Clinical Pharmacology in Drug Development最新文献

A Comparative Analysis of the Pharmacodynamic and Pharmacokinetic Properties of 2 Controlled-Release Formulations Versus a Marketed Orlistat Product.

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-01-09 DOI: 10.1002/cpdd.1503

Stefan Grudén, Anders Forslund, Helena Litorp, Sandra Kuusk, Göran Alderborn, Arvid Söderhäll, Ulf Holmbäck

{"title":"A Comparative Analysis of the Pharmacodynamic and Pharmacokinetic Properties of 2 Controlled-Release Formulations Versus a Marketed Orlistat Product.","authors":"Stefan Grudén, Anders Forslund, Helena Litorp, Sandra Kuusk, Göran Alderborn, Arvid Söderhäll, Ulf Holmbäck","doi":"10.1002/cpdd.1503","DOIUrl":"https://doi.org/10.1002/cpdd.1503","url":null,"abstract":"A new modified-release oral formulation combines acarbose and orlistat (MR-OA) to enhance efficacy and reduce adverse effects through controlled drug release. This study aims to compare the pharmacodynamic properties of the orlistat component of MR-OA (MR-O) with a conventional orlistat product, Xenical (Conv-O), analyzing the percentage of fecal fat excretion. In addition, the pharmacokinetic properties of the complete formulation, MR-OA, were compared with Conv-O. In Part I of the study, 20 healthy volunteers were randomized in a single-blind, crossover trial to take MR-O or Conv-O (120-mg orlistat) 3 times daily for 9 days. Fecal fat was measured at baseline and after each treatment. MR-O and Conv-O similarly increased fecal fat percentage from 3.8% to 13.5%, confirming pharmacodynamic equivalence. Adverse events were few and generally rated as mild. In Part II, participants received MR-OA and then Conv-O, with blood samples collected for 12 hours to measure orlistat and acarbose levels. Orlistat's peak concentration stayed below 5 ng/mL, and acarbose plasma levels were mostly undetectable, indicating minimal systemic absorption. This shows that the new weight loss product MR-OA retains the dietary energy loss pathway used in Conv-O. Consistent with previous studies, minimal systemic absorption of orlistat and acarbose was observed for MR-OA, confirming that no significant alteration of the original substances occurs when modifying their release.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":" ","pages":""},"PeriodicalIF":1.5,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945653","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

Determination of the Bioavailability of 3 Intranasal Formulations of Azelastine Hydrochloride in Healthy Male Volunteers.

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":"https://doi.org/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":" ","pages":""},"PeriodicalIF":1.5,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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.

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

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":"https://doi.org/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":" ","pages":""},"PeriodicalIF":1.5,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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.

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

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.

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

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":"https://doi.org/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":" ","pages":""},"PeriodicalIF":1.5,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Phase 1 Study to Evaluate the Pharmacokinetic Drug-Drug Interaction Between Islatravir and Methadone in Participants on Stable Methadone Therapy.

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.1492

Randolph P Matthews, Wendy Ankrom, Whitney Handy, Munjal Patel, Catherine Matthews, Zhiqing Xu, Kezia Gravesande, Shawn Searle, Howard Schwartz, S Aubrey Stoch, Marian Iwamoto

{"title":"A Phase 1 Study to Evaluate the Pharmacokinetic Drug-Drug Interaction Between Islatravir and Methadone in Participants on Stable Methadone Therapy.","authors":"Randolph P Matthews, Wendy Ankrom, Whitney Handy, Munjal Patel, Catherine Matthews, Zhiqing Xu, Kezia Gravesande, Shawn Searle, Howard Schwartz, S Aubrey Stoch, Marian Iwamoto","doi":"10.1002/cpdd.1492","DOIUrl":"10.1002/cpdd.1492","url":null,"abstract":"Islatravir is a nucleoside reverse transcriptase translocation inhibitor in development for the treatment of HIV-1. People living with HIV-1 receiving methadone maintenance therapy may benefit from islatravir. This study was designed to evaluate single-dose islatravir on steady-state methadone pharmacokinetics. A nonrandomized, open-label study (NCT04568603) was conducted and included adult participants receiving methadone therapy. Participants received their standard methadone therapy and a single oral dose of islatravir 60 mg concomitantly. Blood samples were collected to determine methadone and islatravir pharmacokinetics. Fourteen participants aged 26-63 years were enrolled; 13 completed the study. The geometric mean ratios for methadone area under the concentration-time curve from time 0 to 24 hours (AUC0-24), maximum plasma concentration (Cmax), and concentration at 24 hours (C24) were 1.03, 1.01, and 1.07, respectively. Similar effects were seen for the R- and S-enantiomer of methadone (R-methadone: AUC0-24, 1.03; Cmax, 1.02; and C24, 1.06; S-methadone: AUC0-24, 1.03; Cmax, 1.01; and C24, 1.08). For islatravir, based on a comparison with historical data, the geometric mean ratios for AUC0-inf and Cmax were 1.18 and 0.86, respectively. Coadministration of a single dose of islatravir and methadone was generally well tolerated. Single-dose islatravir did not affect steady-state methadone pharmacokinetics in a clinically meaningful way.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":" ","pages":"36-43"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11701965/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794164","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

Relative Bioavailability of Sotorasib Following Administration as a Water Dispersion to Healthy Subjects and Compatibility With Enteral Administration. 健康受试者服用水分散液后索托拉西布的相对生物利用度以及与肠内给药的兼容性。

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-01-01 Epub Date: 2024-09-04 DOI: 10.1002/cpdd.1468

Panli Cardona, Marintan Spring, Jiemin Bao, Yong Xie, Brett Houk

{"title":"Relative Bioavailability of Sotorasib Following Administration as a Water Dispersion to Healthy Subjects and Compatibility With Enteral Administration.","authors":"Panli Cardona, Marintan Spring, Jiemin Bao, Yong Xie, Brett Houk","doi":"10.1002/cpdd.1468","DOIUrl":"10.1002/cpdd.1468","url":null,"abstract":"Sotorasib is approved to be taken as 960 mg orally once daily (8 × 120-mg tablets) for the treatment of KRAS G12C-mutated nonsmall cell lung cancer. Dispersion of tablets in water could be an alternative method for patients who require a liquid formulation due to dysphagia and enteral administration. A clinical study was conducted to assess the pharmacokinetics of 960 mg of sotorasib administered as tablets and as tablets dispersed in water in healthy volunteers. Each subject received 960 mg of sotorasib by mouth, as tablets and as tablets dispersed in water on Days 1 and 4. Sotorasib median time to maximum observed plasma concentration was similar when administered as tablets and as tablets predispersed in water. The geometric least squares mean ratios (water dispersion/tablets) for area under the concentration-time curve from time 0 extrapolated to infinity and maximum observed plasma concentration were 1.049 and 1.080, respectively. Sotorasib 960 mg was well tolerated. Administration of 960 mg of sotorasib as tablets predispersed in water achieved similar systemic exposures to that of sotorasib administered as oral tablets. In vitro evaluations were performed to assess the feasibility of administering sotorasib through an enteral feeding tube. Approximately 98% of sotorasib was recovered, with no new impurities, from enteral feeding tubes. Collectively, these results support that sotorasib can be administered by mouth and via enteral feeding tubes as tablets predispersed in water.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":" ","pages":"44-49"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142125074","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