Clinical Pharmacology in Drug Development最新文献_第2页

Scp776, A Novel IGF-1 Fusion Protein for Acute Therapy to Promote Escape From Apoptosis in Tissues Affected by Ischemic Injury: 2 Randomized Placebo-Controlled Phase 1 Studies in Healthy Adults.

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-01-01 Epub Date: 2024-12-08 DOI: 10.1002/cpdd.1486

Samuel J Pfaff, Terry O'Reilly, Yan Zhang, Walter Olsen, Kristopher Kuchenbecker

{"title":"Scp776, A Novel IGF-1 Fusion Protein for Acute Therapy to Promote Escape From Apoptosis in Tissues Affected by Ischemic Injury: 2 Randomized Placebo-Controlled Phase 1 Studies in Healthy Adults.","authors":"Samuel J Pfaff, Terry O'Reilly, Yan Zhang, Walter Olsen, Kristopher Kuchenbecker","doi":"10.1002/cpdd.1486","DOIUrl":"10.1002/cpdd.1486","url":null,"abstract":"Apoptosis is a major driver of cell loss and infarct expansion in ischemic injuries such as acute ischemic stroke (AIS) and acute myocardial infarction (AMI). Insulin-like growth factor-1 (IGF-1) can mitigate cell death and potentiate recovery following acute ischemic injury, but short half-life and nonspecificity limit its therapeutic potential. Scp776 is an IGF-1 fusion protein designed to target damaged tissue and promote apoptosis escape and is in clinical development as an acute therapy for AIS and AMI. Two phase 1 placebo-controlled studies in healthy volunteers evaluated safety, tolerability, pharmacokinetic profile, and pharmacodynamics under single (1, 2, or 4 mg/kg) or multiple (6, 6.2, or 7.25 mg/kg total doses) dosing regimens. In addition, a blood glucose management plan was developed and implemented to mitigate hypoglycemia that may develop following scp776 injection. Scp776 was well tolerated in healthy volunteers (n = 51) without serious adverse events. Exposure increased in a near dose-proportional manner with a mean half-life across all doses of 8 hours. Adaptive dextrose infusions maintained normal blood glucose levels with occasional mild hypoglycemic events. These results informed scp776 dose selection and the design of blood glucose monitoring protocols for phase 2 studies.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":" ","pages":"65-78"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11701966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794177","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, Single-Center, Double-Blind, Randomized, Placebo-Controlled Studies of the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Oral Doses of the Sirtuin 6 Activator SP-624 in Healthy Adults. 关于健康成人单剂量和多剂量口服 Sirtuin 6 激活剂 SP-624 的安全性、耐受性和药代动力学的 1 期单中心、双盲、随机、安慰剂对照研究。

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-01-01 Epub Date: 2024-11-26 DOI: 10.1002/cpdd.1488

Greg Rigdon, Yuki Prescott, John Hall, Kelly Abernathy, Joel Raskin, William Wargin

{"title":"Phase 1, Single-Center, Double-Blind, Randomized, Placebo-Controlled Studies of the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Oral Doses of the Sirtuin 6 Activator SP-624 in Healthy Adults.","authors":"Greg Rigdon, Yuki Prescott, John Hall, Kelly Abernathy, Joel Raskin, William Wargin","doi":"10.1002/cpdd.1488","DOIUrl":"10.1002/cpdd.1488","url":null,"abstract":"Sirtuin 6 activation is a novel epigenetic mechanism proposed for treatment of depression. Two Phase 1 studies, SP-624-101 and SP-624-102, examined the pharmacokinetics and safety of SP-624, an orally active sirtuin 6 activator, in healthy adults. SP-624-101 was a single-ascending-dose study. In Part A, participants were randomized 6:2 to SP-624 (single oral doses of 3, 10, or 30 mg) or placebo. Part B compared results in 8 participants receiving SP-624 while fasting or after a high-fat, high-calorie breakfast. In SP-624-102, a multiple-ascending-dose study, participants were randomized 6:2 to SP-624 (3 or 10 mg SP-624 daily) or placebo for 5 days and 5:2 to SP-624 20 mg daily or placebo for 10 days. At all doses, maximum concentration (Cmax) exceeded predicted target plasma concentrations of 3.28 ng/mL. Area under the concentration-time curve and Cmax increased dose proportionally. A food effect resulted in significantly lower Cmax, later time to maximum concentration, and comparable AUC for fed versus fasting participants. No serious adverse events were observed. In SP-624-101 and SP-624-102, respectively, 3 (12%) and 5 (29%) SP-624-treated participants experienced treatment-emergent adverse events. SP-624 was well tolerated and reached target concentrations in healthy adults, supporting progression of SP-624 20 mg daily into Phase 2 studies of major depressive disorder.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":" ","pages":"18-25"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11701958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715584","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

Safety, Tolerability, and Pharmacokinetic Profile of the Low-Impact Ampakine CX1739 in Young Healthy Volunteers. 年轻健康志愿者服用低冲击安帕金 CX1739 的安全性、耐受性和药代动力学特征

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-01-01 Epub Date: 2024-09-20 DOI: 10.1002/cpdd.1475

Daniel P Radin, Rok Cerne, Jeffrey M Witkin, Arnold Lippa

{"title":"Safety, Tolerability, and Pharmacokinetic Profile of the Low-Impact Ampakine CX1739 in Young Healthy Volunteers.","authors":"Daniel P Radin, Rok Cerne, Jeffrey M Witkin, Arnold Lippa","doi":"10.1002/cpdd.1475","DOIUrl":"10.1002/cpdd.1475","url":null,"abstract":"AMPA-type glutamate receptors (AMPARs) mediate the majority of fast excitatory synaptic transmission in the mammalian brain. Ampakines, positive allosteric modulators of AMPAR, hold significant potential for the treatment of a wide range of neurological/neuropsychiatric disorders in which excitatory synaptic transmission is compromised. Low-impact ampakines are a distinct subset of ampakines that accelerate channel opening yet minimally affect receptor desensitization, which may explain their lack of seizurogenic effects at therapeutic doses in preclinical models. CX1739 is a low-impact ampakine that has shown efficacy in preclinical studies. The current clinical study examined the tolerability and pharmacokinetics of CX1739 in healthy male volunteers in a 2-part study. Part A was a single dose escalation study (100-1200 mg, 48 patients) and Part B was a multiple dose ascending study (300-600 mg BID for 7-10 days, 32 patients). CX1739 was well tolerated up to 900 mg once daily (QD) and 450 mg twice a day, with the prominent side effects being headache and nausea. Importantly, the half-life of CX1739 was 6-9 hours, and Tmax was 1-5 hours. CX1739 Cmax and AUC were dose-proportional. These findings thus set the stage for further explorations of this drug candidate in phase 2 clinical studies.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":" ","pages":"50-58"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281402","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

Osimertinib Efficacy and Safety in Treating Epidermal Growth Factor Receptor Mutation-Positive Advanced Non-Small-Cell Lung Cancer: A Meta-Analysis. 奥希替尼治疗表皮生长因子受体突变阳性晚期非小细胞肺癌的有效性和安全性：一项 Meta 分析。

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-01-01 Epub Date: 2024-11-08 DOI: 10.1002/cpdd.1483

Mengmeng Zhao, Jian Zhang, Jie Gao, Jianping Wang, Zhenkai Ma

{"title":"Osimertinib Efficacy and Safety in Treating Epidermal Growth Factor Receptor Mutation-Positive Advanced Non-Small-Cell Lung Cancer: A Meta-Analysis.","authors":"Mengmeng Zhao, Jian Zhang, Jie Gao, Jianping Wang, Zhenkai Ma","doi":"10.1002/cpdd.1483","DOIUrl":"10.1002/cpdd.1483","url":null,"abstract":"This study compared the safety and efficacy of osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), with those of other TKIs and its use alongside bevacizumab in patients with EGFR mutation-positive advanced non-small-cell lung cancer. PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wanfang, and VIP databases were used to conduct extensive searches for relevant randomized controlled trials until January 30, 2024. Osimertinib monotherapy favored disease control rate, whereas the comparator treatment arm favored overall survival. Using subgroup analysis, the objective response rate and progression-free survival (PFS) were significantly elevated by Osimertinib monotherapy compared with pemetrexed combined with carboplatin or cisplatin. The comparator treatment arm receiving gefitinib or erlotinib significantly favored progression-free survival and overall survival compared with osimertinib monotherapy. In patients treated with osimertinib monotherapy, the incidence of all adverse events (AEs) decreased compared with comparator treatment arm. Anemia was the only AE associated with osimertinib monotherapy. Pemetrexed combined with carboplatin or cisplatin resulted in greater loss of appetite than osimertinib monotherapy. The most associated AE of osimertinib monotherapy was diarrhea, according to network analysis. Although its efficacy is not consistent with other EGFR TKIs, osimertinib was associated with a decrease in AEs in patients with EGFR mutation-positive advanced non-small-cell lung cancer.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":" ","pages":"5-10"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615431","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

The Safety, Tolerability, and Pharmacokinetics of Active Ingredients From Hydroxysafflor Yellow A in Healthy Chinese Volunteers. 中国健康志愿者对羟基红花黄色素 A 活性成分的安全性、耐受性和药代动力学研究

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-01-01 Epub Date: 2024-11-17 DOI: 10.1002/cpdd.1487

Xiuli Zhao, Shanye Gu, Xia Wang, Yefeng Cai, Ziyi Zhou

{"title":"The Safety, Tolerability, and Pharmacokinetics of Active Ingredients From Hydroxysafflor Yellow A in Healthy Chinese Volunteers.","authors":"Xiuli Zhao, Shanye Gu, Xia Wang, Yefeng Cai, Ziyi Zhou","doi":"10.1002/cpdd.1487","DOIUrl":"10.1002/cpdd.1487","url":null,"abstract":"Hydroxysafflor yellow A (HSYA), an active ingredient extracted from Carthami flos, shows potential for treating ischemic stroke. This phase 1 study assessed the safety, tolerability, and pharmacokinetic (PK) properties of HSYA in healthy Chinese volunteers who received intravenous infusions of pure HSYA powder. The study comprised 2 parts. Part A was a randomized, double-blind, placebo-controlled dose-escalation study that evaluated safety and tolerability. This included a single-dose study with 7 dose levels of HSYA (6.25, 12.5, 25, 50, 75, 100, and 125 mg) in 52 volunteers, and a multidose study (100 and 125 mg) in 16 volunteers. Part B was an open-label study where 12 volunteers received 75 mg of HSYA once daily for 14 consecutive days to examine PKs. There were no adverse events (AEs) leading to treatment discontinuation by HSYA throughout the treatment period. All reported AEs were mild and did not require special treatment. PK analysis revealed rapid absorption (median Tmax of 1.1 hours) and elimination (median t1/2 4.0 and 4.7 hours) of HSYA. Total body clearance on the 1st and 14th days was 1.7 and 1.6 L/h, respectively.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":" ","pages":"79-86"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647072","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

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Neonatal Fc Receptor Inhibitor Rozanolixizumab: An Ethnic Sensitivity Study in Healthy Japanese, Chinese, and White Participants. 新生儿 Fc 受体抑制剂 Rozanolixizumab 的安全性、耐受性、药代动力学和药效学：健康日本人、中国人和白人参与者的种族敏感性研究。

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-01-01 Epub Date: 2024-11-21 DOI: 10.1002/cpdd.1484

Assem El Baghdady, Rocío Lledó-García, Maryam Gayfieva, Romana Lowcock, Shikiko Watanabe, Jagdev Sidhu, Denisa Wilkes

{"title":"Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Neonatal Fc Receptor Inhibitor Rozanolixizumab: An Ethnic Sensitivity Study in Healthy Japanese, Chinese, and White Participants.","authors":"Assem El Baghdady, Rocío Lledó-García, Maryam Gayfieva, Romana Lowcock, Shikiko Watanabe, Jagdev Sidhu, Denisa Wilkes","doi":"10.1002/cpdd.1484","DOIUrl":"10.1002/cpdd.1484","url":null,"abstract":"Rozanolixizumab is an anti-human neonatal Fc receptor humanized immunoglobulin (Ig) G4 monoclonal antibody that reduces IgG, including pathogenic IgG autoantibodies. Rozanolixizumab safety and tolerability have been assessed in previous clinical studies with predominantly White participants. We assessed safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of rozanolixizumab in healthy Japanese and Chinese participants compared with White participants. This double-blind, single-center, UK-based, Phase 1 study randomized 65 participants to rozanolixizumab 4 mg/kg (Japanese and White participants only), 7 mg/kg, or 10 mg/kg. All treatment-emergent adverse events (TEAEs) were mild to moderate in severity; no severe TEAEs, serious TEAEs, or TEAEs leading to discontinuation occurred. Incidences of TEAEs in Japanese and Chinese participants were comparable to those in White participants. Japanese and Chinese participants had lower systemic rozanolixizumab exposure relative to Caucasian participants, attributable to lower actual doses administered due to lower body weight in Chinese and Japanese participants, indicating that body weight is not a relevant predictor of rozanolixizumab pharmacokinetics. All 3 ethnicities demonstrated dose-dependent IgG reductions, with IgG nadir achieved around Day 10 and gradual return to baseline levels by Day 56. These data support the applicability of safety data from previous clinical studies of rozanolixizumab to individuals of Japanese and Chinese ethnicity.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":" ","pages":"26-35"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681079","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

At-Home Self-Collection of Pharmacokinetic Data: Design and Results From a Phase 1 Open-Label Feasibility Trial.

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-01-01 Epub Date: 2024-12-04 DOI: 10.1002/cpdd.1495

Arash Raoufinia, Susan E Shoaf, Brian Rothman, Chelsea Ye, Chris Chung

{"title":"At-Home Self-Collection of Pharmacokinetic Data: Design and Results From a Phase 1 Open-Label Feasibility Trial.","authors":"Arash Raoufinia, Susan E Shoaf, Brian Rothman, Chelsea Ye, Chris Chung","doi":"10.1002/cpdd.1495","DOIUrl":"10.1002/cpdd.1495","url":null,"abstract":"Pharmacokinetic (PK) studies pose unique technical challenges. We present the design of a Phase 1, open-label, fixed-sequence, PK trial that aimed to compare the timing accuracy of participant- versus staff-collected data, and we provide safety and tolerability outcomes for centanafadine treatment. Healthy adults aged 18-55 years received a single 100-mg centanafadine sustained-release tablet at Visits 1, 2, and 4. PK samples (venous sampling and blood microsampling) and safety assessments (12-lead electrocardiograms [ECGs] and vital signs) were collected by clinical site staff only at Visit 1. At Visit 2, site staff collected venous blood, and participants obtained blood microsamples, a 6-lead ECG, and vital signs under staff supervision. At Visit 4, participants obtained blood microsamples, a 6-lead ECG, and vital signs remotely. The absolute differences between actual and scheduled collection times for PK samples, ECGs, and vital signs are reported descriptively. Of the 20 participants, at least 75% obtained blood microsamples within 10 minutes of the planned nominal time. Absolute differences between actual and scheduled collection times of ECGs and vital signs were small. No adverse events were related to treatment. Overall, results support the feasibility of at-home collection of PK samples, ECGs, and vital signs.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":" ","pages":"11-17"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766680","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

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.

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":"https://doi.org/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":" ","pages":""},"PeriodicalIF":1.5,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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.

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":"https://doi.org/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":" ","pages":""},"PeriodicalIF":1.5,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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.

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":"https://doi.org/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":" ","pages":""},"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}

引用次数: 0