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- In-Vitro Comparison of Physical Characteristics, Enzyme Content, and
Release Kinetics of Pancreatic Enzyme Preparations Available in Europe and
Canada-
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Abstract: Introduction Commercially available pancreatic enzyme replacement therapy (PERT) preparations differ significantly in their physical and enzyme properties, raising concern about the interchangeability of these preparations. The current study aimed to compare various commercially available PERT in Europe and Canada for physical properties, enzyme content, enzyme activities, release characteristics, and compliance with the label claim. Methods Particle size was determined using a dynamic image analyzer and represented as Feret Max at 10th (FERET Max D [v, 0.1]), 50th (FERET Max D [v, 0.5]), and 90th percentiles (FERET Max D [v, 0.9]). Particle imaging was performed using scanning electron microscopy and a Quorum sputter coater. Lipase activity was measured according to the European Pharmacopoeia (Ph. Eur) and International Pharmaceutical Federation (FIP) procedures. The measured activity was compared against the label claims to identify the percentage of deviations. Lipase release at different pH (release kinetics) was also determined subsequently. Results The particle size of the PERT preparations differed considerably. There were deviations in the actual lipase content from the label claim, ranging from 85.8% (Gastrozym 10000) to 177.5% (Pancreolan 6000). Under the simulated conditions, most PERT preparations released the enzyme lipase at an acidic pH present in the stomach before reaching the duodenum. Conclusion PERT preparations available in Europe and Canada exhibit significant differences in terms of physical and enzyme release kinetics. Careful evaluation is needed when interchanging these preparations, as it could impact the therapeutic outcomes.
PubDate: 2025-06-26
- Demonstrating Bioequivalence for a Lumacaftor Monosubstance Formulation
Versus Orkambi® (Lumacaftor/Ivacaftor) in Healthy Subjects-
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Abstract: Background and Objective Lumacaftor is an active ingredient in the US Food and Drug Administration-approved combination medication Orkambi®, which is used for treating cystic fibrosis. Experimental evidence suggests that lumacaftor can be used as a monotherapy to improve brain perfusion and memory in heart failure. To clinically assess this therapeutic intervention, a formulation with demonstrated bioequivalence to the currently approved combination product is required. Methods This comparative bioavailability and food-effect study compared lumacaftor pharmacokinetics in healthy patients following: (i) oral administration of lumacaftor (400 mg; Test Product) or Orkambi® (lumacaftor 400 mg/ivacaftor 250 mg; Reference Product) in the fed state and (ii) oral administration of lumacaftor (400 mg; Test Product) in the fasted to fed state. Plasma lumacaftor concentrations were measured with a standard liquid chromatography with tandem mass spectrometry approach. Results The “Test-to-Reference ratio” of the geometric least-square means for maximum plasma concentration and area under the curve met the Food and Drug Administration-defined criteria for bioequivalence; median times to maximum plasma concentration values were not statistically different. The “Fed to Fasted ratio” of the geometric least-square means for maximum plasma concentration and area under the curve indicated a clear food effect on bioavailability. Lumacaftor exposure was approximately two times higher when administered with fatty foods than when taken in a fasting state. The monosubstance formulation was well tolerated. Conclusions We conclude that the lumacaftor monosubstance formulation delivers lumacaftor exposure that is not meaningfully different than the currently approved combination product. Clinical Trial Registration ClinicalTrials.gov identifier: NCT05968612.
PubDate: 2025-06-23
- Pharmacokinetic Comparison of Novel Tablet-in-Tablet and Conventional
Ketorolac Tromethamine Tablets in Beagle Dogs-
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Abstract: Background and Objective Ketorolac tromethamine (KT), a nonsteroidal anti-inflammatory drug (NSAID) and cyclooxygenase inhibitor, is commonly used for the management of moderate to severe pain. The objective of this study was to compare the pharmacokinetic characteristics of KT in beagle dogs following oral administration of conventional tablets and a novel tablet-in-tablet (TIT) formulation. Methods A comparative dissolution study was conducted to evaluate the release profiles of both formulations. Non-compartmental analysis was used to determine the pharmacokinetic parameters of each formulation. Results Approximately 20% of the administered KT from the TIT formulation was released within the first 30 min, with a cumulative release exceeding 90% at 16 h. In contrast, the conventional tablets released about 50% of the drug within 30 min and completed the release at 4 h. In the single-dose study, the time to reach maximum plasma concentration (Tmax) for conventional tablets was 1 h, while Tmax for the TIT formulation was 5 h. Both maximum concentration (Cmax) and area under the concentration–time curve (AUC) for the TIT formulation were lower than those for conventional tablets. In the repeated-dose study, when equivalent doses (35 mg) of conventional tablets were administered in divided daily doses, the TIT formulation showed no significant differences in most steady-state pharmacokinetic parameters, except for Tmax,ss. Conclusion The results of this study suggest that the development of a novel KT tablet formulation utilizing the push-pull osmotic pump (PPOP) and tablet-in-tablet techniques warrants further investigation in clinical trials.
PubDate: 2025-06-21
- Systematic Review and Meta-analysis of the Clinical Efficacy of Octreotide
in Combination with Ulinastatin in the Treatment of Acute Pancreatitis-
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Abstract: Background and Objectives Acute pancreatitis (AP) is a serious disease characterized by local inflammatory responses in the pancreas. The annual incidence rate of acute pancreatitis is 4.9–73.4 per 100,000 people. Among these, approximately 20% develop into moderately severe acute pancreatitis (MSAP) or severe acute pancreatitis (SAP), with a mortality rate of 13–35%. The aim of this study is to evaluate the efficacy and safety of octreotide in combination with ulinastatin in the treatment of acute pancreatitis using meta-analysis. Methods Chinese and English databases, including China National Knowledge Infrastructure Database (CNKI), WanFang database (WANFANG), Chinese Scientific Journals Full-text Database (VIP database), PubMed, Medline, and Web of Science, were searched for randomized controlled trials (RCTs) about octreotide in combination with ulinastatin in the treatment of acute pancreatitis from January 2019 to April 2024. Retrieved literature was screened independently by two researchers, and the methodological quality of included publications was evaluated according to bias risk assessment tool recommended by Cochrane 5.1. Data were statistically analyzed by using RevMan5.3 software. Results A total of 3026 patients from 30 studies in accordance with the criteria were included, including experimental group (n = 1516) and control group (n = 1510). Meta-analysis results showed that octreotide combined with ulinastatin could increase the effective rate of treatment for acute pancreatitis (relative risk (RR) = 1.23, 95% CI 1.19–1.27, P < 0.00001). The time in the experimental group for hospitalization (standardized mean difference (SMD) = −2.00, 95% CI [−2.67, −1.34], P < 0.00001), disappearance of abdominal pain (SMD = −1.75, 95% CI [−2.21, −1.29], P < 0.00001), disappearance of nausea and vomiting (SMD = −2.03, 95% CI [−2.93, −1.13], P < 0.00001), disappearance of abdominal distension (SMD = −2.02, 95% CI [−2.59, −1.44], P < 0.00001), and disappearance of peritoneal irritation (SMD = −2.20, 95%CI [−3.95, −0.46], P < 0.00001) was shorter than in the control group. The levels in the experimental group of TNFα (SMD = −2.01, 95% CI [−2.71, −1.32], P < 0.00001), CRP (SMD = −2.50, 95% CI [−3.20, −1.79], P < 0.00001), IL-6 (SMD = −2.67, 95% CI [−3.48, −1.85], P < 0.00001), IL-8 (SMD = −2.92, 95% CI [−4.02, −1.83], P < 0.00001), serum amylase concentration (SMD = −2.83, 95% CI [−4.07, −1.60], P < 0.00001), and urine amylase concentration (SMD = −2.34, 95% CI [−3.81, −0.88], P < 0.00001) were lower compared with control group. There was no statistically significant difference in the incidence of adverse reactions between the experimental and control groups. Conclusions The combination of octreotide and ulinastatin can improve the intestinal mucosal barrier function, reduce inflammatory response, and decrease amylase levels in patients with acute pancreatitis, without increasing the incidence of adverse reactions. It has significant therapeutic effects and can be promoted as a treatment option for acute pancreatitis in China.
PubDate: 2025-06-20
- Opinion of the Italian Association of Myology on Ataluren for the
Treatment of Nonsense Mutation Duchenne Muscular Dystrophy-
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Abstract: The Italian Duchenne muscular dystrophy expert clinicians, gathered in the Italian Association of Myology (AIM), intend to express a position against the suspension of the Marketing Authorization of ataluren (Translarna®) for the treatment of nonsense mutation Duchenne muscular dystrophy. The marketing authorization has been recently withdrawn by the European Commission following a recommendation from the Committee for Medicinal Products for Human Use of the European Medicines Agency. This negative recommendation was based on the fact that three randomized controlled trials of ataluren in nonsense mutation Duchenne muscular dystrophy (007, 020, and 041) have failed to show statistically significant differencs in favor of the treatment in the selected primary outcomes for each individual study, i.e., 6-min walk distance, in the intent-to-treat population for 007 and 020 and in a subgroup for 041. However, observed differences always favored treatment, and several clinically meaningful secondary outcomes were positive and statistically significant across studies. Importantly, the largest and longest phase III study (041) showed a statistically significant effect in favor of ataluren in the wider intent-to-treat population. Furthermore, a long-term registry of “real-world” ataluren treatment data (Strategic Targeting of Registries and Database of Excellence, STRIDE), in addition to confirming a reassuring safety profile, suggested a prolonged maintenance of ambulatory, upper limb, and respiratory function. We deem that a withdrawal of ataluren from the European market would harm not only patients with nonsense mutation Duchenne muscular dystrophy, but the whole neuromuscular field, in which clinical trials are challenging because of the heterogenous complex slow-progressing nature of the disorders.
PubDate: 2025-05-28
- Network Meta-Analysis of Pharmacological Therapies for Long-Term
Prophylactic Treatment of Patients with Hereditary Angioedema-
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Abstract: Background and objectives Several treatments for long-term prophylaxis (LTP) of hereditary angioedema (HAE) are in clinical use, such as garadacimab, lanadelumab, subcutaneous C1 esterase inhibitor (C1INH), and berotralstat. In the absence of head-to-head comparative evidence, indirect comparison methods are needed to compare LTP treatments in patients with HAE. The objective of this analysis was to estimate the comparative efficacy, safety, and impact on quality of life of LTP treatments for patients with HAE through NMAs. Methods A systematic literature review was conducted to identify randomized controlled trials (RCTs) investigating LTP treatments in patients (at least 12 years old) with HAE (PROSPERO protocol #CRD42022359207). A network meta-analysis (NMA) feasibility assessment evaluated trial suitability and Bayesian NMAs were conducted for evaluable efficacy, safety, and quality of life (QoL) outcomes. Results The results of these NMAs show improved efficacy, QoL, and reduced rate of adverse events with garadacimab (200 mg once monthly), lanadelumab (300 mg every two or four weeks), subcutaneous C1INH (60 IU/kg twice weekly), and berotralstat (150 mg once daily) compared to placebo in the treatment of patients with HAE. For the primary outcome of time-normalized number of HAE attacks, garadacimab statistically significantly reduced the rate of attacks compared to lanadelumab Q4W and berotralstat. A similar statistically significant reduction was shown for HAE attacks treated with on-demand treatment. Garadacimab showed statistically significant reduction in the rate of moderate and/or severe HAE attacks compared to lanadelumab Q2W. Garadacimab also showed statistical improvements in change from baseline in AE-QoL total score as compared to berotralstat. Conclusions Overall, garadacimab ranked as the most probable effective treatment among all comparators assessed, with lanadelumab Q2W or subcutaneous C1INH ranking second, across most outcomes.
PubDate: 2025-05-28
- An Exploratory Pharmacogenetic Pilot Study of Two Reverse Transcriptase
Inhibitors, Tenofovir Alafenamide Fumarate and Tenofovir Disoproxil
Fumarate-
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Abstract: Background and Objectives The nucleoside reverse transcriptase inhibitors tenofovir alafenamide fumarate and tenofovir disoproxil fumarate are frequently employed in treating human immunodeficiency virus. Further, each form of tenofovir requires laboratory monitoring to determine efficacy and tolerability among patients. This study sought to investigate the relationship, if any, of single nucleotide polymorphisms (SNPs) and selected clinical parameters. Methods The study population, predominantly Caucasian males with a median age of 53.0 years [interquartile range 46.0–59.0], was assayed for genetic variations using an iPLEX ADME PGx Pro v1.0 Panel. Results Although several SNP relationships were found with both forms of tenofovir, many of the reported SNPs were displayed only in the comprehensive regimen grouping, making it difficult to distinguish between the two prodrug forms. Conclusions Being an exploratory study, the findings of this substudy serve as potential avenues for further research.
PubDate: 2025-05-25
- Evaluation of Anti-SARS-CoV-2 IgG Responses in a Clinical Study of a
Biosimilar Candidate to Denosumab Using Singlicate Analysis-
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Abstract: Background and Objectives During the coronavirus disease-2019 (COVID-19) pandemic there was the uncertainty that the long-term immune response generated upon natural infection or triggered by available severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) vaccines could impact the clinical endpoints of ongoing clinical trials, in particular, whether the immunogenicity of biotherapeutics could be affected. Methods Here, we describe the different stages to build an adequate COVID-19 serology testing strategy to ultimately assess whether the presence of anti-SARS-CoV-2 antibodies could impact the immunogenicity data of a clinical trial supporting the approval of GP2411 (Jubbonti®/Wyost®; a denosumab biosimilar to Prolia/XGeva) conducted during the pandemic. We first assessed the sensitivity and specificity of US Food and Drug Administration Emergency Use Authorization (FDA EUA)-approved commercial SARS‐CoV‐2 anti‐IgG enzyme-linked immunosorbent (ELISA) assay. Then, we validated the assay in accordance with bioanalytical guidelines and demonstrated that the analysis of validation parameters as singlicates met all bioanalytical acceptance criteria and showed comparable results to those of duplicate analyses. Lastly, we report data on anti-SARS-CoV-2 IgG antibody responses in healthy participants treated with a single dose of a biotherapeutic. Results SARS-CoV-2 serology was assessed in 1970 serum samples collected from 499 healthy participants who were dosed throughout a clinical study that was conducted during the COVID-19 pandemic. Anti-SARS-CoV-2 IgG antibodies triggered by natural infection and/or vaccination were detected in 1165 serum samples from 82% of the study participants. Anti-SARS-COV-2 IgG responses were of comparable magnitude in study participants who were vaccinated during the course of the study or had a confirmed COVID-19 infection. A total of 6408 serum samples from the same study were evaluated for the presence of anti-drug antibodies (ADAs), with 64% of the participants being positive. Independent of the presence of anti-SARS-CoV-2 IgG antibodies, all ADA-positive study participants showed ADAs of very low magnitude. Neutralizing ADAs were detected in less than 1% of study participants without an association to anti-SARS-CoV-2 IgG responses. Conclusions The established bioanalytical strategy allowed the reliable detection of COVID-19 adaptive responses in study participants. The development of anti-SARS-CoV-2 IgG responses (triggered by either a natural infection or a vaccine) did not have any clinically meaningful impact on the immunogenicity of the biotherapeutic administered in the study.
PubDate: 2025-05-23
- Safety Evaluation of Contezolid (MRX-I) Versus Linezolid in Sprague-Dawley
Rats-
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Abstract: Background & Objectives Contezolid (MRX-I) is a novel ortho-fluorophenyl dihydropyridone developed by MicuRx Pharmaceuticals, Inc. It has been approved for the treatment of drug-resistant Gram-positive bacterial infections with relatively lower toxicity than other oxazolidinones such as linezolid. However, the toxicity profile has not yet been completely revealed. The aim of this study was to disclose the toxicity of contezolid in Sprague-Dawley (SD) rats and compare its toxicity profile with linezolid in a standard 4-week toxicity study. Methods In this study, SD rats were orally administered with contezolid at doses of 20, 100, or 200/300 mg/kg/day for 28 consecutive days followed by a 28-day recovery period. Linezolid at doses of 100 or 200 mg/kg/day served as a comparator. Clinical observations, body weight, food consumption, hematology, clinical chemistry, urinalysis, and histopathological examinations were conducted. Results All females in the 200 mg/kg/day linezolid group were subjected to unscheduled death due to myelosuppression within the first 2 weeks. No abnormalities were noted in the 200 mg/kg/day contezolid group, and the dose level was escalated to 300 mg/kg/day from day 15. Myelosuppression or myelosuppression-associated effects were comparable between the 300-mg/kg/day contezolid group and the 100-mg/kg/day linezolid group. The ‘no observed adverse effect level’ (NOAEL) of contezolid was determined to be 100 mg/kg/day (with an average AUC0–24 h of 268.4 μg*h/mL). At the same dose levels, the toxicity of contezolid was significantly lower than that of linezolid. Conclusion These findings demonstrate that contezolid exhibits a favorable safety profile compared with linezolid in this 4-week repeated-dose toxicity study in rats.
PubDate: 2025-05-13
- Bioequivalence and Safety of Two Amisulpride Formulations in Healthy
Chinese Subjects Under Fasting and Fed Conditions: AÂ Randomized,
Open‑Label, Single‑Dose, Crossover Study-
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Abstract: Background and Objectives Amisulpride is a second-generation antipsychotic drug that selectively binds to D2 and D3 dopaminergic receptors in the limbic system. In this study, the bioequivalence of an amisulpride formulation manufactured in China with the original formulation Solian® was evaluated under fasting and fed conditions in healthy Chinese subjects. Methods A single-centre, randomized, open, two-preparation, single-dose, two-period crossover trial in healthy adult subjects was conducted under fasting and fed conditions. A total of 42 and 36 eligible healthy subjects were enrolled in the fasting and fed studies, respectively. The subjects were randomly assigned to receive either the test or the reference formulation with a washout period of 7 days. The concentration of amisulpride in plasma was determined by liquid chromatography‒tandem mass spectrometry (LC‒MS/MS), and the pharmacokinetic (PK) parameters of amisulpride were calculated via the noncompartmental method. Results The geometric mean ratios (GMR) of the maximum observed concentration (Cmax), the area under the plasma concentration‒time curve (AUC) from time zero to the last sampling time (AUC0–t), and the AUC from time zero to infinity (AUC0–∞) from the test/reference formulation under fasting conditions were 93.83, 101.90, and 102.35, respectively, with corresponding 90% confidence intervals (CIs) of 83.93–104.89, 97.58–106.42, and 98.24–106.63. The GMRs of Cmax, AUC0–t, and AUC0–∞ under fed conditions were 102.23, 106.09, and 101.87, respectively, with corresponding 90% CIs of 92.49–112.99, 102.44–109.87, and 97.49–106.44. These data all satisfied the bioequivalence criteria (90% CIs in the range of 80–125%). In terms of safety, no serious adverse events were observed. Conclusions The test and reference amisulpride formulations were bioequivalent under fasting and fed conditions. Both formulations showed similar safety and tolerability in the population studied.
PubDate: 2025-04-26
- Patient-Reported Outcome Measures in Patients with Rheumatoid Arthritis,
Psoriasis, or Psoriatic Arthritis Treated with GP2015, an Etanercept
Biosimilar: Results from Two Phase III Studies (EGALITY and EQUIRA)-
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Abstract: Background and Objective GP2015 is an etanercept biosimilar. Equivalent efficacy and comparable safety of GP2015 to reference etanercept (ref-ETN) was demonstrated in two phase III studies, one in patients with moderate-to-severe chronic plaque-type psoriasis (PsO; EGALITY study) and the other in patients with rheumatoid arthritis (RA; EQUIRA study). EGALITY also included patients with reported psoriatic arthritis (PsA). Here, patient-reported outcome (PRO) data from both studies are presented. Methods EGALITY included 531 patients with PsO and EQUIRA included 376 patients with RA. In EGALITY, patients who had achieved ≥ 50% improvement in Psoriasis Area and Severity Index (PASI) at week 12 either continued the initial treatment or underwent three treatment switches between GP2015 and ref-ETN starting at week 12. In EQUIRA, patients with at least moderate European League Against Rheumatism response at week 24 received GP2015 up to week 48. Assessed PROs included Dermatology Life Quality Index (DLQI) and EuroQol five-dimension health status questionnaire (EQ-5D-5L) in EGALITY, Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue score in EQUIRA, and Health Assessment Questionnaire–Disability Index (HAQ-DI) in both studies. Results In EGALITY, mean DLQI decreased from baseline in the GP2015 and ref-ETN groups, and the mean (standard deviation [SD]) percent reductions from baseline in DLQI were comparable between groups at week 12 (GP2015, – 67.7 [40.7]; ref-ETN, – 67.3 [30.6]), and were sustained after the switch at week 52 (‘continued GP2015,’ – 77.3 [36.5]; ‘continued ref-ETN,’ – 72.8 [33.7]; ‘switched GP2015,’ − 73.9 [37.0]; ‘switched ref-ETN,’ − 78.1 [30.9]). The proportion of patients with EQ-5D-5L scores of 1 (‘no problems’) improved from baseline to week 52 for all five dimensions and was comparable between treatment groups. In EGALITY, in patients with reported PsA at baseline, mean (SD) HAQ-DI scores decreased from baseline, and scores were comparable between treatment groups at week 12 (GP2015, 0.6 [0.7]; ref-ETN, 0.6 [0.6]) and after switching at week 52 (‘continued GP2015,’ – 0.4 [0.6]; ‘continued ref-ETN,’ – 0.4 [0.6]; ‘switched GP2015,’ – 0.4 [0.6]; ‘switched ref-ETN,’ – 0.1 [0.4]). In EQUIRA, the proportion of patients achieving HAQ-DI in normal range (≤ 0.5) was comparable between treatment groups up to week 48 (‘continued GP2015,’ 36.7%; ‘switched to GP2015,’ 39.9%). The mean FACIT-Fatigue scores increased from baseline and the mean (SD) percent change from baseline in FACIT-Fatigue score at week 24 was 9.6 (9.5) in the ‘continued GP2015’ and 11.4 (9.7) in the ‘switched to GP2015’ groups; the scores were sustained after switching until week 48. Conclusion Treatment with GP2015 and ref-ETN resulted in similar improvements in PROs and quality-of-life scores across the three diseases, namely RA, PsA, and PsO. These improvements were sustained after switching, with consistent benefit on PROs during the treatment period. Trial Registration ClinicalTrials.gov identifiers: NCT01891864, NCT02638259.
PubDate: 2025-04-25
- Analysis of Sirolimus Blood Concentration and Influencing Factors in
Pediatric Patients: Implications for Individualized Drug Therapy-
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Abstract: Background and Objective The purpose of this study is to investigate the status of blood concentration of sirolimus (SRL), explore the factors influencing SRL drug blood concentration, and provide guidance for the appropriate utilization of clinical medications. Methods A single-center retrospective cohort study encompassed 1535 blood drug concentration observations obtained from 249 children from August 2018 to June 2023. Participants were categorized into four groups (A, B, C, and D) on the basis of their blood concentration levels at various time intervals. The analysis focused on identifying the factors that influenced blood concentration in the short- and long-term posttreatment. The primary endpoint was factors affecting the sirolimus blood concentration. The effect of physiopathological indicators on the corrected blood drug concentration (C/D value) was analyzed to avoid the effect of differences in the dose of SRL used in patients on SRL blood concentrations. The multiple linear regression model was used to examine the impact of factors influencing pharmacokinetics and pharmacodynamics on the C/D. Results Analysis of SRL blood concentration monitoring indicated that a majority (60.43%) of patients demonstrated a trough sirolimus concentration (C0) below the level of the recommended threshold of 5 ng/mL, while approximately 17.7% of patients exceeded 15 ng/mL. The results indicated a noteworthy association between weight and body surface area (BSA) and the C/D of SRL in groups A, B, and D (P < 0.05). Additionally, aspartate transaminase (AST), alanine aminotransferase (ALT), and albumin (ALB) in group A; ALB in group B; and platelet count (PLT) in group C demonstrated a statistically significant correlation with the C/D of SRL (P < 0.05). Conclusions Clinicians should optimize medication plans by considering the child’s weight, BSA, ALT, AST, PLT, ALB, and relevant factors. These findings may serve as a valuable resource for clinicians.
PubDate: 2025-04-11
- Comparative Preclinical Evaluation of Tuznue Versus Referent Herceptin: A
Registered Trastuzumab Biosimilar-
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Abstract: 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.
PubDate: 2025-04-02
- Analyses of Adverse Drug Reactions to Fluoroquinolones in Spontaneous
Reports Before and After the Referral and in Clinical Routine Cases-
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Abstract: 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 sent by the EMA referring to prescribing trends for fluoroquinolones, our study showed that the characteristics of spontaneous ADR reports for fluoroquinolones after the referral were similar to those before the referral, underlining the importance of adhering to the recommended restrictions issued by the EMA. In addition, we observed individual differences between ciprofloxacin, levofloxacin, and moxifloxacin with regard to their ADR profile. Further studies are needed to confirm our results.
PubDate: 2025-01-21
- A Real-World Data Analysis of Alglucosidase Alfa in the FDA Adverse Event
Reporting System (FAERS) Database-
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Abstract: Background and Objective Alglucosidase alfa for injection is used as an enzyme replacement therapy for the treatment of Pompe disease. The safety profile of alglucosidase alfa-associated adverse events requires a comprehensive evaluation. In this study, we aimed to identify drug safety alert signals and investigate the real-world safety of alglucosidase alfa to guide clinical decision making and optimize the risk-benefit balance. Methods The adverse event reports from the first quarter of 2006 to the fourth quarter of 2023 were selected by exploring the Food and Drug Administration Adverse Event Reporting System (FAERS) database. The new and unexpected potential adverse event signals were detected using a disproportionality analysis, including the reporting odds ratio, the proportional reporting ratio, the Bayesian confidence propagation neural network, and the empirical Bayes geometric mean. Then, the Medical Dictionary for Regulatory Activities was used to systematically classify the results. Results After analyzing 16,945,027 adverse event reports, a total of 4326 cases of adverse events related to alglucosidase alfa were identified, spanning 27 system organ classes. A total of 359 preferred terms of adverse events for glucosidase alpha were detected. Pyrexia ranked first, followed by pneumonia, dyspnea, respiratory failure, and disease progression according to occurrence frequency. The top three system organ classes were general disorders and administration-site conditions (n = 2466), respiratory, thoracic, and mediastinal disorders (n = 1749), and infections and infestations (n = 1551). In addition to adverse effects mentioned in the product label, our study also discovered rare but high signal intensity adverse events such as chronic recurrent multifocal osteomyelitis. Conclusions There are many adverse events associated with the clinical use of alglucosidase alfa, which should be closely monitored in the FAERS database. As the most effective enzyme replacement therapy for Pompe disease, it is crucial to closely monitor these adverse events. Ensuring patient safety while balancing drug effectiveness is particularly important.
PubDate: 2025-01-21
- Characterization for the Similarity Assessment Between the Proposed
Biosimilar SB17 and Ustekinumab Reference Product Using State-of-the-Art
Analytical Methods-
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Abstract: 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.
PubDate: 2025-01-16
- Evaluation of BCRP-Related DDIs Between Methotrexate and Cyclosporin A
Using Physiologically Based Pharmacokinetic Modelling-
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Abstract: Background and Objective This study provides a physiologically based pharmacokinetic (PBPK) model-based analysis of the potential drug–drug interaction (DDI) between cyclosporin A (CsA), a breast cancer resistance protein transporter (BCRP) inhibitor, and methotrexate (MTX), a putative BCRP substrate. Methods PBPK models for CsA and MTX were built using open-source tools and published data for both model building and for model verification and validation. The MTX and CsA PBPK models were evaluated for their application in simulating BCRP-related DDIs. A qualification of an introduced empirical uniform in vitro scaling factor of Ki values for transporter inhibition by CsA was conducted by using a previously developed model of rosuvastatin (sensitive index BCRP substrate), and assessing if corresponding DDI ratios were well captured. Results Within the simulated DDI scenarios for MTX in the presence of CsA, the developed models could capture the observed changes in PK parameters as changes in the area under the curve ratios (area under the curve during DDI/area under the curve control) of 1.30 versus 1.31 observed and the DDI peak plasma concentration ratios (peak plasma concentration during DDI/peak plasma concentration control) of 1.07 versus 1.28 observed. The originally reported in vitro Ki values of CsA were scaled with the uniform qualified scaling factor for their use in the in vivo DDI simulations to correct for the low intracellular unbound fraction of the CsA effector concentration. The resulting predicted versus observed ratios of peak plasma concentration and area under the curve DDI ratios with MTX were 0.82 and 0.99, respectively, indicating adequate model accuracy and choice of a scaling factor to capture the observed DDI. Conclusions All models have been comprehensively documented and made publicly available as tools to support the drug development and clinical research community and further community-driven model development. Graphical abstract
PubDate: 2024-12-24
- Correction: Damoctocog Alfa Pegol, a PEGylated B-domain Deleted
Recombinant Extended Half-life Factor VIII for the Treatment of Hemophilia
A: A Product Review-
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PubDate: 2024-12-20
- Population Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses of
Pegcetacoplan in Patients with Paroxysmal Nocturnal Hemoglobinuria-
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Abstract: 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.
PubDate: 2024-11-29
- Acknowledgement to Referees
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PubDate: 2024-11-23
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