Clinical Drug Investigation最新文献

CT-P39 [Omlyclo^® (omalizumab-igec)] is a biosimilar of the reference monoclonal anti-immunoglobulin E (IgE) antibody omalizumab. It is approved for use in all indications for which reference omalizumab is approved, including allergic asthma, chronic rhinosinusitis with nasal polyps, chronic spontaneous urticaria (CSU) and (in the USA) IgE-mediated food allergy. CT-P39 has similar physicochemical and pharmacodynamic properties to those of reference omalizumab, and the pharmacokinetic equivalence and comparability of the agents has been demonstrated in healthy volunteers and patients with CSU, respectively. CT-P39 demonstrated clinical efficacy equivalent to that of reference omalizumab in patients with CSU and was generally well tolerated in this population. The tolerability, safety and immunogenicity profiles of CT-P39 were similar to those of reference omalizumab, and switching from reference omalizumab to CT-P39 appeared to have no impact on efficacy or safety. The role of reference omalizumab in the management of allergic asthma, chronic rhinosinusitis with nasal polyps, CSU and IgE-mediated food allergy is well established and CT-P39 provides an effective alternative for patients requiring omalizumab therapy.

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.

Background and objective: Lazertinib, a potent and irreversible third-generation oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has shown promising efficacy and favorable tolerability in EGFR-mutated non-small cell lung cancer (NSCLC). On the basis of in vitro findings, lazertinib is primarily metabolized by glutathione conjugation via glutathione-S-transferase mu 1 (GSTM1), occurring via enzymatic activity of GST or non-enzymatic processes, as well as through cytochrome P450 3A4. Here, we report the effect of GSTM1 on lazertinib pharmacokinetics (PK) using clinical evaluations.

Methods: The effect of GSTM1 on lazertinib PK was evaluated in multiple phase 1 pharmacology studies. Clinical studies (NCT03556436, NCT04410081, and NCT05076877) involving healthy adult participants given lazertinib were analyzed on the basis of GSTM1 genotype (null [i.e., no expression] or non-null [i.e., expression]).

Results: In a clinical study where participants were genotyped and analyzed to determine the association of lazertinib plasma maximum concentration (C_max) and area under curve (AUC) with a panel of genes known to affect PK, GSTM1 genotype showed a statistically significant association with AUC. Compared with null GSTM1 participants, non-null GSTM1 participants had relatively lower plasma exposure owing to increased GSTM1-mediated clearance. The mean single-dose and steady-state plasma C_max and AUC of lazertinib was 1.1- to 1.8-fold and 1.4- to 2.2-fold higher in null GSTM1 participants, respectively. The safety profiles of lazertinib were generally comparable across null and non-null GSTM1 participants.

Conclusions: Overall, GSTM1 status affected lazertinib PK in healthy participants and hence further research is warranted to determine the magnitude of PK differences and whether they are clinically meaningful in the NSCLC patient population intended to be treated with lazertinib.

Background and objectives: Bacopa monnieri is a plant used in Ayurvedic medicine with traditional uses for memory and cognitive function. The objective of this study was to examine the effects of supplementation with a Bacopa monnieri extract (Bacumen^®) on cognitive function, stress, and fatigue in adults with self-reported memory and attention problems.

Study design: Two-arm, 12-week, parallel-group, randomized, double-blind, placebo-controlled trial.

Methods: Overall, 101 volunteers aged 40-70 years with self-reported memory and attention problems were supplemented with 300 mg daily of a Bacopa monnieri extract (Bacumen^®) (n = 50) or a placebo (n = 51). Outcome measures included several computer and researcher-administered cognitive tasks assessing verbal learning, attention and working memory (primary outcome measures) and self-report measures assessing memory, mood, and fatigue (secondary outcome measures). Changes in blood concentrations of brain-derived neurotrophic factor, malondialdehyde, and acetylcholine esterase activity were also examined. Cognitive assessments, blood collections and self-reported questionnaires were completed in person on day 0 and week 12. Moreover, self-report questionnaires were completed online at weeks 4 and 8. Participants, researchers and the statistician were blinded until all data was collected and a blind review was completed.

Results: Of the 101 participants randomized, 87 participants completed the study, 47 in the placebo group and 40 in the Bacopa monnieri group. On the basis of complete data collected from 87 participants, there were no between-group differences in changes in the primary outcome measures comprising verbal learning (p = 0.391), attention (p = 0.713), and working memory (p = 0.610). However, in the Bacopa-supplemented participants, there were greater reductions in overall self-reported stress reactivity (p = 0.03); and fatigue and stress levels after exposure to a cognitive-demanding computer task (secondary outcome measures). There were no group differences in changes in blood concentrations of measured markers. Bacopa monnieri supplementation was generally well-tolerated, with no serious adverse reactions, although there was a greater frequency of self-reported adverse reactions in the Bacopa monnieri group (p = 0.024), primarily comprising digestive complaints and headaches.

Conclusions: The results from this study indicate that compared with the placebo, Bacopa monnieri supplementation for 12 weeks did not result in greater improvements in cognitive performance. However, stress reduction and anti-fatigue effects were identified, which requires investigation in future trials.

Clinical trials registration number: Australian New Zealand Clinical Trials Registry (ANZCTR)-ACTRN12623000475640.

Background: 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.

Methods: 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 (AUC_last) of methylphenidate PR formulation to methylphenidate IR being between 80 and 125%. Adverse events (AEs) were documented.

Results: 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 AUC_last 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.

Conclusions: The methylphenidate PR oral suspension and chewable tablet formulations are bioequivalent in terms of the total extent of exposure (AUC_last) to methylphenidate IR tablets and are tolerable in healthy adults.

Background: Despite international evidence demonstrating pre-emptive pharmacogenetics (PGx) screening is cost effective or cost saving in preventing serious or fatal toxicities, it is not routinely adopted in Australia. This study evaluated the cost effectiveness of PGx screening versus standard of care (SOC) among patients with cancer undergoing fluoropyrimidine-based treatment (FP) in Australia.

Methods: From the Australian healthcare perspective, we developed a cohort-based state transition model in TreeAge Pro 2024. The model used PACIFIC-PGx trial data for the PGx arm and literature-based inputs for the SOC arm. Patients transitioned between four health states (full-dose, reduced-dose, treatment termination or death) over two treatment cycles each corresponding to a standard 3-week period. Outcomes included the incremental cost-effectiveness ratio (ICER) per quality-adjusted life years (QALYs) gained, per adverse event averted, and per hospitalisation avoided. Deterministic and probabilistic sensitivity analyses (DSA, PSA) evaluated the effects of varying assumptions and the uncertainty associated with input parameters.

Results: PGx screening yielded incremental QALYs of 0.05 at an additional cost of $274.25 AUD (Australian dollars), resulting in an ICER of $6014.5 AUD per QALY gained compared to SOC. DSA showed the model's outcomes remained robust, with the ICER staying below the specified threshold of $50,000 AUD under a ± 20% variation in input parameters. PSA suggested PGx screening was favourable in 97.6% of iterations.

Conclusion: This Australian single-arm study demonstrated that pre-emptive PGx screening prevents severe, fatal FP-related toxicities and hospitalisations and is likely to be cost effective. Our findings suggest the value of PGx screening and warrant implementation and reimbursement within Australian healthcare settings.