Day 4. Key pharmacokinetic parameters of midazolam and its main metabolites, including the maximum plasma concentration (Cmax), area under the curve (AUC), and elimination half-life (t1/2z), were evaluated. Additionally, in vitro assessments (protein-binding and CYP enzyme induction studies) were conducted to investigate potential mechanisms contributing to the observed interaction. Contrary to the in vitro predictions, fexinidazole significantly reduced midazolam exposure in vivo, resulting in a reduction of 39% in Cmax, 57% in AUC, and 33% in t1/2z, without significant changes in tmax. Mechanistic studies ruled out reduced absorption and plasma protein displacement as potential causes. At clinically relevant concentrations, fexinidazole and M1 exhibited weak induction potential on CYP3A4/5 and no significant induction on other enzymes. Further, in vivo investigations on midazolam metabolites confirmed that CYP3A4/5 induction by fexinidazole was the primary mechanism, increasing the first-pass metabolism and clearance of midazolam. The metabolic ratios of 1-hydroxy-midazolam and N-glucuronide-midazolam were increased by 1.63-fold and 1.24-fold, respectively. Steady-state exposures of fexinidazole and its metabolites M1 and M2 were consistent with those previously assessed in other clinical studies. While in vitro studies showed weak induction by fexinidazole and its metabolite M1, the clinical pharmacokinetic data provided stronger evidence, supporting the conclusion that fexinidazole is a moderate inducer of CYP3A4/5 in vivo. Thus, it is suggested to update the product information by including the potential for CYP3A4/5 induction in vitro, removing the risk of CYP3A4 inhibition in vivo, and adding clinical interaction data highlighting the risk of induction on drugs predominantly metabolised by CYP3A4/5. EudraCT No.: 2021-004533-36.

TONMYA™ is a sublingual eutectic formulation of cyclobenzaprine being developed by Tonix Pharmaceuticals for the treatment of various conditions, including fibromyalgia, post-traumatic stress disorder (PTSD), acute stress disorder, major depressive disorder, post-acute COVID-19 syndrome, alcohol use disorder, and agitation in Alzheimer's disease. The sublingual formulation was designed for rapid transmucosal absorption to produce diurnal variation in peak-to-trough drug concentrations, making it suitable for long-term bedtime use. On 15 August 2025, sublingual cyclobenzaprine was approved for the treatment of fibromyalgia in adults in the USA. This article summarizes the milestones in the development of sublingual cyclobenzaprine leading to this first approval for fibromyalgia.

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. In Part A, eight subjects received a single oral 60mg dose of zongertinib (C-14)-solution containing radiolabeled [14C]zongertinib [3.7MBq] 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 100μg zongertinib solution (C-14), consisting of 10μg [14C]zongertinib [~0.03MBq] and 90μg unlabeled drug. Plasma pharmacokinetics, excretion pathways, metabolism, and bioavailability were assessed. Safety was evaluated in both study parts. After oral dosing in Part A, peak plasma concentration occurred at a median of 1-h post-dose (range 0.5‒2.0h). 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 (106mL/min) and a moderate volume of distribution of 138L. Zongertinib had a manageable safety profile in both study parts. 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. Registered under identifier NCT05879991 (25 May 2023).

With shifting perceptions about the therapeutic potential of cannabis and evolving regulatory frameworks, global prescribing of medicinal cannabis is increasing. While some emerging evidence supports its use for conditions like multiple sclerosis and epilepsy, its efficacy and safety profile for the treatment of mental health conditions remains controversial and under-explored. Previous reviews found inconclusive evidence due to heterogeneity in study design and quality. Accordingly, this review was designed as a scoping review, consistent with established methodological frameworks to map and characterise all available randomised controlled trial (RCT) evidence in this emerging and heterogeneous field. It specifically sought to synthesise the highest-quality trial evidence to date, addressing the question: How effective is medicinal cannabis in treatingmental health conditions, as classified by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), and how safe and tolerable is it, as assessed through adverse events and treatment withdrawals? A scoping review was conducted comprising RCTs investigating medicinal cannabis for mental health conditions. Eligible studies were required to meet predefined inclusion criteria based on population, intervention, comparator, outcomes, and study design (PICOS framework). PubMed, Web of Science, and PsycINFO databases were searched, supplemented by citation tracking and Google Scholar, for studies published between 1980 and 2024. The search identified 8061 studies, with 28 RCTs meeting inclusion criteria across 12 DSM-5 mental health conditions. Indications most frequently studied were schizophrenia (n = 5), cannabis use disorder (n = 4), cocaine use disorder (n = 4), post-traumatic stress disorder (n = 3), anxiety disorders (n = 3), and opioid use disorder (n = 2); there were two trials in autism spectrum disorder and single trials in depression, attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, tobacco use disorder, and Tourette syndrome. Sample sizes ranged from 6 to 150 participants (median = 42), and follow-up durations from 1 day to 13 weeks (median = 6 weeks). Interventions included purified cannabidiol (CBD; single doses of 300-800 mg and daily regimens up to 1000 mg/day), nabiximols or other tetrahydrocannabinol (THC)/CBD oromucosal sprays (up to 113 mg THC/105 mg CBD per day), and smoked or vaporised cannabis flower of varying THC/CBD content. Findings showed substantial heterogeneity and variable quality, with some short-term benefits reported (notably in cannabis use disorder, autism spectrum disorder, and schizophrenia), but no trial demonstrated long-term efficacy. Despite growing interest, substantial heterogeneity limits current evidence for medicinal cannabis in mental health. This review highlights key gaps, underscoring the need for robust, well-powered RCTs with extended follow-up to clarify its role in the management of mental ill health.

This paper aims to introduce a new treatment strategy for salt-sensitive hypertension and heart failure (HF). Hypertension is very common and a major risk factor for cardiovascular disease, coronary heart disease, HF, and death. Yet neither hypertension nor HF are well controlled with the existing medications. Therefore, new means for their control should be pursued. Recently, β-arrestins have been investigated and shown to have beneficial effects in both hypertension and HF. β-Arrestins are a family of intracellular signaling proteins that play a role in the regulation of the G-protein-coupled receptors. The angiotensin II (Ang II) type 1 receptor (AT1R) is also a G-protein-coupled receptor mediating the adverse cardiovascular effects of Ang II. An agonist that activates the β-arrestin pathway downstream of the AT1R, such as TRV027, could act as a therapeutic agent by blocking the adverse effects of Ang II. Yet at present, the therapeutic effects of TRV027 are weak and short lasting. Therefore, there is an urgent need for the development of more effective and long-lasting TRV027 analogs. A review of the recent literature from 2019 to 2024 has disclosed that β-arrestins do possess beneficial effects in lowering hypertension and treating HF.

Various oral methylphenidate formulations are available to treat attention-deficit/hyperactivity disorder, but unmet needs still exist, particularly for individuals with swallowing difficulties or those requiring more flexible dosing options. Two phase 1 studies evaluated the comparative bioavailability and safety/tolerability of two prolonged-release (PR) methylphenidate formulations, an oral suspension and a chewable tablet, compared with an established immediate-release (IR) oral tablet formulation. Healthy volunteers were randomised to receive a single dose of methylphenidate PR oral suspension (total dose 60 mg; study 1) or chewable tablet (total dose 40 mg; study 2) and methylphenidate IR tablets (total dose 60 mg in study 1 and 40 mg in study 2) in a crossover manner, with a 7-day washout between treatment periods. Blood samples were collected over the 24-h post-administration period. Comparative bioavailability was defined as the 90% confidence interval (CI) of the relative mean plasma D-methylphenidate area under the plasma concentration-time curve from zero to last measurable concentration (AUClast) of methylphenidate PR formulation to methylphenidate IR being between 80 and 125%. Adverse events (AEs) were documented. In total, 24 individuals (mean age 39-42 years, approximately 50% male) were randomised in each study, of whom 23 received methylphenidate PR oral suspension in study 1 and 23 received methylphenidate PR chewable tablets in study 2; 24 received methylphenidate IR tablets in each study. The relative mean plasma D-methylphenidate AUClast ratios for methylphenidate PR formulation to methylphenidate IR tablets had 90% CIs of 82.30-87.18% in study 1 and 90.01-97.52% in study 2. Treatment-emergent AEs were reported in 26% and 22% of participants receiving the oral suspension and chewable tablets, respectively (versus 50% and 33% of those receiving the IR tablets in the respective studies). These AEs were typical of orally administered methylphenidate, mild in severity and, in general, resolved prior to study end. The methylphenidate PR oral suspension and chewable tablet formulations are bioequivalent in terms of the total extent of exposure (AUClast) to methylphenidate IR tablets and are tolerable in healthy adults.