Clinical Pharmacology in Drug Development最新文献_第3页

Determination of the Bioavailability of 3 Intranasal Formulations of Azelastine Hydrochloride in Healthy Male Volunteers 3种盐酸氮扎elastine鼻内制剂在健康男性体内的生物利用度测定。

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-01-09 DOI: 10.1002/cpdd.1498

Jean Bousquet, Ludger Klimek, Mark Liu, Duc Tung Nguyen, Rajesh Kumar Ramalingam, Georgio Walter Canonica, William E. Berger

{"title":"Determination of the Bioavailability of 3 Intranasal Formulations of Azelastine Hydrochloride in Healthy Male Volunteers","authors":"Jean Bousquet, Ludger Klimek, Mark Liu, Duc Tung Nguyen, Rajesh Kumar Ramalingam, Georgio Walter Canonica, William E. Berger","doi":"10.1002/cpdd.1498","DOIUrl":"10.1002/cpdd.1498","url":null,"abstract":"The primary objective of the study was to determine the bioavailability of 2 new formulations of azelastine (AZE) hydrochloride (0.10% and 0.15% AZE) containing sorbitol and sucralose compared with the commercially available 0.10% AZE. This study was performed in healthy volunteers based on the pharmacokinetic parameters maximum plasma concentration and area under the plasma concentration–time curve from time zero to the last measurable concentration. This was a Phase 1, open-label, single-center, randomized, parallel-group study. Subjects were randomized to 1 of 3 treatment groups: (1) 0.10% AZE (treatment A), (2) 0.15% AZE (treatment B) (Groups 1 and 2 both containing sorbitol and sucralose), and (3) the commercially available 0.10% AZE (treatment C). A total of 54 subjects were randomized and received treatment A, B, or C. Maximum plasma concentration and area under the plasma concentration–time curve were similar when compared in treatments A and C (0.1%) for AZE and its metabolite, desmethylazelastine. The most frequently reported adverse events were rhinorrhea (5.6%) and sneezing (5.6%).","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"14 3","pages":"217-222"},"PeriodicalIF":1.5,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1498","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945590","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

Bioequivalence Study of 2 Formulations of Fluticasone Nasal Spray in Healthy Chinese Volunteers 氟替卡松鼻喷雾剂两种剂型在中国健康志愿者体内的生物等效性研究。

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-01-09 DOI: 10.1002/cpdd.1505

Gang Chen, Zejuan Wang, Xiaona Liu, Aihua Du, Min Li, Yanan Zhang, Dan Zhang, Xiaolin Wang, Xueyan Li, Wei Cong, Jin Wang

{"title":"Bioequivalence Study of 2 Formulations of Fluticasone Nasal Spray in Healthy Chinese Volunteers","authors":"Gang Chen, Zejuan Wang, Xiaona Liu, Aihua Du, Min Li, Yanan Zhang, Dan Zhang, Xiaolin Wang, Xueyan Li, Wei Cong, Jin Wang","doi":"10.1002/cpdd.1505","DOIUrl":"10.1002/cpdd.1505","url":null,"abstract":"This study aimed to evaluate the pharmacokinetic characteristics, safety, and bioequivalence of 2 formulations of fluticasone nasal spray in healthy Chinese subjects. A single-center, randomized, open-label, single-dose, 2-formulation, 2-sequence, 2-period crossover bioequivalence study was conducted under fasting conditions. A total of 120 healthy male and female subjects were enrolled, of which 119 subjects completed the entire study. The main pharmacokinetic parameters of the parent drug, fluticasone propionate (FP), in plasma were as follows: For the test formulation, maximum plasma concentration (Cmax) was 10.3 pg/mL, area under the plasma concentration–time curve from time zero to the last quantifiable concentration (AUC0-t) was 65.6 pg•h/mL, and area under the plasma concentration–time curve from time zero to infinity (AUC0-∞) was 86.4 pg•h/mL. For the reference formulation: Cmax was 8.80 pg/mL, AUC0-t was 58.2 pg•h/mL, and AUC0-∞ was 75.2 pg•h/mL. The 90% confidence intervals of the geometric means for AUC0-t, AUC0-∞, and Cmax between the 2 formulations were 105%-120%, 103%-120%, and 112%-124%, respectively. The results show that the test and reference formulations were well tolerated, with no serious adverse events reported. According to the criteria for bioequivalence, the FP nasal spray (test formulation) is bioequivalent to the reference formulation.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"14 3","pages":"270-275"},"PeriodicalIF":1.5,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945656","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

Population Pharmacokinetic Modeling of Certepetide in Human Subjects With Metastatic Pancreatic Ductal Adenocarcinoma 转移性胰腺导管腺癌患者certe肽的群体药代动力学模型。

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-01-09 DOI: 10.1002/cpdd.1502

Alex Winning, William K. Sietsema, Kristen K. Buck, Abigail Linsmeier, Pawel Wiczling

{"title":"Population Pharmacokinetic Modeling of Certepetide in Human Subjects With Metastatic Pancreatic Ductal Adenocarcinoma","authors":"Alex Winning, William K. Sietsema, Kristen K. Buck, Abigail Linsmeier, Pawel Wiczling","doi":"10.1002/cpdd.1502","DOIUrl":"10.1002/cpdd.1502","url":null,"abstract":"Certepetide (aka LSTA1 and CEND-1) is a novel cyclic tumor-targeting internalizing arginyl glycylaspartic acid peptide being developed to treat solid tumors. Certepetide is designed to overcome existing challenges in treating solid tumors by delivering co-administered anticancer drugs into the tumor while selectively depleting immunosuppressive T cells, enhancing cytotoxic T cells in the tumor microenvironment, and inhibiting the metastatic cascade. A population pharmacokinetic (PK) analysis was conducted to characterize the concentration-time profile of patients with metastatic exocrine pancreatic cancer receiving certepetide in combination with nab-paclitaxel and gemcitabine, and to investigate the effects of clinically relevant covariates on PK parameters. The PK of certepetide was characterized by a 2-compartment model with linear elimination and a proportional residual error structure. Body weight and baseline creatinine clearance (CrCL) were found to have statistically significant effects on central and peripheral volume (Vc and Vp) and clearance (CL) parameters, respectively, during model development and were included as covariate effects in the final PK model. Forest plots demonstrated a potentially clinically meaningful impact of high body weight (100 kg) on certepetide exposure (steady-state maximum concentration [Cmax,ss] and area under the concentration-time curve [AUCss]), as well as low and high CrCL (50 and 150 mL/min) on AUCss. Exposure predictions illustrated a relationship between certepetide exposure (AUCss) and renal function, with increasing exposure and decreasing CL of certepetide observed with worsening renal function. Modeling will strengthen the understanding of certepetide's PKs and will inform dose optimization in ongoing drug development activities.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"14 3","pages":"240-251"},"PeriodicalIF":1.5,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1502","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945619","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

Pharmacokinetic and Pharmacodynamic Equivalence of Biosimilar and Reference Ultra-Rapid Lispro: A Comparative Clamp Study in Healthy Volunteers 生物仿制药和参比超快速利斯普罗在健康志愿者体内的药代动力学和药效学等效性比较研究。

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-01-07 DOI: 10.1002/cpdd.1497

Sergei Noskov, Ekaterina Koksharova, Anna Arefeva, Veniamin Banko, Kseniia Radaeva, Iuliia Matvienko, Maria Gefen, Igor Makarenko, Roman Drai

{"title":"Pharmacokinetic and Pharmacodynamic Equivalence of Biosimilar and Reference Ultra-Rapid Lispro: A Comparative Clamp Study in Healthy Volunteers","authors":"Sergei Noskov, Ekaterina Koksharova, Anna Arefeva, Veniamin Banko, Kseniia Radaeva, Iuliia Matvienko, Maria Gefen, Igor Makarenko, Roman Drai","doi":"10.1002/cpdd.1497","DOIUrl":"10.1002/cpdd.1497","url":null,"abstract":"Ultra-rapid insulin lispro is an innovative insulin analogue designed to achieve rapid onset and short duration of action, aimed at optimizing glycemic control in patients with diabetes. This was a double-blind, randomized, 2-period, crossover clamp study to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD), along with safety profiles, of a potential biosimilar ultra-rapid insulin lispro compared to the reference product in healthy White men. A total of 35 healthy volunteers completed hyperinsulinemic euglycemic clamp procedures across both study periods. Blood samples were collected at predefined intervals up to 8 hours to assess PK parameters. Plasma glucose levels were monitored every 5 minutes during the 8-hour clamps, with adjustments to the glucose infusion rate to maintain the target range. Insulin quantification in plasma was conducted using a validated enzyme-linked immunosorbent assay method. PD assessment was based on glucose infusion rate profiles during both clamps. Geometric mean ratios for maximum plasma concentration and area under the concentration-time curve from insulin administration to the last measurable concentration for the test and reference drugs fell within the bioequivalence range of 80%-125%. Furthermore, the investigational drugs demonstrated comparable PK/PD profiles of insulin lispro. Both formulations exhibited similar safety profiles primarily characterized by mild injection site reactions.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"14 2","pages":"144-153"},"PeriodicalIF":1.5,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945617","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

Impact of Sotorasib, a KRAS G12C Inhibitor, on the Pharmacokinetics and Therapeutic Window of Digoxin, a P-Glycoprotein Substrate. KRAS G12C抑制剂Sotorasib对p糖蛋白底物地高辛的药代动力学和治疗窗口期的影响

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-01-07 DOI: 10.1002/cpdd.1501

Panli Cardona, Brett Houk

{"title":"Impact of Sotorasib, a KRAS G12C Inhibitor, on the Pharmacokinetics and Therapeutic Window of Digoxin, a P-Glycoprotein Substrate.","authors":"Panli Cardona, Brett Houk","doi":"10.1002/cpdd.1501","DOIUrl":"https://doi.org/10.1002/cpdd.1501","url":null,"abstract":"Sotorasib is a small-molecule Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C inhibitor indicated for the treatment of KRAS G12C-driven cancers. KRAS G12C is a common mutation in solid tumors, including non-small cell lung cancer. In vitro studies suggested that sotorasib is a weak inhibitor of P-glycoprotein transporter. Digoxin is a known substrate for P-glycoprotein. The primary objective of this study was to assess the impact of sotorasib on digoxin pharmacokinetics in healthy subjects. This Phase 1, open-label, fixed-sequence study enrolled 14 healthy subjects. Each subject received 0.5 mg of digoxin on Day 1 and 960 mg of sotorasib followed by 0.5 mg of digoxin on Day 7. Blood samples for digoxin pharmacokinetics were collected before dosing and up to 144 hours after the digoxin dose. Digoxin median time to maximum observed plasma concentration and mean terminal half-life were similar following coadministration of digoxin with sotorasib compared with those of digoxin alone. Geometric mean digoxin area under the concentration-time curve from time 0 extrapolated to infinity following coadministration of digoxin with sotorasib (40.3 h•ng/mL) was similar to that of digoxin alone (33.2 h•ng/mL). Geometric mean digoxin maximum observed plasma concentration following coadministration of digoxin with sotorasib (3.64 ng/mL) was higher compared with that of digoxin alone (1.90 ng/mL). Coadministration of digoxin and sotorasib did not impact sotorasib exposure. Single doses of 0.5 mg of digoxin were safe and well tolerated when administered alone or coadministered with 960 mg of sotorasib. Coadministration of digoxin with a single dose of sotorasib increased digoxin area under the concentration-time curve from time 0 extrapolated to infinity and maximum observed plasma concentration by factors of 1.21 and 1.91, respectively, compared with digoxin alone.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":" ","pages":""},"PeriodicalIF":1.5,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945596","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

Antipyretic Effect of Dexibuprofen Versus Ibuprofen in Children With Fever Caused by Upper Respiratory Tract Infection 德西布洛芬与布洛芬对上呼吸道感染发热患儿的解热效果比较。

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-01-06 DOI: 10.1002/cpdd.1499

Chengsong Zhao, Lin Zhao, Juanjuan Xie, Xinli Wang, Changchong Li, Huanji Cheng, Kunling Shen

{"title":"Antipyretic Effect of Dexibuprofen Versus Ibuprofen in Children With Fever Caused by Upper Respiratory Tract Infection","authors":"Chengsong Zhao, Lin Zhao, Juanjuan Xie, Xinli Wang, Changchong Li, Huanji Cheng, Kunling Shen","doi":"10.1002/cpdd.1499","DOIUrl":"10.1002/cpdd.1499","url":null,"abstract":"Dexibuprofen is the pharmacologically active enantiomer of ibuprofen. However, its application as an antipyretic in children with fever caused by upper respiratory tract infection (URTI) requires more evidence. This study aimed to compare the antipyretic effect between dexibuprofen and ibuprofen in children with fever caused by URTI. Totally, 281 subjects were randomly assigned to the dexibuprofen (N = 142) or ibuprofen (N = 139) group at a 1:1 ratio. The subjects in the dexibuprofen or ibuprofen group were administered dexibuprofen + ibuprofen mimetic solution or ibuprofen + dexibuprofen mimetic solution 1-4 times per day. Dexibuprofen was considered at least as effective as ibuprofen if the lower limit of the 95% confidence interval (CI) for the mean difference in axillary temperature change at 4 hours was greater than −0.3°C. The axillary temperature change after 4 hours was 1.3°C in the dexibuprofen group and 1.4°C in the ibuprofen group. The difference in axillary temperature change at 4 hours was −0.10°C (95% CI, −0.27 to 0.09°C) between the 2 groups, and the lower limit of the 95% CI was greater than −0.3°C, suggesting a comparable antipyretic effect of dexibuprofen to ibuprofen. The axillary temperature change from baseline, rates of normal axillary temperature at 4 hours, time to normal axillary temperature, and disease-related symptoms at 24 or 48 hours were not different between the dexibuprofen and ibuprofen groups (all P > .05). The incidence of adverse events did not differ between the 2 groups (all P > .05). In conclusion, dexibuprofen has a comparable antipyretic effect and safety profile to ibuprofen in Chinese children with fever caused by URTI.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"14 3","pages":"223-230"},"PeriodicalIF":1.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930819","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

Clinical Pharmacology and Approach to Dose Selection of Emestedastat, a Novel Tissue Cortisol Synthesis Inhibitor for the Treatment of Central Nervous System Disease 新型组织皮质醇合成抑制剂艾美司他他治疗中枢神经系统疾病的临床药理学及剂量选择方法

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-01-02 DOI: 10.1002/cpdd.1496

Paul Rolan, Jonathan Seckl, Jack Taylor, John Harrison, Paul Maruff, Michael Woodward, Richard Mills, Mark Jaros, Dana Hilt

{"title":"Clinical Pharmacology and Approach to Dose Selection of Emestedastat, a Novel Tissue Cortisol Synthesis Inhibitor for the Treatment of Central Nervous System Disease","authors":"Paul Rolan, Jonathan Seckl, Jack Taylor, John Harrison, Paul Maruff, Michael Woodward, Richard Mills, Mark Jaros, Dana Hilt","doi":"10.1002/cpdd.1496","DOIUrl":"10.1002/cpdd.1496","url":null,"abstract":"This review demonstrates the value of central pharmacodynamics (PD), including positron emission tomography (PET) and computerized cognitive testing, to supplement pharmacokinetic (PK) and peripheral PD for determining the target dose range for clinical efficacy testing of emestedastat, an 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) inhibitor. Combined data from 6 clinical trials in cognitively normal volunteers and patients with Alzheimer disease included a population PK model, endocrine PD, a human PET trial (11β-HSD1 brain imaging), and computerized cognitive testing. PK and PET findings were similar in volunteers and patients with Alzheimer disease. PK modeling suggested that 20 mg daily would be optimal to maintain cerebrospinal fluid concentrations above the brain half maximal inhibitory concentration. However, subsequent PET scanning suggested that emestedastat doses of 10 or even 5 mg daily may be sufficient to adequately inhibit 11β-HSD1. With once-daily doses of 5-20 mg in cognitively normal, older volunteers, a consistent pattern of pro-cognitive benefit, without dose-response, was seen as improvement in attention and working memory but not episodic memory. Thus, emestedastat therapeutic activity might be attained at doses lower than those predicted from cerebrospinal fluid drug levels. Doses as low as 5 mg daily may be efficacious and were studied in subsequent trials.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"14 2","pages":"105-115"},"PeriodicalIF":1.5,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1496","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920780","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 Phase 1, Open-Label, Randomized, Two-Part Study in Healthy Adult Volunteers to Evaluate the Bioavailability of the Maribavir Powder for Oral Suspension, as Well as Food Effect and Impact of Rabeprazole 一项在健康成人志愿者中进行的ⅰ期、开放标签、随机、两部分的研究，以评估口服混悬剂马里巴韦粉末的生物利用度，以及雷贝拉唑的食物效应和影响。

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2024-12-22 DOI: 10.1002/cpdd.1493

Olivia Campagne, Katarina Ilic, Andre Gabriel, Katsuhiko Sueda, Ran Ye, Fangqiu Zhang, Peixin Xu, Hnin Hnin Ko, Kefeng Sun

{"title":"A Phase 1, Open-Label, Randomized, Two-Part Study in Healthy Adult Volunteers to Evaluate the Bioavailability of the Maribavir Powder for Oral Suspension, as Well as Food Effect and Impact of Rabeprazole","authors":"Olivia Campagne, Katarina Ilic, Andre Gabriel, Katsuhiko Sueda, Ran Ye, Fangqiu Zhang, Peixin Xu, Hnin Hnin Ko, Kefeng Sun","doi":"10.1002/cpdd.1493","DOIUrl":"10.1002/cpdd.1493","url":null,"abstract":"The relative bioavailability and impact of food and the proton pump inhibitor rabeprazole on the pharmacokinetics of a maribavir powder-for-oral-suspension formulation was investigated in a Phase 1 open-label study in healthy adult volunteers. A single 200-mg maribavir dose was administered as the commercial tablet (Treatment A), powder formulation (Treatment B), or powder formulation with a high-fat/high-calorie meal (Treatment C) in Part 1, and as the powder formulation alone (Treatment D) or following administration of rabeprazole 20 mg once daily for 5 days (Treatment E) in Part 2. Maribavir maximum plasma concentration following Treatment B was 18% lower versus Treatment A, whereas the area under the concentration-time curve (AUC) from time 0 to the last quantifiable concentration or infinity were similar. Maribavir maximum plasma concentration, AUC from time 0 to the last quantifiable concentration, and AUC from time 0 to infinity were reduced by 42%, 18%, and 18% (Treatment C vs Treatment B), and by 51%, 30%, and 11% (Treatment E vs Treatment D), respectively. A clinically significant reduction in maribavir exposure is not expected when maribavir powder formulation is taken with food or proton pump inhibitors. Participants assessed the powder for oral suspension as easy to swallow and having an acceptable taste/texture. Safety profiles for maribavir formulations in this study were consistent with those previously published.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"14 2","pages":"133-143"},"PeriodicalIF":1.5,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1493","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876415","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

Phase 1 Studies to Assess Inhaled Seralutinib as a Perpetrator or a Victim of Drug-Drug Interactions in Healthy Participants 评估吸入塞拉鲁替尼在健康参与者中作为药物-药物相互作用的肇事者或受害者的1期研究

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2024-12-22 DOI: 10.1002/cpdd.1491

Jianke Li, Ed Parsley, Matt Cravets, Emanuel DeNoia, Cassandra Key, Anita Mathias

{"title":"Phase 1 Studies to Assess Inhaled Seralutinib as a Perpetrator or a Victim of Drug-Drug Interactions in Healthy Participants","authors":"Jianke Li, Ed Parsley, Matt Cravets, Emanuel DeNoia, Cassandra Key, Anita Mathias","doi":"10.1002/cpdd.1491","DOIUrl":"10.1002/cpdd.1491","url":null,"abstract":"Seralutinib, an inhaled, small-molecule tyrosine kinase inhibitor in clinical development for the treatment of pulmonary arterial hypertension (PAH), was evaluated for its potential as a perpetrator or victim of a metabolic and transporter-based drug-drug interactions in 2 phase 1 studies. In study 1, 24 participants received a cocktail of probe substrates: caffeine (CYP1A2), montelukast (CYP2C8), flurbiprofen (CYP2C9), midazolam (CYP3A), and pravastatin (OATP1B1/1B3), plus digoxin (P-gp) with or without seralutinib. In study 2, 19 participants received seralutinib with/without itraconazole, a strong CYP3A inhibitor, or fosaprepitant, a weak CYP3A inhibitor. Geometric least-squares mean ratios and 90% confidence intervals for maximum observed concentration (Cmax) and area under the plasma concentration-time curve (AUC) were obtained. Safety was monitored throughout the studies. All adverse events were mild or moderate in severity. Seralutinib coadministration increased AUC for midazolam 3.03-fold and caffeine 1.32-fold. The coadministration increased digoxin Cmax 1.28-fold. Seralutinib did not meaningfully alter Cmax and AUC for montelukast, flurbiprofen, or pravastatin. Fosaprepitant and itraconazole increased seralutinib AUC 1.08- and 1.84-fold, respectively. Seralutinib is a moderate CYP3A inhibitor and a weak CYP1A2 inhibitor; it slightly inhibits P-gp. Seralutinib exposure is minimally affected by a weak CYP3A inhibitor but is substantially increased by a strong CYP3A inhibitor.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"14 2","pages":"91-104"},"PeriodicalIF":1.5,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1491","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876418","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

Optimization of Romiplostim Biosimilar Efficacy Trial Using In Silico Clinical Trial Approach for Patients With Immune Thrombocytopenia 应用计算机临床试验方法优化罗米普罗stim生物类似药对免疫性血小板减少症患者的疗效。

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2024-12-19 DOI: 10.1002/cpdd.1494

Aleksandr Petrov, Igor Makarenko, Bella Belova, Anait Melikyan, Valeria Saparova, Kirill Peskov, Nataliya Kudryashova, Vladislav Kovalik, Maria Gefen, Alexandr Khokhlov, Roman Drai

{"title":"Optimization of Romiplostim Biosimilar Efficacy Trial Using In Silico Clinical Trial Approach for Patients With Immune Thrombocytopenia","authors":"Aleksandr Petrov, Igor Makarenko, Bella Belova, Anait Melikyan, Valeria Saparova, Kirill Peskov, Nataliya Kudryashova, Vladislav Kovalik, Maria Gefen, Alexandr Khokhlov, Roman Drai","doi":"10.1002/cpdd.1494","DOIUrl":"10.1002/cpdd.1494","url":null,"abstract":"During biosimilar drug development, conducting a clinical trial of biosimilar efficacy in patients may become necessary in the presence of residual uncertainty regarding the biosimilarity of the drugs. In the development of the biosimilar romiplostim GP40141, we aimed to use a model-based in silico clinical trial (ISCT) approach to optimize the planned biosimilar efficacy trial in patients with immune thrombocytopenia. The population pharmacokinetic/pharmacodynamic model for healthy volunteers was modified and validated to describe platelet dynamics in patients with immune thrombocytopenia. ISCTs were then conducted using the modified model for various expected scenarios of biosimilar efficacy trials. Statistical analysis of the simulation results was subsequently used to confirm the appropriateness of the chosen design for evaluating the planned efficacy end points. Since the planned trial includes both patients naïve to therapy with thrombopoietin receptor agonists and nonnaïve patients, various expected ratios of naïve to nonnaïve patients (1:1, 1:2, 1:3) and the percentage of nonnaïve patients who previously received eltrombopag (0% or 30%) were assessed across 200 ISCTs performed for each scenario. The obtained estimates of empirical power for the equivalence test of platelet response/durable platelet response by the 10th/26th week between the test and reference groups were not less than 94%, regardless of the scenario. Differences in power between the 10- and 26-week end points did not exceed 4%. The analysis of ISCT results allowed for an effective reduction of uncertainty in the biosimilar development of GP40141, demonstrating the appropriateness of using the 10-week efficacy end point as the primary one.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"14 2","pages":"116-126"},"PeriodicalIF":1.5,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863586","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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