Drugs in Research & Development最新文献

Background: SB17 is being developed as a biosimilar to ustekinumab reference product (RP), a human monoclonal antibody (IgG1 kappa immunoglobulin) that binds to the common p40 subunit of cytokines interleukin (IL)-23 and IL-12. Binding to this subunit prevents interaction with their receptor, resulting in modulation in the immune system responses that play a key role in inflammatory disease.

Objective: The objective of this study was to demonstrate structural, physicochemical, and biological similarity between ustekinumab RP and SB17 using various state-of-the-art analytical methods.

Methods: Comprehensive analytical characterization was conducted by the quality range and side-by-side comparison approach for SB17 versus the European Union (EU) and US ustekinumab RP using various analytical methods. Comparisons included purity, product-related impurity, charge heterogeneity, primary structure, posttranslational modification, higher-order structure, quantity, Fab-related biological activities (potency and binding activity), and Fc-related biological activities.

Results: On the basis of the analytical similarity assessment, the structural, physicochemical, and biological characterization results demonstrated that SB17 is comparable to the ustekinumab RP. In the structural aspects, it was confirmed that there is no clinically meaningful difference between posttranslational modification profiles and higher-order structures of SB17 compared with the ustekinumab RP. Product-related impurities in the form of aggregates were also confirmed to be similar. SB17 has lower acidic and basic variants compared with ustekinumab RP, owing to the difference in the producing cell line. Ustekinumab RP is expressed in an Sp2/0 cell line, whereas SB17 is expressed in CHO cell line. However, the difference between SB17 and ustekinumab RP in the charge variants is not considered to be clinically meaningful, since equivalent biological activity was observed. In the case of mechanism of action (MoA)-related biological activities, SB17 is highly similar to the EU and US ustekinumab RP with respect to overall critical and noncritical quality attributes analyzed. Moreover, similarity or lack of activity in Fc-related biological activities was also confirmed. On the basis of these results, SB17 is expected to have comparable safety and efficacy as compared with ustekinumab RP.

Conclusion: In summary, the overall analytical characterization and similarity assessment results show that SB17 is comparable to the EU and US ustekinumab RP in terms of structural, physicochemical, biophysical, and biological attributes.

Introduction: The high cost of trastuzumab (Herceptin^®) limits its accessibility for patients worldwide. Biosimilars, such as Tuznue^® (HD201), represent a promising alternative to improve access to this essential therapy for HER2-positive breast cancer. This study aims to assess the similarity of Tuznue^® with the reference product Herceptin^® through comprehensive analytical and biofunctional evaluations, ensuring similar quality, safety, and efficacy profiles.

Methods: Multiple analytical methods were performed to assess key quality attributes of Tuznue^® and Herceptin^®. Physicochemical properties, HER2 binding, anti-proliferative activity, antibody-dependent cellular cytotoxicity, complement dependent cytotoxicity, and Fc receptor binding were evaluated through various bioassays. Statistical analyses were conducted according to a risk-based tiered approach (Tiers 1-3) to demonstrate biosimilarity. The equivalence margin for critical quality attributes (Tier 1) was set at ±1.5 standard deviations from the reference product's mean.

Results: Tuznue^® showed highly comparable results to Herceptin^® across all evaluated biofunctional assays. HER2 binding affinity, inhibition of cellular proliferation, and antibody-dependent cellular cytotoxicity activity were equivalent between Tuznue^® and Herceptin^®, with 90% confidence intervals within predefined equivalence margins. No complement dependent cytotoxicity activity was observed for either product. Differences in glycosylation profiles were identified but did not affect critical biofunctional properties. Fc receptor binding remained consistent across all tested lots.

Conclusions: The comprehensive analytical characterization confirms the biosimilarity of Tuznue^® to Herceptin^®. This supports Tuznue^® as a safe and effective alternative, offering a more affordable option for patients and healthcare systems. Biosimilar development requires overcoming inherent challenges, particularly when reference products exhibit variability in quality attributes over time. Regulatory guidance and scientific rigor are essential to ensuring biosimilar similarity, facilitating broader patient access to life-saving therapies.

Introduction: In November 2018, the European Medicines Agency (EMA) restricted the use of fluoroquinolones (used by mouth, injections or inhalation) in the context of a referral due to long-lasting and potentially irreversible adverse drug reactions (ADRs). Fluoroquinolones should no longer be used to treat mild or moderate bacterial infections unless other antibacterials cannot be used.

Objectives: The first aim of our study was to analyze whether in the period before compared with after the referral the characteristics of spontaneous ADR reports related to fluoroquinolones differed and whether specific ADRs were more frequently reported for fluoroquinolones compared with cotrimoxazole. Secondly, we analyzed whether the ADR profile differed between individual fluoroquinolones. Finally, the number of fluoroquinolone reports was considered in relation to the number of outpatient drug prescriptions.

Methods: All spontaneous ADR reports from Germany received before the referral (01/2014-12/2019) and after the referral (01/2020-12/2022) for adults in which fluoroquinolones (n = 2575; n = 967) or cotrimoxazole (n = 299, n = 275) were reported as suspected/interacting were identified in the European ADR database, EudraVigilance. The ADR reports were descriptively analyzed concerning the reported characteristics. Odds ratios (ORs) and their 95% confidence intervals (CIs) were estimated by logistic regression analyses, which were performed to investigate whether aortic aneurysms, retinal detachments, cardiac arrhythmias, peripheral polyneuropathies, nervous system disorders, toxic liver diseases and non-traumatic injuries of muscles, tendons and synovialis were more frequently reported for fluoroquinolones compared with cotrimoxazole. Stratified analyses between fluoroquinolones were conducted by calculating ORs and their 95% CIs by using two-by-two tables. Reporting rates were calculated by dividing the number of fluoroquinolone reports by the number of fluoroquinolone prescriptions.

Results: Reporting rates of fluoroquinolones clearly increased until 2019 and decreased afterward. Only minor differences in the characteristics of fluoroquinolone reports (e.g., regarding the indications) were observed in reports received before and after the referral. In both periods, peripheral neuropathies, nervous system, and muscle and tendon disorders were more often reported for fluoroquinolones than cotrimoxazole. In the pooled fluoroquinolone-stratified analyses, (i) peripheral neuropathies and nervous system disorders were more frequently reported for ciprofloxacin, (ii) non-traumatic injuries of muscle, tendon, and synovialis were more often reported for levofloxacin, and (iii) cardiac arrhythmias and toxic liver diseases were more frequently reported for moxifloxacin compared with the other fluoroquinolones.

Conclusion: In accordance with a reminder s

Background: Efgartigimod, a human immunoglobulin G (IgG)1-derived Fc fragment targeting the neonatal Fc receptor, has been developed into intravenous (IV) and subcutaneous (SC) formulations for treating generalized myasthenia gravis (gMG) and other autoimmune diseases. Data in the Chinese population were not available to date, and while both formulations have been approved in the USA, the EU, Japan and China for the treatment of gMG.

Objective: We present the pharmacokinetic, pharmacodynamic, and safety of IV and SC PH20 efgartigimod in healthy Chinese participants.

Methods: In two independent, double-blinded, placebo-controlled, phase I studies of the IV and SC formulations of efgartigimod, healthy Chinese adults were randomized 3:1 to receive active treatment or matching placebo once every 7 days for four doses. Primary endpoints were pharmacokinetic parameters.

Results: After the fourth IV infusion, a mean maximum observed concentration (C_max) of 194 µg/mL was reached at the end of the 1 h infusion; the mean area under concentration-time curve from time zero to 168 h (AUC_0-168h) was 5300 µg × h/mL. After the fourth SC injection, a mean C_max of 42.1 µg/mL was achieved with a median T_max of 47.74 h; the mean AUC_0-168h was 4790 µg × h/mL. Maximal mean reductions from baseline in total IgG levels were reached approximately 24 days after the first dose (60.7%, IV formulation; 66.4%, SC formulation). Treatment-related adverse events (TRAEs) were reported in seven (58.3%) participants receiving SC efgartigimod, mostly injection-site reactions. No TRAEs or AEs of special interest were reported in the IV study.

Conclusions: The efgartigimod IV and SC pharmacokinetic, pharmacodynamic, and safety profiles in Chinese participants were similar to the known profiles in non-Chinese participants. Both formulations effectively reduced total IgG levels by a similar percentage.

Clinical trial registration: CTR20211952 and CTR20211805.

Background and objective: Paroxysmal nocturnal hemoglobinuria is a rare blood disorder characterized by life-threatening hemolysis and thrombosis. Complement C5 inhibitor therapy improves symptoms and life prognosis; however, it can result in insufficient hemolysis control, with residual intravascular hemolysis and extravascular hemolysis in some patients. Pegcetacoplan, the first complement C3 inhibitor approved for patients with paroxysmal nocturnal hemoglobinuria, targets both intravascular and extravascular hemolysis. This analysis evaluated population pharmacokinetic/pharmacodynamic profiles of pegcetacoplan.

Methods: Pooled clinical study data were used to predict pegcetacoplan concentrations and biomarker responses indicative of hemolysis (hemoglobin and lactate dehydrogenase) over time, including the impact of patient characteristics and prior or concurrent complement C5 inhibitor treatment, to support the approved dose of subcutaneous pegcetacoplan 1080 mg twice weekly.

Results: The population pharmacokinetoc analysis included 284 subjects, and the pharmacokinetic/pharmacodynamic analysis included 165 subjects. Subcutaneous pegcetacoplan 1080 mg twice weekly resulted in rapid serum exposures and robust biomarker response within 4 weeks after treatment initiation. Steady-state serum concentrations demonstrated consistent exposure (median ≥ 600 µg/mL) with minimal peak-to-trough variation. The median effective half-life was 8.6 days in patients with paroxysmal nocturnal hemoglobinuria. Body weight significantly impacted pegcetacoplan exposure, and other covariates impacted hemoglobin (sex and creatinine clearance) or lactate dehydrogenase (prior or concurrent complement C5 inhibitor treatment); however, effects were not clinically meaningful.

Conclusions: The approved dose of pegcetacoplan is predicted to produce rapid and sustained exposure and robust hemoglobin and lactate dehydrogenase responses in adult patients with paroxysmal nocturnal hemoglobinuria, with no initial dose adjustments required for any specific patient population.

Background and objective: Often, stability studies do not cover all facets of ensuring patient safety for biologics, unless the impact of the in-use and out-of-fridge conditions is also assessed. This study investigated the physicochemical and biological stability of Sandoz rituximab biosimilar (SDZ-RTX).

Methods: In a worst-case setting, two SDZ-RTX batches in vials were exposed to long-term conditions (5 ± 3 °C) for at least the shelf-life period (36 months). These batches were exposed to out-of-fridge conditions of up to 25 ± 2 °C/60 ± 5% relative humidity in total for 14 days, and subsequently to 30 ± 2 °C/75 ± 5% relative humidity for 7 days. Thereafter, these batches were diluted to 1 mg/mL in 0.9% NaCl in 250-mL polyethylene infusion bags and stored at either 25 ± 2 °C/60 ± 5% relative humidity for 30 days or 30 ± 2 °C/75 ± 5% relative humidity for 14 days, representing in-use conditions. The stability of SDZ-RTX was assessed using a variety of analytical methods, including size-exclusion chromatography, cation exchange chromatography, non-reducing capillary electrophoresis sodium dodecyl sulfate, complement-dependent cytotoxicity-bioactivity, and subvisible particle count by light obscuration.

Results: Results for all assessments were within the stringent shelf-life acceptance criteria for SDZ-RTX for both batches under both in-use conditions.

Conclusions: These data show that the physicochemical and biological quality of SDZ-RTX diluted in 0.9% NaCl infusion bags is assured, even after prolonged worst-case (out-of-fridge and in-use) storage at elevated temperatures up to 30 °C, if the medication is prepared under aseptic conditions according to the Summary of Product Characteristics.

Background and objectives: Azithromycin, a macrolide antibiotic, is commonly used to treat mild-to-moderate bacterial infections. This research aimed to evaluate the pharmacokinetics (PK) properties and bioequivalence (BE) of two azithromycin (EQ 100 mg base/packet) powders for suspension in Chinese healthy participants in fed and fasting conditions.

Methods: A total of 90 Chinese healthy participants were enrolled in this nonblinded, single-dose, randomized, semireplicate, three-period, three-sequence, crossover study. Of them, 42 and 40 were categorized to the fed and fasting conditions, respectively. The washout period between doses was 21 days. Blood specimens were harvested prior to administering the drug and 194 h following administration. The plasma levels of azithromycin were analyzed using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach. PK parameters were measured using noncompartmental analysis. This research compared BE between the reference and test products using the average bioequivalence (ABE) or reference-scaled average bioequivalence (RSABE) method, considering the within-subject variability (S_WR) of the reference preparation. Adverse events (AEs) were monitored to examine safety and tolerability.

Results: The RSABE method (S_WR ≥ 0.294) was used to determine the BE of maximal plasma concentration (C_max) in both fed and fasting conditions. In the ABE approach, (S_WR < 0.294) was adopted to assess the BE of the area under the plasma concentration-time curve from time zero to the last measurable time point (AUC_0-t) and determine the area under the plasma concentration time curve from time zero to time infinity (AUC_0-inf). In the fasting condition, the point estimate of the test/reference ratio for C_max was 1.08, with a 95% upper confidence bound of - 0.05 < 0.00. The geometric mean ratio (GMRs) for AUC_0-t and AUC_0-inf was 115.21% [90% confidence interval (CI) 107.25-123.27%] and 113.07% (90% CI 105.14-121.61%), respectively. In the fed condition, the point estimate of the test/reference ratio for C_max was 0.94, with a 95% upper confidence bound of - 0.10 < 0.00. The GMR for AUC_0-t and AUC_0-inf was 99.51% (90% CI of 91.03-108.78%) and 99.43% (90% CI 91.73-107.78%), respectively. These data all satisfied the BE criteria for drugs with high variability. All AEs were transient and mild, and no severe AEs were observed.

Conclusions: Our study indicated that the test and reference products of azithromycin (EQ 100 mg base/packet) powder for suspension were bioequivalent and safe in healthy Chinese participants, irrespective of the feeding condition. CLINICAL TRIAL REGISTRATION (CHINADRUGTRIALS.ORG.CN): CTR20232646, registered on 25 August 2023.

Background and objective: Hepcidin, an endogenous peptide hormone, binds to ferroportin and is the master regulator of iron trafficking. Rusfertide, a synthetic peptide, is a potent hepcidin mimetic. Clinical studies suggest rusfertide may be effective in the treatment of polycythemia vera. This study investigated the dose-ranging pharmacokinetics, pharmacodynamics, and safety of a lyophilized formulation of rusfertide.

Methods: A randomized open-label crossover study was conducted in two groups of healthy adult subjects to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of subcutaneous rusfertide doses that ranged from 10 to 60 mg of a lyophilized formulation and 20 mg of an aqueous prefilled syringe formulation that were used in clinical trials.

Results: Rusfertide showed a rapid initial absorption. Median time to peak plasma concentrations for the lyophilized formulation was 24 h for doses of 10-30 mg and 2-4 h for doses of 45 and 60 mg. Mean terminal half-life ranged from 19.6 to 57.1 h. Rusfertide peak concentration and area under the concentration-time curve increased with an increasing dose, but in a less than dose-proportional manner. Metabolites M4 and M9 were identified as major metabolites. At the rusfertide 20-mg dose, the lyophilized formulation had an area under the concentration-time curve from time zero to infinity approximately 1.5-fold higher than the aqueous formulation. The elimination half-life was comparable for the two formulations. Dose-related decreases in serum iron and transferrin-iron saturation were seen following rusfertide treatment. The majority of treatment-emergent adverse events were mild; treatment-related treatment-emergent adverse events seen in ≥10% of subjects were injection-site erythema and injection-site pruritus.

Conclusions: Rusfertide was well tolerated; the pharmacokinetic and pharmacodynamic results indicate that lyophilized rusfertide is suitable for once-weekly or twice-weekly administration.

Background: Ondansetron is a highly selective 5-HT3 receptor antagonist that alleviates nausea and vomiting. Bioequivalence evaluation ensures that the efficacy of generic drugs is consistent with that of the original drug.

Objective: The objective of this study was to evaluate the bioequivalence of ondansetron hydrochloride (HCl) tablets taken in single doses under fasting and postprandial conditions in healthy subjects.

Methods: In this randomized, open-label, two-cycle, crossover phase I study, liquid chromatography‒tandem mass spectrometry (LC‒MS/MS) was used to determine the ondansetron concentration in dipotassium-ethylenediaminetetraacetate (K₂-EDTA) plasma after the subjects received a single 8 mg of ondansetron and reference formulation. Twenty-six healthy subjects received one tablet of ondansetron under fasting conditions and 28 subjects received one under postprandial conditions. Bioequivalence was established if the 90% confidence interval (CI) was 80.00-125.00%. The pharmacokinetic parameters were calculated via WinNonLin 8.1 software and the bioequivalence data were evaluated via Phoenix WinNonlin 8.1 statistics software.

Results: The geometric mean ratio (GMR) of the maximum observed concentration (C_max), the area under the plasma concentration‒time curve (AUC) from time zero to the last sampling time (AUC_0-t), and the AUC from time zero to infinity (AUC_0-∞) from the test/reference formulation under fasting conditions were 90.50, 90.43, and 90.25, respectively. The 90% CIs were 83.75-97.79, 82.64-98.95, and 82.25-99.03, respectively. The GMRs of C_max, AUC_0-t, and AUC_0-∞ after a high-fat meal were 96.85, 93.57, and 93.77, respectively; the 90% CIs were 88.43-106.07, 87.35-100.24, and 87.35-100.68, respectively.

Conclusion: The test and reference formulations of ondansetron HCl have bioequivalence for healthy adult subjects under fasting and postprandial conditions.