Clinical Pharmacology in Drug Development最新文献_第6页

Pharmacokinetics, Receptor Occupancy, and Pharmacodynamics of Obexelimab Following Intravenous Administration in Adult Healthy Volunteers and in Patients With Rheumatoid Arthritis 成人健康志愿者和类风湿关节炎患者静脉给药后奥贝昔单抗的药代动力学、受体占用和药效学

IF 1.8 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-06-13 DOI: 10.1002/cpdd.1557

Xiaodong Wang, Minggeng Gao, Mark Matijevic, Shauna Quinn, Mason Yamashita, Sujata Arora, Allen Poma

{"title":"Pharmacokinetics, Receptor Occupancy, and Pharmacodynamics of Obexelimab Following Intravenous Administration in Adult Healthy Volunteers and in Patients With Rheumatoid Arthritis","authors":"Xiaodong Wang, Minggeng Gao, Mark Matijevic, Shauna Quinn, Mason Yamashita, Sujata Arora, Allen Poma","doi":"10.1002/cpdd.1557","DOIUrl":"10.1002/cpdd.1557","url":null,"abstract":"Obexelimab is an investigational, bifunctional, nondepleting, humanized monoclonal antibody that binds CD19 and FcγRIIb to inhibit B-lineage cell activity. This study evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of obexelimab administered intravenously in healthy volunteers (n = 48; single doses of 0.03-10.0 mg/kg) and patients with rheumatoid arthritis (n = 57; 6 doses of 0.3-10.0 mg/kg every 2 weeks). After single-dose administration, obexelimab exhibited nonlinear PK consistent with target-mediated drug disposition, with terminal elimination half-life increasing from 34.4 to 102 hours and clearance decreasing from 42.4 to 16.4 mL/day/kg across the dose range. Multiple dosing every 2 weeks demonstrated more linear PK with low accumulation (8%-22% increase in area under the concentration–time curve). Complete CD19 receptor occupancy occurred rapidly across doses, while CD20+ B-cell counts decreased to approximately 50% of baseline with dose-dependent recovery (15-61 days after single doses). Immunomodulatory effects included partial suppression of CD86 expression and significant reduction in antigen-specific antibody responses. Antidrug antibodies were detected in 44.4% and 17.5% of participants in single- and multiple-dose studies, respectively, with neutralizing antibodies in 0% and 2.5%. Obexelimab was generally well-tolerated, primarily mild-to-moderate gastrointestinal events occurring more frequently than with placebo. These results support further development of obexelimab for autoimmune disorders.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"14 9","pages":"656-668"},"PeriodicalIF":1.8,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pharmacokinetics, Bioequivalence, and Safety Studies of Crisaborole Ointment in Healthy Chinese Subjects Crisaborole软膏在中国健康人体内的药代动力学、生物等效性和安全性研究。

IF 1.8 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-06-09 DOI: 10.1002/cpdd.1552

Yanchao Wang, Xiaofei Zhao, Taixin Wang, Luning Xiong, Xiujuan Liu, Jing Pan, Wen Yin, Chao Zhang, Jining Dong, Kexin Zhao

{"title":"Pharmacokinetics, Bioequivalence, and Safety Studies of Crisaborole Ointment in Healthy Chinese Subjects","authors":"Yanchao Wang, Xiaofei Zhao, Taixin Wang, Luning Xiong, Xiujuan Liu, Jing Pan, Wen Yin, Chao Zhang, Jining Dong, Kexin Zhao","doi":"10.1002/cpdd.1552","DOIUrl":"10.1002/cpdd.1552","url":null,"abstract":"The aim of this study was to evaluate the bioequivalence and safety of a single application of crisaborole ointment to test formulation and reference formulation in healthy subjects under fasting conditions. A total of 32 subjects were included and divided into 2 groups (test-reference; reference-test). A single-center, single-dose, 2-formulation, 2-period, 2-sequence, open, randomized, and crossover trial design was adopted. Eligible healthy subjects were applied with the test preparation (domestic crisaborole ointment) or the reference preparation (original crisaborole ointment), followed by a 7-day washout period. Blood samples were collected at predetermined time points before and after administration. After the development and verification of the blood concentration detection method for this study, the third-party supplier used liquid chromatography-tandem mass spectrometry to determine the plasma concentration of crisaborole and used SAS Version 9.4 software to calculate the pharmacokinetic parameters and evaluate the bioequivalence. In this study, the 90% confidence intervals of the geometric mean ratios of maximum concentration, area under the concentration-time curve over the dosing interval, and area under the concentration-time curve from time 0 to infinity were within the acceptable range (80%-125%). During the study, 5 subjects had 8 adverse events, and no serious adverse events were reported. In this study, the tested formulation of crisaborole ointment is bioequivalent to the reference formulation, and the safety is comparable.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"14 8","pages":"614-620"},"PeriodicalIF":1.8,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1552","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246795","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}

引用次数: 0

Comparative Pharmacokinetics and Bioequivalence of Two Sodium Valproate Tablets in Healthy Chinese Subjects Under Fasting and Fed Conditions 两种丙戊酸钠片在空腹和空腹条件下的比较药动学和生物等效性。

IF 1.8 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-06-08 DOI: 10.1002/cpdd.1563

Yuan Liu, Xueqiong Peng, Mengfei Zhao, Fengzhi Liu, Xintong Wang, Lulu Chen, Chao Li, Ling Zhou, Qing Fang, Weiming Chen, Dongsheng Ouyang, Xiaohui Li, Junmei Xu, Yuyan Lei

{"title":"Comparative Pharmacokinetics and Bioequivalence of Two Sodium Valproate Tablets in Healthy Chinese Subjects Under Fasting and Fed Conditions","authors":"Yuan Liu, Xueqiong Peng, Mengfei Zhao, Fengzhi Liu, Xintong Wang, Lulu Chen, Chao Li, Ling Zhou, Qing Fang, Weiming Chen, Dongsheng Ouyang, Xiaohui Li, Junmei Xu, Yuyan Lei","doi":"10.1002/cpdd.1563","DOIUrl":"10.1002/cpdd.1563","url":null,"abstract":"Sodium valproate, a broad-spectrum antiseizure medication of the fatty acid derivative class, was investigated in this study. The trial was designed as a single-center, open-label, randomized, 2-treatment, 4-period, 2-sequence crossover study conducted among healthy Chinese subjects. The objective was to evaluate the pharmacokinetic properties and bioequivalence of a novel generic 0.2g sodium valproate tablet and the branded reference product under fasting (n = 28) and fed (n = 28) conditions, with a 14-day washout period between dosing periods. Blood samples were collected at predefined time points within 72 hours after dosing, and plasma valproic acid concentrations were quantified using a validated liquid chromatography-tandem mass spectrometry method. The results demonstrated comparable pharmacokinetic profiles between the formulations, with the 90% confidence intervals for both maximum plasma concentration and area under the concentration-time curve falling entirely within the 80%-125% bioequivalence acceptance range. Additionally, although food coadministration reduced maximum plasma concentration and delayed time to maximum concentration, area under the concentration-time curve remained unaffected. Regarding safety, neither formulation caused serious adverse events, and both exhibited similar safety profiles. These findings indicate that the generic sodium valproate tablet is bioequivalent to the reference product, with both formulations showing consistent bioequivalence and safety.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"14 9","pages":"728-734"},"PeriodicalIF":1.8,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Effect of Itraconazole or Rifampin on Zilurgisertib Pharmacokinetics When Administered Orally in Healthy Participants 伊曲康唑或利福平对健康受试者口服Zilurgisertib药代动力学的影响

IF 1.8 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-06-04 DOI: 10.1002/cpdd.1553

Yan-ou Yang, Xiaohua Gong, Phillip Wang, Xiang Liu, Jay Getsy, Jennifer Sheng, Swamy Yeleswaram, Xuejun Chen, Kevin Rockich

{"title":"Effect of Itraconazole or Rifampin on Zilurgisertib Pharmacokinetics When Administered Orally in Healthy Participants","authors":"Yan-ou Yang, Xiaohua Gong, Phillip Wang, Xiang Liu, Jay Getsy, Jennifer Sheng, Swamy Yeleswaram, Xuejun Chen, Kevin Rockich","doi":"10.1002/cpdd.1553","DOIUrl":"10.1002/cpdd.1553","url":null,"abstract":"Zilurgisertib is an oral, activin receptor-like kinase 2 (ALK2) inhibitor being developed for the treatment of patients with fibrodysplasia ossificans progressiva. In vitro metabolism studies suggest zilurgisertib is primarily eliminated via cytochrome P450 (CYP) 3A4/5-mediated metabolism, with an additional contribution from renal excretion. A drug-drug interaction study was conducted to evaluate the impact of the strong CYP3A inhibitor itraconazole and the strong CYP3A4 inducer rifampin on the pharmacokinetics of zilurgisertib in healthy participants. Participants in Cohort 1 (n = 18) received zilurgisertib 100 mg on Days 1 and 10 and itraconazole 200 mg once daily on Days 6-13. Participants in Cohort 2 (n = 18) received zilurgisertib 100 mg on Days 1 and 13 and rifampin 600 mg once daily on Days 6-15. With the concomitant administration of itraconazole, the geometric mean maximum plasma drug concentration (Cmax) and area under the concentration-time curve from time 0 to infinity (AUC0-inf) of zilurgisertib increased by 1.28- and 2.13-fold, respectively. With the concomitant administration of rifampin, there was a 2.27- and 4.76-fold reduction in the geometric mean Cmax and AUC0-inf of zilurgisertib, respectively. No dose-limiting toxicities occurred in either cohort, and all treatment-emergent adverse events were Grade 1 in severity. Zilurgisertib dose adjustment may be necessary with concomitant administration of strong CYP3A4 inhibitors, and coadministration of zilurgisertib with strong CYP3A4 inducers is not recommended.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"14 8","pages":"583-591"},"PeriodicalIF":1.8,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Bioequivalence of a Donepezil/Memantine 10/20 mg Fixed-Dose Combination Versus Single-Component Tablets in Healthy Korean Males 多奈哌齐/美金刚10/ 20mg固定剂量组合与单组分片剂在健康韩国男性中的生物等效性

IF 1.8 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-05-30 DOI: 10.1002/cpdd.1556

Minkyu Choi, Byung Hak Jin, Do Hoon Keum, Kyoung Hoon Mo, Min Soo Park, Juhwan Lee, Sungjin Park, Choon Ok Kim

{"title":"Bioequivalence of a Donepezil/Memantine 10/20 mg Fixed-Dose Combination Versus Single-Component Tablets in Healthy Korean Males","authors":"Minkyu Choi, Byung Hak Jin, Do Hoon Keum, Kyoung Hoon Mo, Min Soo Park, Juhwan Lee, Sungjin Park, Choon Ok Kim","doi":"10.1002/cpdd.1556","DOIUrl":"10.1002/cpdd.1556","url":null,"abstract":"A fixed-dose combination (FDC) tablet formulation of donepezil/memantine (10/20 mg) was developed to improve medication compliance in patients with Alzheimer's disease (AD). This study compared the pharmacokinetic (PK) characteristics and safety profiles of an FDC formulation (donepezil/memantine [10/20 mg]) and single components (SCs) of donepezil (10 mg) and memantine (20 mg). In a randomized, open-label, single-dose, 2-way crossover study, 24 healthy Korean participants received a single oral dose of FDC in 1 period and an SC of donepezil and memantine in another period. For PK analysis, blood samples were collected up to 240 hours after administration. The geometric mean ratios and their 90% confidence intervals for the main PK parameters (Cmax and AUClast) indicated PK equivalence between the FDC and SC formulations. Regarding the safety profile, all adverse events were mild, with no serious adverse events. These findings support the use of an FDC formulation as a viable alternative to SCs of donepezil and memantine, potentially improving treatment adherence in patients with moderate-to-severe AD.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"14 9","pages":"710-716"},"PeriodicalIF":1.8,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1556","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186666","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}

引用次数: 0

Microtracer-Based Assessment of the Mass Balance, Pharmacokinetics, and Excretion of [14C]Berzosertib, an Intravenous ATR Inhibitor, in Patients With Advanced Solid Tumors: A Phase 1 Study 基于微示踪剂评估晚期实体瘤患者静脉注射ATR抑制剂Berzosertib的质量平衡、药代动力学和排泄：一项1期研究

IF 1.8 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-05-28 DOI: 10.1002/cpdd.1554

Jayaprakasam Bolleddula, Holger Scheible, Florian Huber, Annick Seithel-Keuth, Hanno Schieferstein, Deepthi S. Vagge, Nadra Mammasse, Eva Jaks, Jordi Ferrer, Camilo Moulin, Jennifer Dong, Karthik Venkatakrishnan, Zsuzsanna Papai

{"title":"Microtracer-Based Assessment of the Mass Balance, Pharmacokinetics, and Excretion of [14C]Berzosertib, an Intravenous ATR Inhibitor, in Patients With Advanced Solid Tumors: A Phase 1 Study","authors":"Jayaprakasam Bolleddula, Holger Scheible, Florian Huber, Annick Seithel-Keuth, Hanno Schieferstein, Deepthi S. Vagge, Nadra Mammasse, Eva Jaks, Jordi Ferrer, Camilo Moulin, Jennifer Dong, Karthik Venkatakrishnan, Zsuzsanna Papai","doi":"10.1002/cpdd.1554","DOIUrl":"10.1002/cpdd.1554","url":null,"abstract":"Berzosertib is a small-molecule ataxia telangiectasia and Rad3-related protein inhibitor. To assess the clearance mechanism(s) of berzosertib, a Phase 1, 2-period, open-label study was conducted in adults with advanced solid tumors who were treated with a single intravenous dose of 210 mg/m2 berzosertib containing approximately 3 µCi of [14C]berzosertib (Period 1 Mass Balance), followed by assessment of berzosertib in combination with topotecan (Period 2 [Extension]) (NCT05246111). A total of 6 patients were enrolled in Period 1; 5 of them rolled over to Period 2. By Day 14, the mean total recovery of drug-related material (total radioactivity) in urine and feces combined was 89.5% (feces: 73.7%; urine: 15.8%). Pharmacokinetic data suggested that a substantial amount of various circulating metabolites of berzosertib were present in plasma (78% of drug-related material), with a longer terminal elimination half-life of total radioactivity than unchanged berzosertib. M11, which is pharmacologically inactive, was identified as the major circulating metabolite (28.2% of drug-related material). The safety profile of berzosertib and topotecan was consistent with prior clinical experience. Overall, the study established the predominant role of metabolic clearance in berzosertib disposition and characterized its metabolites structurally. No new safety concerns were identified with berzosertib as a single agent or in combination with topotecan.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"14 9","pages":"700-709"},"PeriodicalIF":1.8,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1554","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144173224","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}

引用次数: 0

A Randomized Thorough QT Trial Using Concentration-QT Analysis to Evaluate the Effects of Centanafadine on Cardiac Repolarization 一项随机、全面的QT试验，使用浓度-QT分析来评估Centanafadine对心脏复极的影响。

IF 1.8 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-05-27 DOI: 10.1002/cpdd.1545

Osman S. Turkoglu, Xiaofeng Wang, Jennifer Repella-Gordon, Susan E. Shoaf

{"title":"A Randomized Thorough QT Trial Using Concentration-QT Analysis to Evaluate the Effects of Centanafadine on Cardiac Repolarization","authors":"Osman S. Turkoglu, Xiaofeng Wang, Jennifer Repella-Gordon, Susan E. Shoaf","doi":"10.1002/cpdd.1545","DOIUrl":"10.1002/cpdd.1545","url":null,"abstract":"Centanafadine is a norepinephrine/dopamine/serotonin reuptake inhibitor in development for treatment of attention-deficit/hyperactivity disorder. This double-blind, placebo- and moxifloxacin-controlled, 3-period crossover trial evaluated the effects of centanafadine (EB-1020) and its metabolite (EB-10601) on cardiac repolarization in 30 healthy adults (18-65 years). Dosing sequences included centanafadine sustained-release 800 mg (supratherapeutic) total daily dose, placebo, and moxifloxacin 400 mg. Electrocardiogram parameters and heart rate (HR) were assessed. The primary endpoint was placebo-corrected change from baseline QTc (ΔΔQTc), analyzed using concentration-QTc (C-QTc) analysis. The C-QTc slopes for centanafadine (−0.001 ms/[ng/mL]) and EB-10601 (−0.0003 ms/[ng/mL]) were not statistically significant. Assay sensitivity was confirmed by the statistically significant C-QTc slope for moxifloxacin (0.004 ms/[ng/mL]) and a 2-sided 90% confidence interval lower bound >5 milliseconds. No change from baseline in QTcF or placebo-corrected QTcF ≥10 milliseconds for centanafadine was observed at any postdose time point. No centanafadine-treated participants had QTcF increases of >30 milliseconds and no relevant PR/QRS interval or HR increases were observed. The predicted ΔΔQTcF values of centanafadine, EB-10601, and moxifloxacin at the geometric mean Cmax were −2.72, −1.59, and 11.75 milliseconds, respectively. No serious treatment-emergent adverse events or deaths were reported. Centanafadine was generally safe and well-tolerated, with no clinically meaningful effect on cardiac repolarization.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"14 8","pages":"621-630"},"PeriodicalIF":1.8,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1545","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157223","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}

引用次数: 0

Combined Immediate-Release and Extended-Release Formulation of Sodium Valproate Provides Stable Plasma Levels for Inhibition of Histone Deacetylation 丙戊酸钠速释和缓释联合制剂提供稳定的血浆水平来抑制组蛋白去乙酰化。

IF 1.8 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-05-27 DOI: 10.1002/cpdd.1555

Nikhil Ahuja, Susanna Kääriäinen, Zsófia Lovró, Mia Lundblad, Kristina Drott, Elsa Lilienberg, Marica T. Engström, Karla Saukkonen, Mika Scheinin

{"title":"Combined Immediate-Release and Extended-Release Formulation of Sodium Valproate Provides Stable Plasma Levels for Inhibition of Histone Deacetylation","authors":"Nikhil Ahuja, Susanna Kääriäinen, Zsófia Lovró, Mia Lundblad, Kristina Drott, Elsa Lilienberg, Marica T. Engström, Karla Saukkonen, Mika Scheinin","doi":"10.1002/cpdd.1555","DOIUrl":"10.1002/cpdd.1555","url":null,"abstract":"A modified controlled-release sodium valproate formulation (VAL001, test) was compared with an approved enteric-coated tablet formulation (Absenor, reference). Pharmacokinetics and safety/tolerability were evaluated in healthy subjects to bridge with positive efficacy results from an early-phase patient trial of valproate in combination with chemotherapy in diffuse large B-cell lymphoma. In Part I (n = 12), both formulations were administered as single doses (30 mg/kg) in a randomized crossover fashion. Equivalent exposures (area under the plasma concentration–time curve) for total and free valproate were observed under fasted conditions. Intake with food delayed the absorption of valproate from the test formulation, with no impact on AUC. In Part II (n = 27), both formulations were administered over 3 consecutive days, at 30 mg/kg twice daily (test) or 20 mg/kg 3 times daily (reference). Similar steady-state levels were observed, but fluctuation was less with the test product (23% vs. 47%, P = .0102). Inhibition of histone deacetylase activity was evidenced by increased levels of acetylated H3K9 in peripheral blood mononuclear cells. No serious or severe adverse events were observed. The novel capsule formulation of valproate, containing a combination of immediate-release granules and extended-release pellets, appears to have suitable pharmacokinetic properties for cancer treatments aiming for histone deacetylase inhibition.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"14 9","pages":"717-727"},"PeriodicalIF":1.8,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1555","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157226","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}

引用次数: 0

Pharmacokinetics, Safety, and Tolerability of Single-Dose Dazukibart in Healthy Adults in China and Japan: Results From 2 Randomized, Double-Blind, Phase 1 Studies 中国和日本健康成人单剂量大佐吉bart的药代动力学、安全性和耐受性：来自2项随机、双盲、1期研究的结果

IF 1.8 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-05-22 DOI: 10.1002/cpdd.1522

Naihan Chen, Yamato Sano, Xiaohong Wang, Shuiyi Hu, Junichi Tabira, Xin Luo, Hiroki Yoshimatsu, John Prybylski, Myron Chu, Haiyan Li, Kenji Takazawa

{"title":"Pharmacokinetics, Safety, and Tolerability of Single-Dose Dazukibart in Healthy Adults in China and Japan: Results From 2 Randomized, Double-Blind, Phase 1 Studies","authors":"Naihan Chen, Yamato Sano, Xiaohong Wang, Shuiyi Hu, Junichi Tabira, Xin Luo, Hiroki Yoshimatsu, John Prybylski, Myron Chu, Haiyan Li, Kenji Takazawa","doi":"10.1002/cpdd.1522","DOIUrl":"10.1002/cpdd.1522","url":null,"abstract":"Dazukibart is a humanized monoclonal antibody selectively targeting interferon-β. The pharmacokinetics (PK), safety, tolerability, and immunogenicity of dazukibart were evaluated in 2 double-blind, randomized, placebo-controlled, single-dose, Phase 1 studies in healthy adults in China (Study 1: N = 18; dazukibart 900 mg = 15; placebo = 3) and Japan (Study 2: N = 12; Cohort 1: dazukibart 300 mg = 5, placebo = 1; and Cohort 2: dazukibart 900 mg = 5, placebo = 1). PK parameters were assessed after dosing in Study 1 and Study 2, and no significant differences were observed between PK findings among participants in both studies. A biphasic decline in dazukibart serum concentrations was observed in both studies. Exposures increased dose proportionally in Study 2. Body weight, but not race, was identified as an independent covariate of exposure using population PK modeling (including data from a Phase 1 US study [NCT02766621]). No deaths/discontinuations or serious/severe adverse events were observed, mostly mild adverse events were reported. No participants in Study 1 were antidrug antibody positive; 20.0% in Study 2 were positive for treatment-induced antidrug antibodies and neutralizing antibodies. PK parameters and immunogenicity rates were consistent with the US study, and no new safety signals were identified.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"14 8","pages":"572-582"},"PeriodicalIF":1.8,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1522","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119135","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}

引用次数: 0

Pharmacokinetics and Safety Study of HN0141, a Novel Anti-Human Cytomegalovirus Inhibitor, in Healthy Volunteers 新型抗人巨细胞病毒抑制剂HN0141在健康志愿者体内的药动学及安全性研究

IF 1.8 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-05-16 DOI: 10.1002/cpdd.1542

George Hill, Hong Gao, Yingzhe Fan, Rui Zhang, Lu Wang, Zhaoshan Zong, Yi Zhou, Donghui Qin, Jie Hou

{"title":"Pharmacokinetics and Safety Study of HN0141, a Novel Anti-Human Cytomegalovirus Inhibitor, in Healthy Volunteers","authors":"George Hill, Hong Gao, Yingzhe Fan, Rui Zhang, Lu Wang, Zhaoshan Zong, Yi Zhou, Donghui Qin, Jie Hou","doi":"10.1002/cpdd.1542","DOIUrl":"10.1002/cpdd.1542","url":null,"abstract":"HN0141 is a human cytomegalovirus (HCMV) DNA terminase complex inhibitor being developed for prophylaxis and/or preemptive treatment of HCMV infection and diseases. This study evaluated the safety, tolerability, and pharmacokinetics (PK) of HN0141, following oral administration in healthy volunteers. The double-blind, placebo-controlled Phase 1 study comprised Part 1, an escalating, single-dose study involving 50-, 100-, 200-, 300-, 400-, and 525-mg doses; and Part 2, a multiple-dose study over 7 days involving 50-, 100-, 200-, and 400-mg twice-daily doses. HN0141 was rapidly absorbed following oral doses, with median time to maximum concentration achieved within 1-2 hours across all doses. At doses ranging from 50 to 100 mg, the PK profile was reasonably linear, while at doses above 200 mg, the PK profile was more than proportional. The predicted therapeutic dose would be 50-200 mg twice daily, which is at a reasonable linear PK range. All exposures tested (up to 525-mg single dose and 400-mg twice-daily multiple doses) were within the no-observed-adverse-effect level defined in animal toxicity studies. There was a mild accumulation on systemic exposure at steady state, which was achieved within 72 hours of multiple twice-daily dosing. No serious or severe adverse events were reported. HN0141's PK profile favors the twice-daily dosing, which gives a smaller concentration variation during the treatment, and thus could bring a better treatment effect with sufficient convenience. These Phase 1 data in safety and PK profile warrant further drug development in both preemptive and prophylactic treatment in patients with HCMV.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"14 9","pages":"680-687"},"PeriodicalIF":1.8,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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