Clinical Pharmacology & Therapeutics最新文献

{"title":"Mechanistic Population Pharmacokinetic Modeling of Extended-Release Metformin in Obese South African Women Living with HIV on Dolutegravir.","authors":"Rohan M Benecke, Veshni Pillay-Fuentes Lorente, Eric Decloedt, Roland van Rensburg","doi":"10.1002/cpt.70565","DOIUrl":"https://doi.org/10.1002/cpt.70565","url":null,"abstract":"<p><p>Regulatory limits on metformin co-administered with dolutegravir (DTG) derive from healthy-volunteer studies in which DTG increased metformin exposure by 79% through organic cation transporter 2 inhibition, prompting a 1,000 mg/day metformin dose restriction. Whether this applies to women with HIV and severe obesity, a clinically important and understudied population for metformin-DTG coadministration, is unknown. In a secondary analysis of a reported cohort, we developed a population pharmacokinetic model of extended-release (XR) metformin with a zero-order-release, first-order-absorption structure scaled by lean body mass (LBM). Estimated glomerular filtration rate and DTG exposure were evaluated as clearance covariates, including DTG as a time-varying competitive inhibitor. We simulated steady-state exposures across body mass index (BMI) 30-60 kg/m² at 1000-3000 mg once daily compared to a DTG-free reference model. Fifteen women contributed evaluable profiles (mean BMI 45.6 kg/m²). Apparent clearance was 70.2 L/h, approximately 40% higher than reported non-obese values, and DTG exposure was approximately 54% lower than in volunteer studies. LBM dominated clearance and volume, while no DTG exposure-dependent effect on metformin clearance was identifiable within the observed low DTG exposure range. Simulated exposures rose near-proportionally with dose and minimally with BMI; the proportion exceeding the lactic acidosis-associated maximum concentration of 5 mg/L was 4.4% at 2000 mg/day, 16.9% at 2500 mg/day and 37.9% at 3000 mg/day, whereas none exceeded the lactic acidosis-associated average steady-state concentration of 4 mg/L. Although an interaction at higher DTG exposures cannot be excluded, the low exposures observed suggest the 1,000 mg/day restriction may underdose this obese population, supporting investigation of doses up to 2000 mg/day as the maximum authorized daily dose for metformin XR.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149369745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Implementation of Pharmacogenomics in Pediatric-Focused Institutions Within the Pharmacogenomics Global Research Network.","authors":"Laura B Ramsey, Chad Bousman, Rebecca Brand, Kelsey Cook, David B Gregornik, Cyrine E Haidar, Nancy Hakooz, Nicole Keuler, Nathan Lamb, Mohamed Nagy, Jenny Q Nguyen, Courtney Paetznick, April Schultz, D Max Smith, Evangelia Eirini Tsermpini, Amanda L Elchynski","doi":"10.1002/cpt.70553","DOIUrl":"https://doi.org/10.1002/cpt.70553","url":null,"abstract":"<p><p>Descriptions of how pediatric-focused institutions implement pharmacogenomic testing are scarce, and often not differentiated from adult-focused institutions. We aimed to provide a detailed description of how pediatric-focused institutions across the world implemented pharmacogenomic testing in clinical practice. A survey was distributed to members of the Pharmacogenomics Global Research Network to assess program infrastructure, implementation efforts, genes tested, method of testing, and clinical decision support. The survey was completed by 43 institutions that have implemented pharmacogenomics: 12 pediatric-focused, 10 adult-focused, and 21 institutions serving all ages. All pediatric-focused institutions provide testing for CYP2C19, CYP2C9, CYP2D6, CYP3A5, NUDT15, and TPMT. Psychiatry and hematology/oncology were the specialties most commonly reported as implementing pharmacogenomics at pediatric-focused institutions. Most institutions have clinical decision support incorporated into their electronic health record and a similar number of compensated employees contributing to the program, regardless of age group focus. All pediatric-focused institutions were non-profit and often received programmatic funding from internal sources. A higher proportion of pediatric-focused sites provided patient education (92%) compared to adult-focused (60%) and those caring for all ages (76%). Pediatric-focused institutions interested in implementing or expanding their pharmacogenomic services will encounter many of the same opportunities and considerations as adult institutions. The results of this survey highlight additional unique considerations for pediatric-focused pharmacogenomic implementation and may serve as a roadmap for pediatric institutions interested in implementing or expanding pharmacogenomic services.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149369744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of Food and Beverage on Enlicitide Pharmacokinetics and LDL-C Lowering.","authors":"Douglas G Johns, Maja Skataric, Susan Zhou, Ferdous Gheyas, Ednan Bajwa, Puja Banka, Filippos Kesisoglou, Allen Hunt, David Bruce, Corey Anderson, Helen Manthos, Jonathan Pollock, Paul J Donabella, Campbell Thompson, Daniel Freire, Kiet Giang, Frank Pietrantonio, Dennis Wolford, Piyali Basak, Maxwell Pistilli, Bhavna Kantesaria, Prajakti Kothare, Islam R Younis","doi":"10.1002/cpt.70541","DOIUrl":"10.1002/cpt.70541","url":null,"abstract":"<p><p>Enlicitide decanoate is a macrocyclic peptide first-in-class oral PCSK9 inhibitor that lowers LDL-C, with maximal efficacy achieved when administered on an empty stomach. This work characterizes the effects of food, pre-dose fasting duration (2-8 hours), water volume, common beverages (black coffee and plain tea), and other real-world scenarios on enlicitide exposure and predicts the impact on clinical efficacy. Three phase I, open-label, crossover studies in healthy participants evaluated the effects of these conditions on enlicitide exposure following a single 20 mg dose. Enlicitide steady-state exposure and corresponding LDL-C reductions under various conditions were predicted using population pharmacokinetic and exposure-response models. Administration of enlicitide 30 minutes after a high-fat meal resulted in an approximately 48% reduction in steady-state AUC and delayed absorption compared with fasted conditions (median Tmax ~8 hours vs. 0.5-1 hour). Increasing pre-dose fasting duration from 2 to 8 hours increased exposure. Water volume, black coffee or plain tea had no meaningful effect on enlicitide exposure. Model-predicted LDL-C reductions remained robust across various conditions, with LDL-C reductions of approximately 64% under fasted conditions, 62% to 63% when occasionally administered with food or if a dose is occasionally missed, 60% with black coffee or plain tea, and 59% following a 4-hour fast. These data support the recommended dosing and administration instructions for enlicitide, which are expected to provide ~60% LDL-C reduction, as seen in the enlicitide phase III clinical trials. Furthermore, these findings highlight the pharmacokinetic forgiveness potential of enlicitide, suggesting that occasional departures from the recommended dosing or sporadic lapses in compliance may be tolerated with minimal impact on efficacy.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149356983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"I Have a Medical Degree. Should I Consider a Career in Clinical Pharmacology in 2026?","authors":"Jean Terrier","doi":"10.1002/cpt.70564","DOIUrl":"10.1002/cpt.70564","url":null,"abstract":"","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13741074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149339993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Navigating the Role of Clinical Pharmacists in Integrative Oncology Care Teams: Time to Create Higher Training and Practice Standards.","authors":"Eran Ben-Arye, Sunita Vohra, Noah Samuels, Alexandre Chan","doi":"10.1002/cpt.70559","DOIUrl":"10.1002/cpt.70559","url":null,"abstract":"<p><p>Integrative oncology (IO) programs are committed to offer evidence-based complementary medicine within conventional cancer care, addressing quality of life-related concerns. As part of a multidisciplinary team, clinical pharmacists provide guidance on potential effectiveness and safety of herbal supplement use, identifying potential toxicities and herb-drug interactions. In this commentary, we discuss the need to establish clinical competencies based on a structured training syllabus addressing patients' preferences and expectations, while ensuring safe IO practices.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13732498/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149316459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dapagliflozin vs. Acetazolamide in Patients With Acute Heart Failure: A Randomized Controlled Trial (CHOICE-AHF).","authors":"Hossam Sharaf, Moheb Wadie, Noha O Mansour, Mohamed E E Shams","doi":"10.1002/cpt.70540","DOIUrl":"10.1002/cpt.70540","url":null,"abstract":"<p><p>Early adjunctive therapies may improve decongestion and symptoms in acute heart failure. This trial compared dapagliflozin with acetazolamide when initiated early, focusing on dyspnea relief as the primary outcome and decongestive, diuretic, natriuretic, and safety outcomes. In this randomized, active-controlled trial, 108 adults hospitalized with acute heart failure, dyspnea, and objective evidence of congestion requiring intravenous loop diuretics were randomized to receive dapagliflozin 10 mg (N = 55) or acetazolamide 500 mg (N = 53) once daily for 3 days alongside standard care. The primary endpoint was the between-group difference in 72-hour dyspnea visual analog scale area under the curve. Secondary endpoints included successful decongestion within 3 days, diuretic and natriuretic responses, the relative change in N-terminal pro-B-type natriuretic peptide levels from baseline to day 3, and safety. Acetazolamide produced a significantly lower 72-hour dyspnea area under the curve than dapagliflozin (2647.9 ± 1213.8 vs. 2988.7 ± 1196.7 mm × hour; P = 0.048). It increased cumulative urine output over 72 hours (12,200 vs. 10,000 mL; P = 0.019) and total natriuresis over 48 hours (824.7 vs. 547.9 mmol; P = 0.001). Dapagliflozin achieved a larger reduction in N-terminal pro-B-type natriuretic peptide at 72 hours (-34.2% vs. -25.0%; P = 0.003). Safety events were infrequent and similar. In conclusion, acetazolamide provided greater dyspnea relief, diuresis, and natriuresis, whereas dapagliflozin produced a larger short-term reduction in N-terminal pro-B-type natriuretic peptide. Further studies are needed to validate these findings. Trial registration: https://clinicaltrials.gov/study/NCT06783166.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13731440/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149316458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to \"REGBOT: Artificial Intelligence-Driven Compliance Automation for Global Pharmacogenomics Data Sharing (Abstract PS02.38)\".","authors":"","doi":"10.1002/cpt.70556","DOIUrl":"10.1002/cpt.70556","url":null,"abstract":"","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13727758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149316457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Pharmacology in Transgender Medicine: What Gaps Remain?","authors":"Lauren R Cirrincione","doi":"10.1002/cpt.70549","DOIUrl":"10.1002/cpt.70549","url":null,"abstract":"<p><p>Mechanistic information is limited about the effects of gender-affirming hormone therapy and the unique factors that influence the absorption, distribution, metabolism, and excretion properties of medications across therapeutic classes for transgender people. Opportunities exist to address knowledge gaps in transgender medicine using well-designed probe substrate studies, endogenous biomarkers of drug-metabolizing enzymes and transporters, and real-world data to identify and address factors that contribute to interindividual variability in drug disposition for transgender people across the life course.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13727757/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149316456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmaceutical Industry Pay-Per-Click Advertising Strategies to Influence Public Opinions on Drug Pricing.","authors":"Daniel Eisenkraft Klein, Aaron S Kesselheim","doi":"10.1002/cpt.70538","DOIUrl":"10.1002/cpt.70538","url":null,"abstract":"<p><p>This analysis characterizes the magnitude, timing, and keyword targeting strategies of the Pharmaceutical Research and Manufacturers of America's (PhRMA) pay-per-click advertising expenditures and their relation to major drug pricing policy developments (2019-2025). Pay-per-click advertising allows advertisers to purchase prominent placement in search engine results, allowing their content to appear above organic results when users search for specific terms. We extracted pay-per-click advertising data from Semrush, a commercial digital marketing intelligence platform, for the domain www.phrma.org from February 2019 through December 2025. We classified keywords into mutually exclusive categories using a specificity-based pattern-matching algorithm and categorized landing-page URLs by content theme using URL string matching. We analyzed monthly spending against a timeline of major legislative and regulatory events. PhRMA spent an estimated $58.8 million across 283,517 keyword instances, generating 17.1 million paid visits to phrma.org and its subdomains. Insurance and health plan keywords dominated spending ($32.4 million; 55.1%), including general and non-health insurance terms. Nearly half of total expenditures (47.5%; $27.9 million) drove traffic to pages classified as criticizing pharmacy benefit managers. Monthly spending showed little linear association with the selected Google Trends index (r = -0.05), but spending surged around well-publicized US legislative and regulatory actions, peaking at $4.8 million in May 2023; March-September 2023 accounted for 36.5% of total spending. Overall, PhRMA pay-per-click spending surges coincided with major US drug pricing policy developments.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13727760/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149316460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated assessment of rifampicin-mediated induction of transporters and drug-metabolizing enzymes in a long-term human liver tissue chip system.","authors":"Mattie E Hartauer, Raeanne M Lanphier, Shivam Ohri, Jessica Snyder, Jacqueline B Tiley, John K Fallon, Henry Ho, Murat Cirit, Shiny Amala Priya Rajan, Kim L R Brouwer","doi":"10.1002/cpt.70418","DOIUrl":"10.1002/cpt.70418","url":null,"abstract":"<p><p>Rifampicin is a prototypical clinical inducer used in drug-drug interaction (DDI) studies. However, the clinical relevance and predictability of rifampicin-mediated hepatic transporter induction remain poorly defined. Conventional hepatocyte culture models fail to capture clinically relevant regulation of transporters and drug-metabolizing enzymes (DMEs), particularly at the protein level. In this study, we characterized a liver tissue chip (LTC) as a new approach methodology (NAM) for long-term transporter- and DME-mediated induction risk assessment. Transporter-certified® cryopreserved primary human hepatocytes from three donors were cultured in the LTC under recirculating flow with or without 10 μM rifampicin for 7 days. The LTC facilitated simultaneous mRNA-protein quantification for transporters and mRNA-protein-activity profiling for cytochrome P450s (CYPs) within individual chips across treatment and control conditions. In addition, extracellular bile acid profiling and intracellular rifampicin concentrations were measured by LC-MS/MS. Rifampicin induced multiple transporters and enzymes at the protein level, including organic anion transporting polypeptide (OATP)2B1, P-glycoprotein, CYP3A4, CYP2C19, and uridine 5'-diphospho-glucuronosyltransferase (UGT)1A4. Induction patterns differed between transporter mRNA and protein in many cases, suggesting regulatory mechanisms beyond PXR-mediated activation. Matched mRNA-protein-activity measurements of five CYP enzymes also revealed discrepancies in rifampicin-mediated induction magnitude. Rifampicin altered bile acid composition, increasing taurine-conjugated bile acids and inducing bile acid-related genes. Measured intracellular rifampicin concentrations differed substantially from experimentally employed media concentrations. Overall, these findings demonstrate that the LTC enables integrated assessment of mRNA, protein, and activity measurements in addition to bile acid profiles and intracellular drug exposure, which may improve mechanistic understanding of induction processes.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":"1368-1378"},"PeriodicalIF":4.9,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13473850/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148758470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}