Drugs in Research & Development最新文献

{"title":"Predictive Potential of Acido-Basic Properties, Solubility and Food on Bioequivalence Study Outcome: Analysis of 128 Studies.","authors":"Dejan Krajcar,&nbsp;Rebeka Jereb,&nbsp;Igor Legen,&nbsp;Jerneja Opara,&nbsp;Iztok Grabnar","doi":"10.1007/s40268-023-00426-6","DOIUrl":"https://doi.org/10.1007/s40268-023-00426-6","url":null,"abstract":"<p><strong>Background and objectives: </strong>Risk assessment related to bioequivalence study outcome is critical for effective planning from the early stage of drug product development. The objective of this research was to evaluate the associations between solubility and acido-basic parameters of an active pharmaceutical ingredient (API), study conditions and bioequivalence outcome.</p><p><strong>Methods: </strong>We retrospectively analyzed 128 bioequivalence studies of immediate-release products with 26 different APIs. Bioequivalence study conditions and acido-basic/solubility characteristics of APIs were collected and their predictive potential on the study outcome was assessed using a set of univariate statistical analyses.</p><p><strong>Results: </strong>There was no difference in bioequivalence rate between fasting and fed conditions. The highest proportion of non-bioequivalent studies was for weak acids (10/19 cases, 53%) and neutral APIs (23/95 cases, 24%). Lower non-bioequivalence occurrence was observed for weak bases (1/15 cases, 7%) and amphoteric APIs (0/16 cases, 0%). The median dose numbers at pH 1.2 and pH 3 were higher and the most basic acid dissociation constant (pKa) was lower in the non-bioequivalent group of studies. Additionally, APIs with low calculated effective permeability (cPeff) or low calculated lipophilicity (clogP) had lower non-bioequivalence occurrence. Results of the subgroup analysis of studies under fasting conditions were similar as for the whole dataset.</p><p><strong>Conclusion: </strong>Our results indicate that acido-basic properties of API should be considered in bioequivalence risk assessment and reveal which physico-chemical parameters are most relevant for the development of bioequivalence risk assessment tools for immediate-release products.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 3","pages":"211-220"},"PeriodicalIF":3.0,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/df/91/40268_2023_Article_426.PMC10439087.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10034996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative Efficacy of Different Drugs for the Treatment of Dilated Cardiomyopathy: A Systematic Review and Network Meta-analysis.","authors":"Xinyu Tong,&nbsp;Lijuan Shen,&nbsp;Xiaomin Zhou,&nbsp;Yudan Wang,&nbsp;Sheng Chang,&nbsp;Shu Lu","doi":"10.1007/s40268-023-00435-5","DOIUrl":"https://doi.org/10.1007/s40268-023-00435-5","url":null,"abstract":"<p><strong>Background and objective: </strong>At present, the therapies of dilated cardiomyopathy concentrated on the symptoms of heart failure and related complications. The study is to evaluate the clinical efficacy of a combination of various conventional and adjuvant drugs in treating dilated cardiomyopathy via network meta-analysis.</p><p><strong>Methods: </strong>The study was reported according to the PRISMA 2020 statement. From inception through 27 June 2022, the PubMed, Embase, Cochrane library, and Web of Science databases were searched for randomized controlled trials on medicines for treating dilated cardiomyopathy. The quality of the included studies was evaluated according to the Cochrane risk of bias assessment. R4.1.3 and Revman5.3 software were used for analysis.</p><p><strong>Results: </strong>There were 52 randomized controlled trials in this study, with a total of 25 medications and a sample size of 3048 cases. The network meta-analysis found that carvedilol, verapamil, and trimetazidine were the top three medicines for improving left ventricular ejection fraction (LVEF). Ivabradine, bucindolol, and verapamil were the top 3 drugs for improving left ventricular end-diastolic dimension (LVEDD). Ivabradine, L-thyroxine, and atorvastatin were the top 3 drugs for improving left ventricular end-systolic dimension (LVESD). Trimetazidine, pentoxifylline, and bucindolol were the top 3 drugs for improving the New York Heart Association classification (NYHA) cardiac function score. Ivabradine, carvedilol, and bucindolol were the top 3 drugs for reducing heart rate (HR).</p><p><strong>Conclusion: </strong>A combination of different medications and conventional therapy may increase the clinical effectiveness of treating dilated cardiomyopathy. Beta-blockers, especially carvedilol, can improve ventricular remodeling, cardiac function, and clinical efficacy in patients with dilated cardiomyopathy (DCM). Hence, they can be used if patients tolerate them. If LVEF and HR do not meet the standard, ivabradine can also be used in combination with other treatments. However, since the quality and number of studies in our research were limited, large sample size, multi-center, and high-quality randomized controlled trials are required to corroborate our findings.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 3","pages":"197-210"},"PeriodicalIF":3.0,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/f4/d5/40268_2023_Article_435.PMC10439079.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10048252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Risk of Hyponatremia after Tramadol/Acetaminophen Single-Pill Combination Therapy: A Real-World Study Based on the OMOP-CDM Database.","authors":"Yu Jeong Lee,&nbsp;Jinmi Kim,&nbsp;Youngmi Han,&nbsp;Kyuhyun Hwang,&nbsp;Byungkwan Choi,&nbsp;Tae Ryom Oh,&nbsp;Il Young Kim,&nbsp;Harin Rhee","doi":"10.1007/s40268-023-00436-4","DOIUrl":"https://doi.org/10.1007/s40268-023-00436-4","url":null,"abstract":"<p><strong>Background and objective: </strong>Tramadol has been reported to cause hyponatremia but the evidence is conflicting. The risk of hyponatremia resulting from combination oral tramadol/acetaminophen (TA) therapy is thus unknown. This study examined whether, compared with acetaminophen (AA), TA use is associated with an increased risk of hyponatremia.</p><p><strong>Methods: </strong>Hospital data compatible with the Observational Medical Outcomes Partnership-Common Data Model (OMOP-CDM; version 5.3) for 30,999 patients taking TA or AA from 2011 through 2020 were analyzed. New-onset hyponatremia was defined as a serum sodium level < 135 mEq/L within 10 days after drug initiation. The incidence rate ratio was calculated based on crude and 1:1 propensity-score-matched models. Subgroup analyses compared patients taking TA extended-release (TA-ER) and TA immediate-release (TA-IR) formulations.</p><p><strong>Results: </strong>Among the 30,999 patients, 12,122 (39.1%) were aged > 65 years and 16,654 (53.7%) were male. Hyponatremia within 10 days developed in 1613 (8.4%) of the 19,149 patients in the TA group; the incidence rate was higher than in the AA group (4.2%; 493 out of 11,850 cases). In the propensity-score-matched model, the incidence rate of hyponatremia in the TA group was 6.8 per 1000 person-days (PD), which was 1.57-fold (1.31, 1.89) higher than that in the AA group (4.3 per 1000 PD). In both the crude and propensity-score-matched models, the incidence rate of hyponatremia was significantly higher in the TA-ER than TA-IR subgroup.</p><p><strong>Conclusion: </strong>In this real-world study, hyponatremia was more frequently observed in the TA than AA group, and in the TA-ER than TA-IR subgroup. Therefore, it is imperative to prescribe tramadol cautiously and closely monitor electrolyte levels.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 3","pages":"289-296"},"PeriodicalIF":3.0,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/1c/90/40268_2023_Article_436.PMC10439094.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10420216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and Effectiveness of Rasburicase in the Control of Hyperuricemia in Pediatric Patients with Non-Hodgkin's Lymphoma and Acute Leukemia: An Open-Label, Single-Arm, Multi-center, Interventional Study.","authors":"Tianyou Wang,&nbsp;Xiaofan Zhu,&nbsp;Yumei Chen,&nbsp;Shuhong Shen,&nbsp;Yongmin Tang,&nbsp;Jingying Zhang,&nbsp;Yingyi He,&nbsp;Hui Zhang,&nbsp;Ju Gao,&nbsp;Jianpei Fang,&nbsp;Rong Liu,&nbsp;Xiaoyan Wu,&nbsp;Jinchuan Sun,&nbsp;Minlu Zhang","doi":"10.1007/s40268-023-00420-y","DOIUrl":"https://doi.org/10.1007/s40268-023-00420-y","url":null,"abstract":"<p><strong>Introduction: </strong>Despite rasburicase's proven efficiency in Caucasians, Japanese, and Koreans, studies evaluating the safety and effectiveness of rasburicase in Chinese pediatric patients with non-Hodgkin's lymphoma (NHL) and acute leukemia (AL) in particular are lacking.</p><p><strong>Objective: </strong>The aim was to evaluate the safety and effectiveness of rasburicase in Chinese pediatric patients with NHL and AL.</p><p><strong>Methods: </strong>In this phase IV, open-label, non-randomized, single-arm, multi-center, interventional study (NCT04349306), children newly diagnosed with NHL or AL who received 0.20 mg/kg/day of rasburicase were included. The primary objective was to assess the safety of rasburicase by the incidence of adverse events (AEs). The secondary objective was to determine the effectiveness of rasburicase in the control of hyperuricemia.</p><p><strong>Results: </strong>Out of 50 patients, 25 reported a total of 76 treatment-emergent adverse events (TEAEs), including eight TEAEs of grade ≥ 3 in 12 patients. A drug-related serious AE was reported in one patient, and there was no incidence of death. The response rate in the intent-to-treat population was 100.0% (95% confidence interval 82.4-100.0) in patients (n = 19) with baseline uric acid level of > 8.0 mg/dL. Similarly, the response rate was 86.2% (n = 25) among 29 patients (60.4%) with baseline uric acid levels of ≤ 8.0 mg/dL. The maximum mean percentage decrease of plasma uric acid level in the overall patients was 96.9%.</p><p><strong>Conclusion: </strong>Rasburicase was well tolerated and effective in controlling hyperuricemia in Chinese pediatric patients with NHL and AL.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 2","pages":"129-140"},"PeriodicalIF":3.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/5d/f2/40268_2023_Article_420.PMC10293550.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10224901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Estetrol: From Preclinical to Clinical Pharmacology and Advances in the Understanding of the Molecular Mechanism of Action.","authors":"Céline Gérard,&nbsp;Jean-Michel Foidart","doi":"10.1007/s40268-023-00419-5","DOIUrl":"https://doi.org/10.1007/s40268-023-00419-5","url":null,"abstract":"<p><p>Estetrol (E4) is the most recently described natural estrogen. It is produced by the human fetal liver during pregnancy and its physiological function remains unclear. E4 is the estrogenic component of a recently approved combined oral contraceptive. It is also in development for use as menopausal hormone therapy. In the context of these developments, the pharmacological activity of E4, alone or in combination with a progestin, has been extensively characterized in preclinical models as well as in clinical studies in women of reproductive age and postmenopausal women. Despite the clinical benefits, the use of oral estrogens for contraception or menopause is also associated with unwanted effects, such as an increased risk of breast cancer and thromboembolic events, due to their impact on non-target tissues. Preclinical and clinical data for E4 point to a tissue-specific activity and a more selective pharmacological profile compared with other estrogens, including a low impact on the liver and hemostasis balance. This review summarizes the characterization of the pharmacological properties of E4 as well as recent advances made in the understanding of the molecular mechanisms of action driving its activity. How the unique mode of action and the different metabolism of E4 might support its favorable benefit-risk ratio is also discussed.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 2","pages":"77-92"},"PeriodicalIF":3.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/06/55/40268_2023_Article_419.PMC10293541.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9760649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy of Baricitinib in Patients with Refractory Adult-Onset Still's Disease.","authors":"Ziyi Sun,&nbsp;Rongqi Li,&nbsp;Yingai Wang,&nbsp;Feng Han,&nbsp;Wei Wei,&nbsp;Xin Li","doi":"10.1007/s40268-023-00417-7","DOIUrl":"https://doi.org/10.1007/s40268-023-00417-7","url":null,"abstract":"<p><strong>Background and objective: </strong>Adult-onset Still's disease (AOSD) is an idiopathic systemic inflammatory disease of unknown aetiology. Some patients exhibit resistance to conventional treatment during long-term therapy. Janus kinase inhibitors (JAKinibs) may contribute to the improvement in AOSD symptoms via the JAK-signal transducer and activator of transcription (STAT) pathway. We aimed to explore the efficacy and safety of baricitinib in patients with refractory AOSD.</p><p><strong>Methods: </strong>Patients were enrolled if they fulfilled the Yamaguchi AOSD classification criteria in China between 2020 and 2022. All patients were recognized as having refractory AOSD and were treated with oral baricitinib at a dosage of 4 mg once daily. A systemic score and prednisone dosage were used to evaluate the efficacy of baricitinib at months 1, 3, and 6 and at the last follow-up visit. The safety profiles were recorded and analysed at every assessment.</p><p><strong>Results: </strong>Seven female patients with refractory AOSD received baricitinib. The median age was 31 (IQR 10) years. Treatment was terminated in one patient due to progressive macrophage activation syndrome (MAS). Others continued baricitinib treatment until the last assessment. The systemic score decreased significantly at 3 months (p = 0.0216), 6 months (p = 0.0007), and the last follow-up visit (p = 0.0007) compared with baseline. One month after the initiation of baricitinib, the rates of improvement in fever, rash, sore throat, and myalgia symptoms were 71.4% (5/7), 40% (2/5), 80% (4/5), and 66.7% (2/3), respectively. Five patients remained symptom-free at the last follow-up visit. In most patients, their laboratory values had returned to normal by the last follow-up visit. A significant reduction in the levels of C-reactive protein (CRP) (p = 0.0165) and ferritin (p = 0.0047) was observed at the last visit compared with baseline. The daily prednisolone dosage significantly decreased from 35.7 ± 15.1 mg/day at baseline to 8.8 ± 4.4 mg/day by month 6 (p = 0.0256), and it was 5.8 ± 4.7 mg/day at the last assessment (p = 0.0030). Leukopenia due to MAS was noted in one patient. Except for mild abnormalities in lipid parameters, no other severe adverse events occurred during follow-up.</p><p><strong>Conclusions: </strong>Our findings suggest that baricitinib therapy could provide rapid and durable clinical and laboratory improvement in patients with refractory AOSD. Treatment seemed to be well tolerated by these patients. The long-term efficacy and safety of baricitinib therapy for AOSD should be assessed further in prospective controlled clinical trials in the future.</p><p><strong>Trial registration: </strong>Trial registration number (TRN): ChiCTR2200061599. Date of registration: 29 June 2022 (retrospectively registered).</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 2","pages":"109-120"},"PeriodicalIF":3.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/44/8b/40268_2023_Article_417.PMC10293510.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9705900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Randomized, Double-Blind, Parallel-Controlled Phase I Study Comparing the Pharmacokinetics, Safety, and Immunogenicity of SCT510 to Bevacizumab (Avastin^®) in Healthy Chinese Males.","authors":"Jing Wu,&nbsp;Guolan Wu,&nbsp;Liangzhi Xie,&nbsp;Duo Lv,&nbsp;Chang Xu,&nbsp;Huili Zhou,&nbsp;Lihua Wu,&nbsp;Jingjing Zhang,&nbsp;Jianzhong Shentu","doi":"10.1007/s40268-023-00424-8","DOIUrl":"https://doi.org/10.1007/s40268-023-00424-8","url":null,"abstract":"<p><strong>Background: </strong>SCT510 is a recombinant humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF), which is intended as a candidate biosimilar of bevacizumab that is approved for various metastatic cancers.Please confirm change in wording to match definition for VEGF belowYes.</p><p><strong>Objective: </strong>This study aimed to compare the pharmacokinetics profiles, safety, and immunogenicity of SCT510 to bevacizumab (Avastin^®) in healthy Chinese males.</p><p><strong>Methods: </strong>This was a single-center, double-blind, parallel-group phase I study. A total of 84 participants were randomly assigned (1:1) to receive a single 3 mg/kg infusion of either SCT510 or bevacizumab and followed up for 99 days. Primary endpoints were area under the serum concentration-time curve from time 0 extrapolated to infinity (AUC_0-∞), area under the serum concentration-time curve from time 0 to last quantifiable concentration (AUC_0-t), and the maximum observed concentration (C_max). Secondary endpoints included safety and immunogenicity.Kindly check and confirm the edit made in the article title.Yes.</p><p><strong>Results: </strong>A total of 82 subjects completed the study. Geometric means ratios (GMR) for AUC_0-∞, AUC_0-t, and C_max were 0.88, 0.89, and 0.97, respectively, for SCT510 versus bevacizumab (USA). The 90% confidence intervals for GMRs of AUC_0-∞, AUC_0-t, and C_max were all within the prespecified criteria (80-125%). No adverse events (AEs) led to study termination, and no serious adverse events (SAEs) were reported. None of the anti-drug antibodies (ADAs) identified were found to be neutralizing antibodies (NAbs), and only one subject from the SCT510 group tested positive for the ADA at the day 99 visit.</p><p><strong>Conclusion: </strong>This study demonstrated that the pharmacokinetics, safety, and immunogenicity of SCT510 were equivalent to bevacizumab (Avastin^®). As a proposed biosimilar drug to bevacizumab, SCT510 was well tolerated in healthy Chinese males.</p><p><strong>Clinical trials registration: </strong>NCT05113511.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 2","pages":"175-183"},"PeriodicalIF":3.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/1e/17/40268_2023_Article_424.PMC10293153.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9706556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a Biosimilar of Agalsidase Beta for the Treatment of Fabry Disease: Preclinical Evaluation.","authors":"André B P van Kuilenburg,&nbsp;Carla E M Hollak,&nbsp;Ana Travella,&nbsp;Melisa Jacobs,&nbsp;Lucas D Gentilini,&nbsp;René Leen,&nbsp;Karen M M Ghauharali-van der Vlugt,&nbsp;Femke S Beers Stet,&nbsp;Susan M I Goorden,&nbsp;Sanne van der Veen,&nbsp;Marcelo Criscuolo,&nbsp;Mariana Papouchado","doi":"10.1007/s40268-023-00421-x","DOIUrl":"https://doi.org/10.1007/s40268-023-00421-x","url":null,"abstract":"<p><strong>Background and objective: </strong>Fabry disease (FD) is a rare lysosomal storage disorder caused by a deficiency of the enzyme α-galactosidase A (aGal A). Since 2001, two different enzyme replacement therapies have been authorized, with agalsidase beta being used in most parts of the Western world. Currently, biosimilars of several expensive enzyme therapies are under development to improve their accessibility for patients. We present the preclinical results of the development of a biosimilar to agalsidase beta.</p><p><strong>Methods: </strong>Produced in a Chinese hamster ovary (CHO)-cell system, the biosimilar aGal A Biosidus (AGABIO), was compared with agalsidase beta with respect to amino acid sequence, glycosylation, specific α-galactosidase activity, stability in plasma, and effects on cultured human Fabry fibroblasts and Fabry mice.</p><p><strong>Results: </strong>AGABIO had the same amino acid composition and similar glycosylation, enzymatic activity, and stability as compared with agalsidase beta. After uptake in fibroblasts, α-galactosidase A activity increased in a dose-dependent manner, with maximum uptake observed after 24 h, which remained stable until at least 48 h. Both enzymes were localized to lysosomes. Reduction of accumulated globotriaosylceramide (Gb3) and lysoGb3 in cultured Fabry fibroblasts by AGABIO and agalsidase beta showed comparable dose-response curves. In Fabry knockout mice, after a single injection, both enzymes were rapidly cleared from the plasma and showed equal reductions in tissue and plasma sphingolipids. Repeated dose studies in rats did not raise any safety concerns. Anti-drug antibodies from patients with FD treated with agalsidase beta showed equal neutralization activity toward AGABIO.</p><p><strong>Conclusion: </strong>These findings support the biosimilarity of AGABIO in comparison with agalsidase beta. The clinical study phase is currently under development.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 2","pages":"141-153"},"PeriodicalIF":3.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/84/bf/40268_2023_Article_421.PMC10293523.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9709367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioavailability of Cariban^® Capsules: A Modified-Release Fixed-Dose Combination of Doxylamine and Pyridoxine to Relieve Nausea and Vomiting During Pregnancy.","authors":"Paula Saz-Leal, Laura Zamorano-Domínguez, Jesús Frías, Pedro Guerra, Marc Saura-Valls, Ramón Roca-Juanes, Joaquín Nebot-Troyano, Eva García-Aguilar, Tatiana Vilchez, Katia Urso","doi":"10.1007/s40268-023-00425-7","DOIUrl":"10.1007/s40268-023-00425-7","url":null,"abstract":"<p><strong>Background: </strong>Nausea and vomiting is a very prevalent condition during pregnancy. Combination of doxylamine and pyridoxine is placed as first-line pharmacological option for its treatment in most clinical guidelines. Among different release forms available, Cariban^® is a fixed-dose combination of doxylamine/pyridoxine 10/10 mg, formulated as modified-release capsules.</p><p><strong>Objectives: </strong>In the present study, we aimed to characterize the bioavailability performance of Cariban^® in vitro and in vivo.</p><p><strong>Methods: </strong>An in vitro dissolution test was performed to evaluate the release profile of Cariban^®, together with immediate- and delayed-release formulations available on the market. A single-center, single-dose, open-label bioavailability study following Cariban^® administration in 12 healthy adult female patients was carried out to explore the drug behavior in vivo (protocol NBR-002-13; EUDRA-CT 2013-005422-35). These data were additionally used to perform a computational pharmacokinetic simulation of the posology approved for this drug.</p><p><strong>Results: </strong>Cariban^® capsules demonstrate a prolonged-release performance, with an early, gradual, and progressive release of both actives until reaching a complete dissolution after 4-5 h in solution. The pharmacokinetic features of these capsules show that doxylamine and pyridoxine metabolites are early absorbed, being all detectable in plasma within 1 h following oral administration. Computational pharmacokinetic simulation predicts that different posology provides distinct profiles of metabolites in plasma, with 1-1-2 (morning-midafternoon-night) being the one that concentrates higher plasma levels but lower dose dumping for 24 h.</p><p><strong>Conclusion: </strong>Cariban^® behaves as a prolonged-release formulation, which correlates with rapid absorption and arising of the actives in the plasma, but also long-lasting and sustained bioavailability, especially when administered following the complete posology. These results would underlie its demonstrated efficacy to relieve nausea and vomiting of pregnancy (NVP) under clinical settings.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 2","pages":"185-195"},"PeriodicalIF":2.2,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/98/42/40268_2023_Article_425.PMC10293548.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10084391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Phase I Study to Investigate the Safety, Tolerability and Pharmacokinetics of Napabucasin Combined with Sorafenib in Japanese Patients with Unresectable Hepatocellular Carcinoma.","authors":"Takuji Okusaka, Manabu Morimoto, Yuichiro Eguchi, Shinichiro Nakamura, Shuichi Iino, Rie Kageyama","doi":"10.1007/s40268-023-00416-8","DOIUrl":"10.1007/s40268-023-00416-8","url":null,"abstract":"<p><strong>Background and objective: </strong>For patients with advanced hepatocellular carcinoma (HCC), the standard of care for many years has been sorafenib. Preliminary data have suggested that the combination of the NAD(P)H:quinone oxidoreductase 1 bioactivatable agent napabucasin plus sorafenib may improve clinical outcomes in patients with HCC. In this phase I, multicenter, uncontrolled, open-label study, we evaluated napabucasin (480 mg/day) plus sorafenib (800 mg/day) in Japanese patients with unresectable HCC.</p><p><strong>Methods: </strong>Adults with unresectable HCC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled in a 3 + 3 trial design. The occurrence of dose-limiting toxicities was assessed through 29 days from the start of napabucasin administration. Additional endpoints included safety, pharmacokinetics, and preliminary antitumor efficacy.</p><p><strong>Results: </strong>In the six patients who initiated treatment with napabucasin, no dose-limiting toxicities occurred. The most frequently reported adverse events were diarrhea (83.3%) and palmar-plantar erythrodysesthesia syndrome (66.7%), all of which were grade 1 or 2. The pharmacokinetic results for napabucasin were consistent with prior publications. The best overall response (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) was stable disease in four patients. Using Kaplan-Meier methodology, the 6-month progression-free survival rate was 16.7% per RECIST 1.1 and 20.0% per modified RECIST for HCC. The 12-month overall survival rate was 50.0%.</p><p><strong>Conclusions: </strong>These findings confirm the viability of napabucasin plus sorafenib treatment, and there were no safety or tolerability concerns in Japanese patients with unresectable HCC.</p><p><strong>Clinical trial registration: </strong>ClinicalTrials.gov identifier NCT02358395, registered on 9 February 2015.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 2","pages":"99-107"},"PeriodicalIF":2.2,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/9b/41/40268_2023_Article_416.PMC10293504.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9704732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}