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

Tramadol/Diclofenac Fixed-Dose Combination for Acute Pain Management: Bioavailability Assessment of a Generic Product 用于急性疼痛治疗的曲马多/双氯芬酸固定剂量复方制剂：仿制产品生物利用度评估。

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2024-05-08 DOI: 10.1002/cpdd.1410

Thalita Martins da Silva, Marcelo Gomes Davanço, Jessica Meulman, Débora Renz Barreto Vianna, Fernando Costa, Fernando Bastos Canton Pacheco, Silvana Aparecida Calafatti Carandina, Eduardo Issa, Celso Francisco Pimentel Vespasiano

{"title":"Tramadol/Diclofenac Fixed-Dose Combination for Acute Pain Management: Bioavailability Assessment of a Generic Product","authors":"Thalita Martins da Silva, Marcelo Gomes Davanço, Jessica Meulman, Débora Renz Barreto Vianna, Fernando Costa, Fernando Bastos Canton Pacheco, Silvana Aparecida Calafatti Carandina, Eduardo Issa, Celso Francisco Pimentel Vespasiano","doi":"10.1002/cpdd.1410","DOIUrl":"10.1002/cpdd.1410","url":null,"abstract":"The multimodal analgesia strategy for acute pain involves using 2 or more analgesic medications with distinct mechanisms of action. This study assessed the bioavailability and tolerability of 2 tramadol hydrochloride (50 mg)/diclofenac sodium (50 mg) fixed-dose combination formulations under fed conditions to attend the Brazilian regulatory requirements for generic product registration. An open-label, randomized, single-dose, 2-period, 2-way crossover trial was conducted, including healthy subjects of both sexes. Subjects received a single dose of either the test or reference formulation of tramadol/diclofenac fixed-dose combination tablets with a 7-day washout period. Blood samples were collected up to 36 hours after dosing for tramadol and 12 hours for diclofenac and quantified using a validated liquid chromatography-tandem mass spectrometry method. Of 56 subjects enrolled, 53 completed the study. The 90% confidence intervals for maximum plasma concentration and area under the concentration-time curve from time 0 to the last quantifiable concentration were within acceptable bioequivalence limits of 80%-125%. Considering the results presented in this study, the test formulation is bioequivalent to the reference formulation and could be interchangeable in medical practice.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"13 8","pages":"907-914"},"PeriodicalIF":1.5,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1410","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140876051","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

Effect of Food, Crushing of Tablets, and Antacid Coadministration on Maribavir Pharmacokinetics in Healthy Adult Participants: Results From 2 Phase 1, Open-Label, Randomized, Crossover Studies 食物、碾碎药片和同时服用抗酸剂对健康成人参与者服用马利巴韦药代动力学的影响：两项一期开放标签随机交叉研究的结果

IF 2 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2024-05-06 DOI: 10.1002/cpdd.1406

Kefeng Sun, Katarina Ilic, Peixin Xu, Ran Ye, Jingyang Wu, Ivy H. Song

{"title":"Effect of Food, Crushing of Tablets, and Antacid Coadministration on Maribavir Pharmacokinetics in Healthy Adult Participants: Results From 2 Phase 1, Open-Label, Randomized, Crossover Studies","authors":"Kefeng Sun, Katarina Ilic, Peixin Xu, Ran Ye, Jingyang Wu, Ivy H. Song","doi":"10.1002/cpdd.1406","DOIUrl":"10.1002/cpdd.1406","url":null,"abstract":"The effect of food composition, tablet crushing, and antacid coadministration on maribavir pharmacokinetics was assessed in 2 Phase 1 studies in healthy adults. In the first, a single maribavir 400-mg dose was administered under fasting conditions, with a low-fat/low-calorie or a high-fat/high-calorie meal. In the second, a single maribavir 100-mg dose was administered under fasting conditions, as a crushed tablet, or as a whole tablet alone or with an antacid. The 90% confidence intervals of the geometric mean ratios were within 80%-125% for area under the concentration-time curve (AUC), but not for maximum plasma concentration (Cmax) for low-fat/low-calorie and high-fat/high-calorie meals versus fasting or for whole tablet with antacid versus whole tablet alone. The 90% confidence intervals of the geometric mean ratios for AUC and Cmax were within 80%-125% for crushed versus whole tablet. Maribavir median time to Cmax value in plasma under fed conditions was delayed versus fasting conditions, but there was no statistical difference for crushed versus whole tablet or with versus without antacid. As the antiviral efficacy of maribavir is driven by AUC but not Cmax, findings suggest that maribavir can be administered with food or antacids or as a crushed tablet.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"13 6","pages":"644-654"},"PeriodicalIF":2.0,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1406","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140848165","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 of Atogepant Co-administered with Quinidine Gluconate in Healthy Participants: A Phase 1, Open-Label, Drug-Drug Interaction Study 健康参与者服用阿托格潘与葡萄糖酸奎尼丁的药代动力学和安全性：一期开放标签药物相互作用研究

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2024-05-03 DOI: 10.1002/cpdd.1407

Ramesh Boinpally, Lisa Borbridge, Veronica Wangsadipura

{"title":"Pharmacokinetics and Safety of Atogepant Co-administered with Quinidine Gluconate in Healthy Participants: A Phase 1, Open-Label, Drug-Drug Interaction Study","authors":"Ramesh Boinpally, Lisa Borbridge, Veronica Wangsadipura","doi":"10.1002/cpdd.1407","DOIUrl":"10.1002/cpdd.1407","url":null,"abstract":"Atogepant, an oral calcitonin gene-related peptide receptor antagonist, is approved for the preventive treatment of migraine. Atogepant is a substrate of P-glycoprotein (P-gp), breast cancer resistance protein, organic anion transporting polypeptide transporters, and cytochrome P450 (CYP)3A4 and 2D6. Quinidine is a strong P-gp and CYP2D6 inhibitor. A phase 1 open-label study evaluated the effect of P-gp and CYP2D6 inhibition by quinidine on the pharmacokinetics of atogepant, and the safety and tolerability of atogepant and quinidine gluconate (QG) when co-administered and when given alone in 33 healthy adults. There was no significant change in the atogepant maximum plasma concentration with QG co-administration. The overall systemic exposure, the area under the plasma concentration-time curve (from time 0 to time t or to infinity), of atogepant increased by 25% when co-administered with QG. However, such an increase was not considered clinically relevant. Atogepant did not alter the mean plasma concentration of quinidine at steady state. The incidence of treatment-emergent adverse events (TEAEs) was highest when QG was administered alone (42.4%), which was primarily due to QT prolongation. Most TEAEs reported were mild in severity and resolved within 1-2 days. Co-administration of atogepant with QG did not result in any unexpected tolerability findings in this phase 1 study in healthy participants. The increase in atogepant exposure during QG co-administration could be due to inhibition of CYP2D6 (a minor contributor to atogepant clearance) as well as inhibition of P-gp.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"13 8","pages":"930-937"},"PeriodicalIF":1.5,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1407","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140832562","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

Apixaban Pharmacokinetics and Bioequivalence of Two Tablet Formulations: A Randomized, Open-Label, Crossover Study, Fasting Condition in Healthy Indonesian Volunteers 阿哌沙班两种片剂的药代动力学和生物等效性：在印度尼西亚健康志愿者中进行的一项随机、开放标签、交叉研究（空腹状态

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2024-04-30 DOI: 10.1002/cpdd.1409

Chuei Wuei Leong, Kar Ming Yee, Ivan Liew, Nur Athirah Khaleb, Shahnun Ahmad, Tracy Ann Rani, Kheng Jim Lau, Danang Agung Yunaidi, Ronal Simanjuntak, Vicky A. Ginanjar

{"title":"Apixaban Pharmacokinetics and Bioequivalence of Two Tablet Formulations: A Randomized, Open-Label, Crossover Study, Fasting Condition in Healthy Indonesian Volunteers","authors":"Chuei Wuei Leong, Kar Ming Yee, Ivan Liew, Nur Athirah Khaleb, Shahnun Ahmad, Tracy Ann Rani, Kheng Jim Lau, Danang Agung Yunaidi, Ronal Simanjuntak, Vicky A. Ginanjar","doi":"10.1002/cpdd.1409","DOIUrl":"10.1002/cpdd.1409","url":null,"abstract":"The present study aimed to assess the bioequivalence of a new apixaban generic with reference formulation. Twenty-six healthy volunteers were recruited for an open-label, balanced, randomized, 2-treatment, 2-sequence, 2-period, single oral dose study. Following overnight fasting, each volunteer received 5 mg of apixaban test and reference formulations as single doses, separated by a 1-week washout period. Twenty blood samples were collected at predose and multiple time points between 0.5 and 72 hours after dosing. A validated ultra-performance liquid chromatography-tandem mass spectrometry detection method following a protein precipitation step was implemented to determine apixaban concentrations. Noncompartmental analysis was used to derive the pharmacokinetic parameters, which were then compared between the test and reference products using a multivariate analysis of variance. The pharmacokinetic parameters of the test product were not statistically different from the reference product, and the 90% confidence intervals of apixaban natural log-transformed area under the concentration-time curve from time 0 to infinity, area under the concentration-time curve from time 0 to the last measurable concentration, and maximum concentration were within 80%-125% based on the bioequivalence acceptance range criteria. The test and reference formulations of apixaban are bioequivalent in healthy subjects under fasting conditions.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"13 8","pages":"890-896"},"PeriodicalIF":1.5,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140832594","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

Comparative Pharmacokinetics and Safety Assessment of 1st- and 2nd-Generation Zinpentraxin Alfa Drug Products in Healthy Volunteers: A Randomized Crossover Study 第 1 代和第 2 代 Zinpentraxin Alfa 药物产品在健康志愿者中的药代动力学和安全性比较评估：随机交叉研究。

IF 2 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2024-04-23 DOI: 10.1002/cpdd.1403

Tu H. Mai, Rajbharan Yadav, Audrey Arjomandi, Christine Jung, Monika M. Meier, Francis Donaldson, Rui Zhao, Han-Ting Ding, Joy C. Hsu, Nikhil Kamath, Lin Pan

{"title":"Comparative Pharmacokinetics and Safety Assessment of 1st- and 2nd-Generation Zinpentraxin Alfa Drug Products in Healthy Volunteers: A Randomized Crossover Study","authors":"Tu H. Mai, Rajbharan Yadav, Audrey Arjomandi, Christine Jung, Monika M. Meier, Francis Donaldson, Rui Zhao, Han-Ting Ding, Joy C. Hsu, Nikhil Kamath, Lin Pan","doi":"10.1002/cpdd.1403","DOIUrl":"10.1002/cpdd.1403","url":null,"abstract":"Zinpentraxin alfa is a recombinant form of the human pentraxin-2 that was studied in idiopathic pulmonary fibrosis (IPF). To improve the purity and yield of the drug material, a 2nd-generation drug product was developed. To characterize and compare the pharmacokinetic (PK) properties of the 1st- and 2nd-generation zinpentraxin alfa, PK studies were conducted in healthy volunteers (HVs). In a phase 1 randomized, double-blind, 2-sequence crossover, sequential 2-stage study (ISRCTN59409907), single intravenous (IV) doses of 1st- and 2nd-generation zinpentraxin alfa at 10 mg/kg were studied with a blinded interim analysis (IA) at the end of stage 1. Bioequivalence (BE) was achieved for the maximum observed plasma concentration (Cmax), but the overall exposure was higher for the 2nd- compared to the 1st-generation zinpentraxin alfa. The study was stopped after stage 1 as the gating criteria were met based on the result of the blinded IA. Safety profiles were similar for the 1st- and 2nd-generation drug products, and antidrug antibody (ADA) was not observed in this study.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"13 6","pages":"655-664"},"PeriodicalIF":2.0,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1403","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140669460","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 Pharmacokinetics of Anaprazole, a Novel Proton Pump Inhibitor, in Healthy Chinese Subjects 新型质子泵抑制剂阿纳普拉唑在中国健康受试者中的安全性、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 : 2024-04-17 DOI: 10.1002/cpdd.1405

Fangfang Wang, Xiaoye Niu, Fei Liu, Xifeng Ma, Fang Cheng, Haiyan Xu, Li Wang, Yanjun Xu, Haiyan Li

{"title":"Safety, Tolerability, and Pharmacokinetics of Anaprazole, a Novel Proton Pump Inhibitor, in Healthy Chinese Subjects","authors":"Fangfang Wang, Xiaoye Niu, Fei Liu, Xifeng Ma, Fang Cheng, Haiyan Xu, Li Wang, Yanjun Xu, Haiyan Li","doi":"10.1002/cpdd.1405","DOIUrl":"10.1002/cpdd.1405","url":null,"abstract":"Anaprazole, a newly developed oral proton pump inhibitor, was evaluated for safety, tolerability, and pharmacokinetics in healthy Chinese subjects. This study involved administering either anaprazole sodium enteric-coated tablet or placebo, followed by monitoring the incidence and severity of any adverse events (AEs). The pharmacokinetic parameters of anaprazole, its isomer, and main metabolisms were determined. The results showed that both single-dose (2.5-120 mg) and multiple-dose (20 mg once daily, 40 mg once daily, or 20 mg twice daily) oral administration of anaprazole sodium enteric-coated tablet were safe and well tolerated. Following single-dose administration, the median time to reach maximum plasma concentration of anaprazole was between 3.50 and 5.25 hours, with mean elimination half-life of 1.22-3.79 hours. The absorption and elimination of anaprazole in the human body appeared to basically follow linear kinetics. After repeated dosing, steady-state concentrations of anaprazole, its isomer, and primary metabolites were achieved, with a median time to reach maximum plasma concentration of 3-3.75 hours and a mean elimination half-life of 1.61-2.27 hours for anaprazole. There was no significant drug accumulation after multiple-dose oral administration. In conclusion, anaprazole sodium enteric-coated tablets were found to be safe and well tolerated in healthy Chinese individuals. Anaprazole is absorbed and metabolized consistently in the human body without any accumulation.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"13 7","pages":"782-789"},"PeriodicalIF":1.5,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140615961","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

Effects of Quinidine or Rifampin Co-administration on the Single-Dose Pharmacokinetics and Safety of Rilzabrutinib (PRN1008) in Healthy Participants 奎尼丁或利福平联合用药对健康参与者服用 Rilzabrutinib (PRN1008) 单剂量药代动力学和安全性的影响

IF 2 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2024-04-16 DOI: 10.1002/cpdd.1404

Christian Rask-Madsen, Suresh Katragadda, Mengyao Li, Sibel Ucpinar, Leslie Chinn, Puneet Arora, Patrick Smith

{"title":"Effects of Quinidine or Rifampin Co-administration on the Single-Dose Pharmacokinetics and Safety of Rilzabrutinib (PRN1008) in Healthy Participants","authors":"Christian Rask-Madsen, Suresh Katragadda, Mengyao Li, Sibel Ucpinar, Leslie Chinn, Puneet Arora, Patrick Smith","doi":"10.1002/cpdd.1404","DOIUrl":"10.1002/cpdd.1404","url":null,"abstract":"This open-label, phase 1 study was conducted with healthy adult participants to evaluate the potential drug-drug interaction between rilzabrutinib and quinidine (an inhibitor of P-glycoprotein [P-gp] and CYP2D6) or rifampin (an inducer of CYP3A and P-gp). Plasma concentrations of rilzabrutinib were measured after a single oral dose of rilzabrutinib 400 mg administered on day 1 and again, following a wash-out period, after co-administration of rilzabrutinib and quinidine or rifampin. Specifically, quinidine was given at a dose of 300 mg every 8 hours for 5 days from day 7 to day 11 (N = 16) while rifampin was given as 600 mg once daily for 11 days from day 7 to day 17 (N = 16) with rilzabrutinib given in the morning of day 10 (during quinidine dosing) or day 16 (during rifampin dosing). Quinidine had no significant effect on rilzabrutinib pharmacokinetics. Rifampin decreased rilzabrutinib exposure (the geometric mean of Cmax and AUC0-∞ decreased by 80.5% and 79.5%, respectively). Single oral doses of rilzabrutinib, with or without quinidine or rifampin, appeared to be well tolerated. These findings indicate that rilzabrutinib is a substrate for CYP3A but not a substrate for P-gp.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"13 6","pages":"590-600"},"PeriodicalIF":2.0,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1404","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140572636","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

Population Pharmacokinetics and Dosing Simulations for Aripiprazole 2-Month Ready-to-Use Long-Acting Injectable in Adult Patients With Schizophrenia or Bipolar I Disorder 阿立哌唑 2 个月即用型长效注射剂在精神分裂症或 I 型躁狂症成人患者中的群体药代动力学和剂量模拟

IF 2 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2024-04-11 DOI: 10.1002/cpdd.1397

Yanlin Wang, Matthew Harlin, Frank Larsen, Xiaofeng Wang, Wansu Park, Benjamin Rich, Jogarao V. Gobburu, Arash Raoufinia

{"title":"Population Pharmacokinetics and Dosing Simulations for Aripiprazole 2-Month Ready-to-Use Long-Acting Injectable in Adult Patients With Schizophrenia or Bipolar I Disorder","authors":"Yanlin Wang, Matthew Harlin, Frank Larsen, Xiaofeng Wang, Wansu Park, Benjamin Rich, Jogarao V. Gobburu, Arash Raoufinia","doi":"10.1002/cpdd.1397","DOIUrl":"10.1002/cpdd.1397","url":null,"abstract":"A ready-to-use (RTU) long-acting injectable (LAI) formulation of aripiprazole monohydrate for administration once every 2 months, available in 960 mg (Ari 2MRTU 960) or 720 mg doses, has been developed for the treatment of schizophrenia or bipolar I disorder. A previously developed and validated population pharmacokinetic model for characterizing aripiprazole plasma concentrations following administration of oral aripiprazole or aripiprazole once-monthly (AOM) intramuscular injection was expanded to include the RTU LAI formulation of aripiprazole (Ari RTU LAI). Overall, 8899 aripiprazole pharmacokinetic samples from 1191 adults from 10 clinical trials were included in the final combined analysis data set. Aripiprazole plasma concentration-time profiles were simulated for various Ari RTU LAI initiation and maintenance scenarios in 1000 virtual patients. Diagnostic plots demonstrated that the final population pharmacokinetic model, which incorporated data for oral aripiprazole, AOM, and Ari RTU LAI, adequately described aripiprazole concentrations following Ari RTU LAI administration. Absorption of Ari RTU LAI was modeled by a parallel zero-order and lagged first-order process. Simulations across multiple scenarios were performed to inform dosing recommendations, including various treatment initiation regimens for a 2-monthly formulation of Ari RTU LAI in patients with or without prior stabilization on oral aripiprazole, and for patients switching from AOM. Additional simulations accounted for missed/delayed doses, cytochrome (CYP) 2D6 metabolizer status, and concomitant use of CYP2D6 or CYP3A4 inhibitors. Overall, simulations across a variety of scenarios demonstrated an Ari RTU LAI pharmacokinetic exposure profile that was comparable to AOM, with a longer dosing interval.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"13 6","pages":"631-643"},"PeriodicalIF":2.0,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1397","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140572530","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 Elagolix/Estradiol/Norethindrone Acetate Fixed-Dose Combination Product: Phase 1 Results in Healthy Pre- and Postmenopausal Women Elagolix/雌二醇/醋酸炔诺酮固定剂量复方产品的生物等效性：绝经前和绝经后健康妇女的第一阶段研究结果

IF 2 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2024-04-09 DOI: 10.1002/cpdd.1399

Mong-Jen Chen, Patrick Marroum, Yi-Lin Chiu, Melina Neenan, Nael M. Mostafa, Mohamad Shebley

{"title":"Bioequivalence of Elagolix/Estradiol/Norethindrone Acetate Fixed-Dose Combination Product: Phase 1 Results in Healthy Pre- and Postmenopausal Women","authors":"Mong-Jen Chen, Patrick Marroum, Yi-Lin Chiu, Melina Neenan, Nael M. Mostafa, Mohamad Shebley","doi":"10.1002/cpdd.1399","DOIUrl":"10.1002/cpdd.1399","url":null,"abstract":"Fixed-dose combination (FDC) therapies can enhance patient convenience and adherence to prescribed treatment regimens. Elagolix is a novel oral gonadotropin-releasing hormone receptor antagonist approved for management of moderate to severe pain associated with endometriosis and heavy menstrual bleeding associated with uterine fibroids. Hormonal add-back therapy can attenuate the reversible hypoestrogenic effects of elagolix. An FDC formulation containing elagolix/estradiol (E2)/norethindrone acetate (NETA) 300/1/0.5 mg as the morning dose and an elagolix 300 mg capsule as the evening dose, were evaluated in 2 bioequivalence studies including the effects of food. Study 1 in premenopausal women assessed the bioavailability of the elagolix 300-mg capsule relative to the commercially available elagolix 300-mg tablet. Study 2 in postmenopausal women, elagolix/E2/NETA (300 mg/1 mg/0.5 mg) FDC capsule was assessed relative to the elagolix 300-mg tablet coadministered with E2/NETA 1-mg/0.5-mg tablet, the regimen that was studied in Phase 3 uterine fibroid studies. Under fasting conditions, the test elagolix 300-mg capsule was bioequivalent to the reference elagolix 300-mg tablet. Under fasting conditions, the elagolix/E2/NETA FDC capsule was bioequivalent to the coadministered elagolix 300-mg tablet and E2/NETA 1/0.5-mg tablet. Following administration of elagolix/E2/NETA FDC capsule after a high-fat breakfast, elagolix mean maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) were 38% and 28% lower, relative to fasting conditions. NETA mean Cmax was 51% lower and AUC from time 0 to infinity was 20% higher, while baseline-adjusted total estrone mean Cmax and AUC were 46% and 14% lower, respectively. No safety concerns were identified. These results enabled bridging the elagolix/E2/NETA FDC capsule.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"13 6","pages":"601-610"},"PeriodicalIF":2.0,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1399","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140602970","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 Population Pharmacokinetic Assessment of the Effect of Food on Selumetinib in Patients with Neurofibromatosis Type 1-Related Plexiform Neurofibromas and Healthy Volunteers 食物对1型神经纤维瘤相关丛状神经纤维瘤患者和健康志愿者服用赛卢米替尼的影响的群体药代动力学评估

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2024-04-09 DOI: 10.1002/cpdd.1400

Peiying Zuo, Million Arefayene, Wei-Jian Pan, Tomoko Freshwater, Jonathan Monteleone

{"title":"A Population Pharmacokinetic Assessment of the Effect of Food on Selumetinib in Patients with Neurofibromatosis Type 1-Related Plexiform Neurofibromas and Healthy Volunteers","authors":"Peiying Zuo, Million Arefayene, Wei-Jian Pan, Tomoko Freshwater, Jonathan Monteleone","doi":"10.1002/cpdd.1400","DOIUrl":"10.1002/cpdd.1400","url":null,"abstract":"Selumetinib is clinically used for pediatric patients with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas. Until recently, selumetinib had to be taken twice daily, after 2 hours of fasting and followed by 1 hour of fasting, which could be inconvenient. This population analysis evaluated the effect of low- and high-fat meals on the pharmacokinetic (PK) parameters of selumetinib and its active metabolite N-desmethyl selumetinib. The dataset comprised 511 subjects from 15 clinical trials who received ≥1 dose of selumetinib and provided ≥1 measurable postdose concentration of selumetinib and N-desmethyl selumetinib. A 2-compartment model with sequential 0- and 1st-order delayed absorption and 1st-order elimination adequately described selumetinib PK characteristics. A 1-compartment model reasonably described N-desmethyl selumetinib PK characteristics over time simultaneously with selumetinib. Selumetinib geometric mean area under the concentration–time curve ratio (1-sided 90% confidence interval [CI] lower bound) was 76.9% (73.3%) with a low-fat meal and 79.3% (76.3%) with a high-fat meal versus fasting. The lower bound of the 1-sided 90% CI demonstrated a difference of <30% between fed and fasted states. Considering the flat exposure-response relationship within the dose range (20-30 mg/m2), the observed range of exposure, and the variability in the SPRINT trial, this was not considered clinically relevant.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"13 7","pages":"770-781"},"PeriodicalIF":1.5,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1400","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140572645","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}

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