Clinical Pharmacology in Drug Development最新文献_第9页

Comparative Bioequivalence Study of 2 Clopidogrel 75-mg Tablet Formulations in Moroccan Volunteers 摩洛哥志愿者服用两种氯吡格雷 75 毫克片剂的生物等效性比较研究

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2024-06-26 DOI: 10.1002/cpdd.1442

Aimen El Orche, Choukri El Khabbaz, Amine Cheikh, Houda Bouchafra, Samira Jawhari, Faouzi My El Abbes, Yahya Cherrah

{"title":"Comparative Bioequivalence Study of 2 Clopidogrel 75-mg Tablet Formulations in Moroccan Volunteers","authors":"Aimen El Orche, Choukri El Khabbaz, Amine Cheikh, Houda Bouchafra, Samira Jawhari, Faouzi My El Abbes, Yahya Cherrah","doi":"10.1002/cpdd.1442","DOIUrl":"10.1002/cpdd.1442","url":null,"abstract":"This study investigates the pharmacokinetic properties and bioequivalence of 2 formulations of clopidogrel tablets administered to a cohort of healthy Moroccan male volunteers. The primary objective was to assess the rate and extent of drug absorption from the test formulation in comparison to a reference formulation, focusing on critical parameters including maximum plasma concentration (Cmax), area under the concentration-time curve from 0 to the last measurable time (AUC0-t), and area under the concentration-time curve extrapolated to infinity (AUC0-∞). The results revealed that the geometric mean ratios of Cmax, AUC0-t, and AUC0–∞ for the test formulation relative to the reference formulation were 105.7%, 105.6%, and 105.6%, respectively. The 90% confidence intervals for these parameters fell within the predefined bioequivalence range of 80%-125%, indicating a statistically and clinically equivalent performance between the 2 formulations. This investigation sheds light on the pharmacokinetic behavior of clopidogrel in the context of the Moroccan male population, offering valuable insights into the comparability of formulations.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"13 9","pages":"1044-1050"},"PeriodicalIF":1.5,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141455762","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, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Trial of AWZ1066S, an Anti-Wolbachia Candidate Macrofilaricide AWZ1066S--一种抗狼鞭毛虫候选大丝虫杀虫剂的 1 期随机、双盲、安慰剂对照、单剂量递增试验。

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2024-06-24 DOI: 10.1002/cpdd.1441

Graham Devereux, Marcin Bula, Karen Tripp, Richard Fitzgerald, Nicola Eraut, Muhammad Salman Alam, Tomoyuki Moriyama, Raku Shinkyo, Lauren Walker, Duolao Wang, Fabian Gusovsky, Jeannette van der Velde, Joseph D. Turner, Weiqian David Hong, Paul M. O'Neill, Mark J. Taylor, Stephen A. Ward

{"title":"A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Trial of AWZ1066S, an Anti-Wolbachia Candidate Macrofilaricide","authors":"Graham Devereux, Marcin Bula, Karen Tripp, Richard Fitzgerald, Nicola Eraut, Muhammad Salman Alam, Tomoyuki Moriyama, Raku Shinkyo, Lauren Walker, Duolao Wang, Fabian Gusovsky, Jeannette van der Velde, Joseph D. Turner, Weiqian David Hong, Paul M. O'Neill, Mark J. Taylor, Stephen A. Ward","doi":"10.1002/cpdd.1441","DOIUrl":"10.1002/cpdd.1441","url":null,"abstract":"AWZ1066S has been developed as a potential treatment for the neglected tropical diseases lymphatic filariasis and onchocerciasis. AWZ1066S targets the Wolbachia bacterial endosymbiont present in the causative nematode parasites. This phase 1, first-in-human study aimed to assess the safety and pharmacokinetics of AWZ1066S in healthy human participants. In a randomized double-blind, placebo-controlled, single ascending dose study, healthy adults received a single oral dose of AWZ1066S (or placebo) and were followed up for 10 days. The planned single doses of AWZ1066S ranged from 100 to 1600 mg, and each dose was administered to a cohort of 8 participants (6 AWZ1066S and 2 placebo). In total 30 people participated, 18 (60%) female, median age 30.0 years (minimum 20, maximum 61). The cohorts administered 100, 200, 300, and 400 mg of AWZ1066S progressed unremarkably. After single 700-mg doses all 4 participants developed symptoms of acute gastritis and transient increases in liver enzymes. The severity of these adverse events ranged from mild to severe, with 1 participant needing hospital admission. Pharmacokinetic analysis indicated that AWZ1066S is rapidly absorbed with predictable pharmacokinetics. In conclusion, safety concerns prevented this study from reaching the human exposures needed for AWZ1066S to be clinically effective against lymphatic filariasis and onchocerciasis.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"13 9","pages":"1071-1081"},"PeriodicalIF":1.5,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1441","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141455759","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, Cross-Over Study Investigating the Comparability of Somatrogon-ghla in 2 Different Drug Product Presentations 一项随机交叉研究调查了两种不同药物产品中 Somatrogon-ghla 的可比性。

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2024-06-24 DOI: 10.1002/cpdd.1434

Allison Manners, Joan Korth-Bradley, Michael P. Wajnrajch

{"title":"A Randomized, Cross-Over Study Investigating the Comparability of Somatrogon-ghla in 2 Different Drug Product Presentations","authors":"Allison Manners, Joan Korth-Bradley, Michael P. Wajnrajch","doi":"10.1002/cpdd.1434","DOIUrl":"10.1002/cpdd.1434","url":null,"abstract":"Somatrogon-ghla is a long-acting, recombinant human growth hormone approved for the treatment of pediatric patients with growth hormone deficiency. Forty-nine healthy, adult males were enrolled in a randomized, crossover study to compare somatrogon exposure after subcutaneous doses administered using a frozen vial presentation or a prefilled, multiple dose pen. Somatrogon, insulin-like growth factor-I, and IGF-1 binding protein-3 concentrations were collected for up to 240 hours post dose to assess pharmacokinetic and pharmacodynamic responses. There was a 2-week washout between administration of the doses. Seven participants did not complete the study due to withdrawal of consent (n = 2) or loss to follow-up. Two treatment-emergent adverse events, headaches, were judged by the investigator as possibly related to study drug administration. Both were mild. Injection site reactions were observed in 6/48 participants after administration with the pen and 12/46 after administration using the vial. Drug and biomarker concentrations were assessed using validated assays and noncompartmental methods were used to determine pharmacokinetic and pharmacodynamic parameters. Bioequivalence was demonstrated for somatrogon area under the concentration-time curve, but not for the peak somatrogon concentration, where the lower limit of the 90% confidence interval for the ratio of pen/vial was 74.2%, which is less than the lower limit, 80.0%, dictated by bioequivalence criteria. The IGF-1 responses were largely within bioequivalence limits. It was concluded that the 2 formulations are comparable.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"13 10","pages":"1108-1114"},"PeriodicalIF":1.5,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1434","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141455760","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 of Recombinant Human Teriparatide Injection in Healthy Adult Female Subjects in the Fasting State 空腹状态下重组人特立帕肽注射液在健康成年女性受试者中的生物等效性。

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2024-06-24 DOI: 10.1002/cpdd.1440

Shengling Hu, Yalei Wen, Jing Li, Wenming Chen, Yichuan Bai, Fengyun Gong

{"title":"Bioequivalence of Recombinant Human Teriparatide Injection in Healthy Adult Female Subjects in the Fasting State","authors":"Shengling Hu, Yalei Wen, Jing Li, Wenming Chen, Yichuan Bai, Fengyun Gong","doi":"10.1002/cpdd.1440","DOIUrl":"10.1002/cpdd.1440","url":null,"abstract":"A single-center, randomized, open, 2-period, self-crossover, single-dose trial was conducted to evaluate the bioequivalence of the test (T) and reference (R) preparations in healthy adult female subjects under fasting conditions. Seventy-six subjects were enrolled in the study, and subjects were randomly divided into 2 groups at a 1:1 ratio and were administered once per period, with a 4-day washout period. In each period, plasma drug concentrations, blood calcium changes, and antibodies were determined for pharmacokinetics, pharmacodynamics, and immunogenicity analysis, respectively, and adverse events were recorded for safety analysis. The 90% confidence intervals for the geometric mean ratios (T:R) of maximum plasma concentration, area under the plasma concentration-time curve from time 0 to the last measurable concentration, and area under the plasma concentration-time curve from time 0 to infinity were within the predefined bioequivalence criterion of 80%-125%, indicating bioequivalence between the T and R preparations under fasting conditions. Comparable serum calcium levels demonstrated pharmacodynamics similarity, and no differences were found in immunogenicity profiles. Additionally, the incidence of adverse reactions to the T preparation was 18.4% lower than that of the R preparation (31.6%). This study confirmed the bioequivalence of the T and R preparations under fasting conditions, along with comparable immunogenicity profiles and good safety.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"13 10","pages":"1151-1156"},"PeriodicalIF":1.5,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141455761","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 Food on the Oral Absorption of N-Acetyl-D-Mannosamine in Healthy Men and Women 食物对健康男性和女性口服 N-乙酰基-D-甘露糖胺吸收的影响

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2024-06-20 DOI: 10.1002/cpdd.1433

Allan M. Evans, Gianfranco Fornasini, Tahlia R. Meola, William A. Gahl, Marjan Huizing, Thomas M. Polasek, Stephanie E. Reuter

{"title":"Impact of Food on the Oral Absorption of N-Acetyl-D-Mannosamine in Healthy Men and Women","authors":"Allan M. Evans, Gianfranco Fornasini, Tahlia R. Meola, William A. Gahl, Marjan Huizing, Thomas M. Polasek, Stephanie E. Reuter","doi":"10.1002/cpdd.1433","DOIUrl":"10.1002/cpdd.1433","url":null,"abstract":"N-Acetyl-D-mannosamine (ManNAc) is an endogenous monosaccharide and precursor of N-acetylneuraminic acid (Neu5Ac), a critical sialic acid. ManNAc is currently under clinical development to treat GNE myopathy, a rare muscle-wasting disease. In this randomized, open-label, 2-sequence, crossover study, 16 healthy women and men were administered a single oral dose of ManNAc under fasting and fed conditions. Blood samples were collected for 48 hours after dosing for quantification of plasma ManNAc and Neu5Ac concentrations. Noncompartmental pharmacokinetic and deconvolution analyses were performed using baseline-corrected plasma concentration data. Administration of ManNAc in the fed state resulted in a 1.6-fold increase in ManNAc exposure, compared to fasting conditions. A concurrent increase in Neu5Ac exposure was observed in the presence of food. Deconvolution analysis indicated that the findings were attributed to prolonged absorption rather than an enhanced rate of absorption. The impact of food on ManNAc pharmacokinetics was greater in women than men (fed/fasted area under the concentration-time curve from time 0 to infinity mean ratio: 198% compared to 121%). It is hypothesized that the presence of food slows gastric emptying, allowing a gradual release of ManNAc into the small intestine, translating into improved ManNAc absorption. The results suggest that taking ManNAc with food may enhance its therapeutic activity and/or reduce the daily dosage requirement.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"13 8","pages":"876-883"},"PeriodicalIF":1.5,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1433","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141426507","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 Velpatasvir/Sofosbuvir Oral Coated Tablets in Healthy Volunteers Under Fasting Conditions 健康志愿者在空腹条件下服用韦帕他韦/索非布韦口服包衣片的生物等效性研究

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2024-06-16 DOI: 10.1002/cpdd.1435

Sergei Noskov, Anna Arefeva, Kseniia Radaeva, Igor Makarenko, Maria Gefen, Roman Drai

{"title":"Bioequivalence Study of Velpatasvir/Sofosbuvir Oral Coated Tablets in Healthy Volunteers Under Fasting Conditions","authors":"Sergei Noskov, Anna Arefeva, Kseniia Radaeva, Igor Makarenko, Maria Gefen, Roman Drai","doi":"10.1002/cpdd.1435","DOIUrl":"10.1002/cpdd.1435","url":null,"abstract":"This study was conducted as a single-site, open-label, randomized, replicated crossover trial with 4 treatment periods. The aim was to evaluate the bioequivalence of a generic test drug containing velpatasvir and sofosbuvir compared to an established brand-name medication in healthy White subjects under fasting conditions. Blood samples were collected at specified intervals up to 72 hours after dosing to measure the concentrations of velpatasvir and sofosbuvir using a certified high-performance liquid chromatography with tandem mass spectrometry method. The bioequivalence of the 2 formulations was confirmed when statistical analysis showed that confidence intervals for the log-transformed peak concentration and area under the concentration-time curve from time 0 to the last quantifiable sample were within an acceptable range from 80% to 125%. Criteria for bioequivalence were met for both area under the concentration-time curve from time 0 until the last quantifiable sample and peak concentration parameters. No adverse effects were reported during this trial in both groups.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"13 10","pages":"1123-1129"},"PeriodicalIF":1.5,"publicationDate":"2024-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141330465","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 and Bioequivalence of Vardenafil Hydrochloride in Healthy Chinese Volunteers 盐酸伐地那非在中国健康志愿者中的药代动力学和生物等效性。

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2024-06-10 DOI: 10.1002/cpdd.1432

Sheng He, Xinyi Wu, Wanggang Zhang, Keli Wang, Yu Chen, Zhibo Zheng, Ting Zhang, Lili Chen, Qingqing Duan, Dongyuan He, Binbin Wu

{"title":"Pharmacokinetics and Bioequivalence of Vardenafil Hydrochloride in Healthy Chinese Volunteers","authors":"Sheng He, Xinyi Wu, Wanggang Zhang, Keli Wang, Yu Chen, Zhibo Zheng, Ting Zhang, Lili Chen, Qingqing Duan, Dongyuan He, Binbin Wu","doi":"10.1002/cpdd.1432","DOIUrl":"10.1002/cpdd.1432","url":null,"abstract":"Vardenafil hydrochloride tablet is an inhibitor of phosphodiesterase type 5, primarily for the treatment of erectile dysfunction. This postprandial study evaluated the pharmacokinetics and bioequivalence of the test and reference formulations of vardenafil hydrochloride tablets in healthy Chinese volunteers. An open, randomized, single-center, single-dose, 2-period, 2-sequence bioequivalence test was conducted on 66 healthy subjects under fed conditions. Subjects were randomly assigned to a 20-mg test or reference formulation with a 7-day washout period. Venous blood samples (4 mL) were collected from each subject 25 times spanning predose (0 hour) to 24 hours after dosing. The plasma concentration of vardenafil was determined by high-performance liquid chromatography-tandem mass spectrometry. Sixty-two volunteers completed the study. Under fed conditions, the maximum plasma concentration was 29.1 ng/mL, the area under the concentration–time curve (AUC) from time 0 to the time of the last measurable concentration was 85.3 ng•h/mL, and AUC from time 0 to infinity was 87.1 ng•h/mL. The 90% confidence intervals of the geometric mean ratio of AUC time 0 to the time of the last measurable concentration and AUC from time 0 to infinity were within the bioequivalence acceptance range of 0.80-1.25. The test formulation was a bioequivalent alternative to the reference formulation when taken under fed conditions in healthy Chinese subjects.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"13 8","pages":"884-889"},"PeriodicalIF":1.5,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141295678","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

Enhanced Bioavailability and Reduced Variability of Dasatinib and Sorafenib with a Novel Amorphous Solid Dispersion Technology Platform 利用新型无定形固体分散技术平台提高达沙替尼和索拉非尼的生物利用度并降低其变异性。

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2024-05-29 DOI: 10.1002/cpdd.1416

Hans Lennernäs, Magnus Brisander, Charlotta Liljebris, Gérald Jesson, Per Andersson

{"title":"Enhanced Bioavailability and Reduced Variability of Dasatinib and Sorafenib with a Novel Amorphous Solid Dispersion Technology Platform","authors":"Hans Lennernäs, Magnus Brisander, Charlotta Liljebris, Gérald Jesson, Per Andersson","doi":"10.1002/cpdd.1416","DOIUrl":"10.1002/cpdd.1416","url":null,"abstract":"Despite clinical advances with protein kinase inhibitors (PKIs), oral administration of many PKIs is associated with highly variable plasma exposure and a narrow therapeutic window. We developed a novel hybrid nanoparticle-amorphous solid dispersion (ASD) technology platform consisting of an amorphous PKI embedded in a polymer matrix. The technology was used to manufacture immediate-release formulations of 2 tyrosine kinase inhibitors (TKIs), dasatinib and sorafenib. Our primary objective was to improve the absorption properties and reduce the pharmacokinetic (PK) variability of each TKI. The PKs of XS004 (dasatinib-ASD, 100 mg tablet) and XS005 (sorafenib-ASD, 2 × 50 mg capsules) were compared with their crystalline formulated reference drugs (140 mg of dasatinib-reference and 200 mg of sorafenib-reference). The in vitro biopharmaceutics of dasatinib-ASD and XS005-granulate showed sustained increased solubility in the pH range 1.2-8.0 compared to their crystalline references. In vivo, XS004 was bioequivalent at a 30% lower dose and showed increased absorption and bioavailability, with 2.1-4.8 times lower intra- and intersubject variability compared to the reference. XS005 had an increased absorption and bioavailability of 45% and 2.2-2.8 times lower variability, respectively, but it was not bioequivalent at the investigated dose level. Taken together, the formulation platform is suited to generate improved PKI formulations with consistent bioavailability and a reduced pH-dependent absorption process.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"13 9","pages":"985-999"},"PeriodicalIF":1.5,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1416","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141161422","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 Model-Informed Drug Development Approach to Design a Phase 3 Trial of Teverelix Drug Product in Advanced Prostate Cancer Patients with Increased Cardiovascular Risk 以模型为依据的药物开发方法，设计 Teverelix 药物产品在心血管风险增加的晚期前列腺癌患者中的 3 期试验。

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2024-05-17 DOI: 10.1002/cpdd.1415

Chenna Keshava Reddy Sannala, Carol MacLean, Finn Larsen, Steve van Os, Pravin Jadhav, Neal Shore, Alicia K. Morgans, Tochukwu Okwuosa, Joga Gobburu

{"title":"A Model-Informed Drug Development Approach to Design a Phase 3 Trial of Teverelix Drug Product in Advanced Prostate Cancer Patients with Increased Cardiovascular Risk","authors":"Chenna Keshava Reddy Sannala, Carol MacLean, Finn Larsen, Steve van Os, Pravin Jadhav, Neal Shore, Alicia K. Morgans, Tochukwu Okwuosa, Joga Gobburu","doi":"10.1002/cpdd.1415","DOIUrl":"10.1002/cpdd.1415","url":null,"abstract":"Teverelix drug product (DP) is a parenteral gonadotropin-releasing hormone (GnRH) antagonist that has been successfully tested in phase 2 trials for hormone-sensitive advanced prostate cancer (APC) and benign prostatic hyperplasia (BPH). In previous APC trials, teverelix DP was administered as intramuscular (IM) and subcutaneous (SC) injections, using a loading dose and (in a single trial) a maintenance dose. Our objective was to derive an optimal dosing regimen for phase 3 clinical development, using a pharmacometrics modeling approach. Data from 9 phase 2 studies (229 patients) was utilized to develop a population pharmacokinetic (PK) model that described the concentration profile accommodating both IM and SC routes of administration. A 2-compartment model with sequential first-order absorption (slow and fast) and lag times best described the PK profiles of teverelix following SC and IM administration. An indirect response model with inhibition of production rate was fit to describe testosterone (T) concentrations based on physiological relevance. The final population PK–pharmacodynamic model was used to conduct simulations of various candidate dosing regimens to select the optimal dosing regimen to achieve clinical castration (T < 0.5 ng/mL by day 28) and to sustain clinical castration for 26 weeks. Model simulation showed that a loading dose of 360 mg SC and 180 mg IM with a maintenance dose of 360 mg SC 6-weekly (Q6W) starting at day 28 can achieve a ≥95% castration rate up to 52 weeks. This dose regimen was selected for phase 3 clinical development, which includes cardiovascular safety assessment in comparison to a GnRH agonist.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"13 8","pages":"915-929"},"PeriodicalIF":1.5,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140956500","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 of Fipaxalparant, a Small-Molecule Selective Negative Allosteric Modulator of Lysophosphatidic Acid Receptor 1, and the Effect of Food in Healthy Volunteers 健康志愿者体内溶血磷脂酸受体 1 的小分子选择性负异构型调节剂 Fipaxalparant 的药代动力学及食物的影响。

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2024-05-17 DOI: 10.1002/cpdd.1417

Yang Song, Farah N. Ali, Zhan Ye, Jennifer Zarzoso, John Rogowski, Yajing Sun, Yan Xin

{"title":"Pharmacokinetics of Fipaxalparant, a Small-Molecule Selective Negative Allosteric Modulator of Lysophosphatidic Acid Receptor 1, and the Effect of Food in Healthy Volunteers","authors":"Yang Song, Farah N. Ali, Zhan Ye, Jennifer Zarzoso, John Rogowski, Yajing Sun, Yan Xin","doi":"10.1002/cpdd.1417","DOIUrl":"10.1002/cpdd.1417","url":null,"abstract":"Dysregulated lysophosphatidic acid receptor 1 (LPAR1) signaling is implicated in fibrotic diseases, including systemic sclerosis (SSc) and idiopathic pulmonary fibrosis (IPF). Fipaxalparant (HZN-825) is a small molecule acting as a negative allosteric modulator of LPAR1 and is in phase 2 clinical evaluations for treating diffuse cutaneous SSc and IPF. This open-label, phase 1 study examined the pharmacokinetics (PKs), food effect, and safety of fipaxalparant in healthy volunteers. Dose proportionality was evaluated for fipaxalparant single doses of 150, 300, and 450 mg under fasted conditions. Food effect was tested with a 450-mg single dose under fasted conditions or with a high-fat meal. Multiple-dose PKs for twice-daily dosing of either 300 or 450 mg with low- or high-fat meals was also assessed. Fipaxalparant was safe and well tolerated in healthy volunteers (n = 36) under all conditions. Fipaxalparant exposure increased in a less than dose-proportional manner from 150 to 450 mg. At 450 mg, a high-fat meal increased the maximum observed concentration and area under the curve by approximately 1.9- and 2.1-fold, respectively. These results, combined with prior preclinical and phase 2a data, informed dose selection of fipaxalparant 300 mg once and twice daily with a meal for phase 2b studies.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"13 7","pages":"819-827"},"PeriodicalIF":1.5,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1417","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140956504","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