Journal of Clinical Pharmacology最新文献

{"title":"Evaluation of Potential Adverse Effects of Gender-Affirming Hormonal Therapy; Findings from the Spanish Pharmacovigilance System Database.","authors":"Elena María Pérez-López, Jorge Navarro Roldán, Luisa María Herrera Rojas, Carmen María Jiménez Martín, Mercedes Ruiz Pérez, María Nieves Merino Kolly, Asunción Mengíbar García, María Esperanza Segura Molina, Ana Francisca Melcón de Dios, Luis Miguel Calderón López, María Del Pilar Máiquez Asuero","doi":"10.1002/jcph.70052","DOIUrl":"https://doi.org/10.1002/jcph.70052","url":null,"abstract":"<p><p>The Spanish Pharmacovigilance System for Medicines for Human Use (SEFV-H) is responsible for recording and evaluating adverse reactions suspected to be due to medicines. The aim of this study was to review all reports of suspected adverse drug reactions (ADRs) in the SEFV-H database derived from the gender-affirming hormone therapy (GAHT). For this purpose, we consulted the Andalusian Centre for Pharmacovigilance (CAFV) and used three search algorithms to select only those reports derived from hormone therapy used by trangender people. A total of 21 reports were obtained, 13 corresponding to masculinizing therapy with testosterone and 8 corresponding to feminizing therapy with estradiol and cyproterone acetate. Most of these reports were of non-serious symptoms. Skin and subcutaneous tissue disorders, neoplasms, and psychiatric, vascular, gastrointestinal, and nervous system disorders were the most common suspected ADRs. The median age was 23.6 years for masculinizing therapy and 27 years for feminizing therapy. These data highlight the need for well-designed studies specifically focused on transgender people undergoing hormone therapy. Such studies are essential to develop evidence-based treatment guidelines tailored to this population and to provide accurate, population-specific information about the potential health risks associated with gender-affirming hormone use.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144152564","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}

{"title":"Comparison of Population Pharmacokinetics-Related Information in Drug Labeling Between Japan, the United States, and the European Union.","authors":"Kei Fukuhara, Mamoru Narukawa","doi":"10.1002/jcph.70048","DOIUrl":"https://doi.org/10.1002/jcph.70048","url":null,"abstract":"<p><p>Quantitative decision making using the population pharmacokinetic (PPK) approach is useful not only in drug development but also in clinical practice. A previous study investigating the labeling of new active substances (NASs) approved between 2012 and 2015 in Japan and the United Sates reported a significant gap in the percentage of drug labeling providing PPK-related information between Japan (17.6%) and the United States (56.6%). However, whether the state of Japanese labeling has improved compared with the US and European Union (EU) labeling after a Japanese guideline on PPK analysis was released in 2019 has not been investigated yet. This study evaluated the labeling of 138 NASs approved in Japan, the United States, and the EU in or after 2019 and found that the percentage of NASs which provide PPK-related information in the drug labeling with an explicit statement that it was based on PPK analysis was 50.0%, 46.2%, and 76.9% in Japan, the United States, and the EU, respectively, indicating a remarkable improvement in Japan labeling. However, we also found that Japan labeling was still considerably behind the US/EU labeling in terms of application of quantitative decision making by the PPK approach. This is because the percentage of NASs with PPK-derived information used to support dosing recommendations in special populations was much lower in Japan labeling than in the US/EU labeling. While the PPK guideline played an important role in improving Japan's drug labeling, more utilization of PPK-derived information in quantitative decision making is required for healthcare professionals and patients in Japan.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144121245","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}

{"title":"Pharmacokinetic Characterization of Iopamidol and Iohexol for Optimizing Measured Glomerular Filtration Rate Assessment in Clinical Practice and Drug Development.","authors":"Levi Hooper, Michael Heung, Lu Wang, Aleksas Matvekas, Radin Alikhani, Michael T Kenes, Kathleen A Stringer, Bruce A Mueller, Manjunath P Pai","doi":"10.1002/jcph.70046","DOIUrl":"10.1002/jcph.70046","url":null,"abstract":"<p><p>Accurate kidney function assessment supports healthcare and clinical decision-making in practice and drug development. Measured glomerular filtration rate (mGFR) via iohexol clearance is the gold standard, but cost, supply issues, and logistical challenges limit its clinical use. Iopamidol, another iodinated contrast agent widely used in CT imaging, has not been studied in humans for mGFR assessment. This study aims to evaluate the pharmacokinetic interchangeability of iohexol and iopamidol for mGFR assessment and to develop a limited sampling strategy to facilitate clinical implementation. In a parallel-group, single-dose pharmacokinetic study, 24 healthy adult volunteers with varying kidney function, as defined by the 2021 CKD-EPI eGFRcr equation (range: 35-140 mL/min; median: 72 mL/min), received iohexol and iopamidol. Plasma concentrations were measured using liquid chromatography-mass spectrometry, and population pharmacokinetic modeling estimated drug clearance. Clearance estimates for both agents showed strong agreement (R² = 0.82, p < .005), with Bland-Altman analysis indicating minimal bias (mean difference: 15.69 mL/min; LoA: -3.76 to 35.15). A limited sampling strategy using one (1-h, R² = 0.91) or two (1 and 5 h, R² = 0.92) time points yielded accurate clearance estimates. These findings suggest that iopamidol may be a viable alternative to iohexol for mGFR determination. Broader access to accurate kidney function testing can enhance drug dosing, reduce misclassification, and improve care for patients with chronic kidney disease. Further research should validate these findings in larger, more diverse populations, including those with advanced kidney impairment.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12353758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144112496","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}

{"title":"Dextromethorphan versus Dextrorphan: A Quantitative Comparison of Antitussive Potency following Separate Administration of Metabolite.","authors":"Saeed Rezaee, Caroline E Wright, Alyn H Morice, Amin Rostami-Hodjegan","doi":"10.1002/jcph.70049","DOIUrl":"https://doi.org/10.1002/jcph.70049","url":null,"abstract":"<p><p>To assess the antitussive effects of dextrorphan (DOR) relative to its parent compound, dextromethorphan (DEX) a double-blind, randomized, placebo-controlled crossover study was conducted in 23 healthy volunteers using citric acid cough challenge test after administering placebo, DEX, or DOR. Plasma concentrations and cough frequency were monitored over 24 h, followed by model independent analysis and pharmacokinetic-pharmacodynamic (PKPD) modelling to discern the relative potency of each moiety. Model-independent pairwise analysis of the area under the effect curve (AUEC₀₋₂₄ _h) showed no significant difference between DOR, DEX, and placebo's antitussive effects (p >  .06), indicating the influence of considerable inter-individual variability and the need for larger sample sizes. The model-based analysis established DOR's relative potency at 26% compared to DEX, with maximum cough inhibition of 23% and IC50 of 0.3 ng/mL. PKPD measures were more accurate for DEX than DOR, particularly at lower baseline cough counts. In conclusion, while DOR retains some antitussive potency, since it is substantially less potent than DEX, higher relative concentrations are required to reach the same effect. Although separate administration of metabolite on its own is considered gold standard to establish its relative potency compared to parent compound, the variability in effect may prevent clear demonstration of effects without modelling particularly when these take benefit of the perturbing the balance of parent/metabolite ratios (e.g. via inhibition) or using the natural variational of such ratios in different individuals.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144081398","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}

{"title":"FCGR2A/FCGR3A Gene Polymorphisms and Clinical Variables as Predictors of Response to Tocilizumab and Rituximab in Patients With Rheumatoid Arthritis.","authors":"Alberto Jiménez Morales,&nbsp;Mar Maldonado-Montoro,&nbsp;Juan Enrique Martínez de la Plata,&nbsp;Cristina Pérez Ramírez,&nbsp;Abdelali Daddaoua,&nbsp;Carolina Alarcón Payer,&nbsp;Manuela Expósito Ruiz,&nbsp;Carlos García Collado","doi":"10.1002/jcph.1341","DOIUrl":"https://doi.org/10.1002/jcph.1341","url":null,"abstract":"<p><p>We evaluated the influence of clinical, biochemical, and genetic factors on response in 142 patients diagnosed with rheumatoid arthritis, of whom 87 patients were treated with tocilizumab (61.26%) and 55 patients were treated with rituximab (38.7%;) according to the variables European League Against Rheumatism (EULAR) response, remission, low disease activity, and improvement in Disease Activity Score, 28 joints (DAS28) at 6, 12, and 18 months. A retrospective prospective cohort study was conducted. Patients carrying the FCGR3A rs396991-TT genotype treated with tocilizumab showed higher EULAR response (OR, 5.075; 95%CI, 1.20-21.33; P = .027) at 12 months, those who were naive for biological disease-modifying antirheumatic drugs (bDMARDs) at the beginning of treatment showed satisfactory EULAR response, higher remission, and greater improvement in DAS28 at 6 months. Younger age at start of tocilizumab treatment was associated with satisfactory EULAR response at 18 months and greater remission at 6 and 18 months. Subcutaneous tocilizumab administration was associated with higher remission at 6 months and improved low disease activity rate at 12 months. In patients treated with rituximab, carriers of the FCGR2A rs1801274-TT genotype had higher EULAR response at 6 months (OR, 4.861; 95%CI, 1.11-21.12; P = .035), 12 months (OR, 4.667; p = 0.066, 95%CI, 0.90-24.12; P = .066), and 18 months (OR, 2.487; 95%CI, 0.35-17.31; P = .357), higher remission (OR: 10.625; p = 0.044, CI_95% : 1.07, 105.47) at 6 months, and greater improvement in DAS28 at 12 months (B = 0.782; 95%CI, -0.15 to 1.71; P = .098) and 18 months (B = 1.414; 95%CI, 0.19-2.63; P = .025). The FCGR3A rs396991-G allele was associated with improved low disease activity rate (OR, 4.904; 95%CI, 0.84-28.48; P = .077) and greater improvement in DAS28 (B = -1.083; 95%CI, -1.98 to -0.18; P = .021) at 18 months. Patients with a lower number of previous biological therapies had higher remission at 12 months. We suggest that the FCGR3A rs396991-TT genotype, higher baseline value of DAS28, subcutaneous tocilizumab administration, younger age at the beginning of treatment, and being bDMARD naive are associated with better response to tocilizumab. In patients treated with rituximab, we found better response in those patients with the FCGR2A rs1801274-TT genotype, the FCGR3A rs396991-G allele, and lower number of previous biological therapies.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"59 4","pages":"517-531"},"PeriodicalIF":2.9,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1341","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36749159","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}

{"title":"Food Effect Study Design With Oral Drugs: Lessons Learned From Recently Approved Drugs in Oncology.","authors":"Mark Farha,&nbsp;Eric Masson,&nbsp;Helen Tomkinson,&nbsp;Ganesh Mugundu","doi":"10.1002/jcph.1351","DOIUrl":"https://doi.org/10.1002/jcph.1351","url":null,"abstract":"<p><p>Evaluation of the effect of food on the pharmacokinetics of oral oncology drugs is critical to drug development, as food can mitigate or exacerbate toxicities and alter systemic exposure. Our aim is to expand on current US Food and Drug Administration (FDA) guidance and provide data-driven food-effect study design recommendations specific to the oncology therapeutic area. Data for recently approved small-molecule oncology drugs was extracted from the clinical pharmacology review in the sponsor's FDA submission package. Information on subject selection, meal types, timing of the study relative to the pivotal trial, and study outcomes was analyzed. The number of subjects enrolled ranged from 12 to 60, and the majority of studies (19 of 29) were conducted in healthy volunteers. Using AstraZeneca cost data, healthy volunteer studies were estimated to cost 10-fold less than cancer patient studies. Nine of 29 (31%) studies included meals with multiple levels of fat content. Analysis of a subset of 16 drugs revealed that final results for the food-effect study were available before the start of the pivotal trial for only 2 drugs. Conducting small food-effect studies powered to estimate effect, rather than confirm no effect, with only a standardized high-fat meal according to FDA guidance may eliminate unnecessary studies, reduce cost, and improve efficiency in oncology drug development. Starting food-effect studies as early as possible is key to inform dosing in pivotal trials.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"59 4","pages":"463-471"},"PeriodicalIF":2.9,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1351","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36769125","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}

{"title":"Population Pharmacokinetics of Adjunctive Lacosamide in Pediatric Patients With Epilepsy.","authors":"Julia Winkler,&nbsp;Rik Schoemaker,&nbsp;Armel Stockis","doi":"10.1002/jcph.1340","DOIUrl":"https://doi.org/10.1002/jcph.1340","url":null,"abstract":"<p><p>A pediatric population pharmacokinetic model including covariate effects was developed using data from 2 clinical trials in pediatric patients with epilepsy (SP0847 and SP1047). Lacosamide plasma concentration-time data (n = 402) were available from 79 children with body weights ranging from 6 to 76 kg, and a balanced age distribution (6 months to <2 years: n = 14; 2 to <6 years: n = 22; 6 to <12 years: n = 25; 12 to <18 years: n = 18). A single-compartment population pharmacokinetic model with first-order absorption and elimination described the data adequately. Plasma clearance was modeled using allometric scaling on body weight with a freely estimated allometric exponent, while volume of distribution used a fixed theoretical allometric exponent. Covariate search identified a significant effect of enzyme-inducing antiepileptic drugs resulting in a 35% decrease in lacosamide average plasma concentration. No additional effects on clearance could be attributed to race, sex, age, or renal function. Different dosing adaptation schemes by body weight bands were simulated to approximate, in pediatric patients aged 4 to 17 years, the same average plasma concentration as in adult patients receiving the maximum recommended lacosamide daily dose.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"59 4","pages":"541-547"},"PeriodicalIF":2.9,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1340","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36677841","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}

{"title":"Population Pharmacokinetics and Exposure-Response Modeling Analyses of Golimumab in Children With Moderately to Severely Active Ulcerative Colitis.","authors":"Yan Xu,&nbsp;Omoniyi J Adedokun,&nbsp;Daphne Chan,&nbsp;Chuanpu Hu,&nbsp;Zhenhua Xu,&nbsp;Richard S Strauss,&nbsp;Jeffrey S Hyams,&nbsp;Dan Turner,&nbsp;Honghui Zhou","doi":"10.1002/jcph.1353","DOIUrl":"https://doi.org/10.1002/jcph.1353","url":null,"abstract":"<p><p>Population pharmacokinetics (PK) and exposure-response (E-R) analyses were conducted to compare the PK and E-R relationships of golimumab between children and adults with ulcerative colitis. PK data following subcutaneous golimumab administration to children with ulcerative colitis (6-17 years) in the PURSUIT-PEDS-PK study, adults with ulcerative colitis in the PURSUIT study, and children with pediatric polyarticular juvenile idiopathic arthritis (2-17 years) in the GO-KIDS study, were included in the population PK analysis. E-R analysis was conducted using logistic regression to link serum golimumab concentration and Mayo score-based efficacy outcomes in pediatric and adult ulcerative colitis. Golimumab PK was adequately described by a 1-compartment model with first-order absorption and elimination. Golimumab apparent clearance and volume of distribution increased with body weight. Golimumab apparent clearance was higher in patients with lower serum albumin, no methotrexate use, and positive antibodies to golimumab; age was not an influential factor after accounting for body weight. Model-estimated terminal half-life (9.2 days in children; 9.5 days in adults) and other PK parameters suggest that golimumab PK properties are generally comparable between children and adults with ulcerative colitis. Simulations suggest that a higher induction dose than that tested in PURSUIT-PEDS-PK may be needed for children ≤45 kg to achieve exposures comparable to adults. Comparable E-R relationships between children and adults with ulcerative colitis were observed, although children appeared to be more responsive for the more stringent remission end point. The overall comparable PK and E-R relationships between children and adults support the extrapolation of golimumab efficacy from the adult to the pediatric ulcerative colitis population.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"59 4","pages":"590-604"},"PeriodicalIF":2.9,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1353","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36769091","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}

{"title":"Dosing Recommendations for Quetiapine When Coadministered With HIV Protease Inhibitors.","authors":"Mario R Sampson,&nbsp;Kelly Y Cao,&nbsp;Paula L Gish,&nbsp;Kyong Hyon,&nbsp;Poonam Mishra,&nbsp;William Tauber,&nbsp;Ping Zhao,&nbsp;Esther H Zhou,&nbsp;Islam R Younis","doi":"10.1002/jcph.1345","DOIUrl":"https://doi.org/10.1002/jcph.1345","url":null,"abstract":"<p><p>Although current quetiapine labeling recommends that its dosage should be lowered 6-fold when coadministered with strong cytochrome P450 (CYP)3A inhibitors, a reported case of coma in a patient receiving quetiapine with lopinavir and ritonavir prompted the reevaluation of labeling recommendations for the dosing of quetiapine when coadministered with human immunodeficiency virus (HIV) protease inhibitors. Literature and database (FDA Adverse Event Reporting System and United States Symphony Health Solutions' Integrated Dataverse Database) searches allowed us to identify cases of coma and related adverse events involving the coadministration of quetiapine and HIV protease inhibitors and to estimate the frequency of concomitant use. Literature review and physiologically based pharmacokinetic modeling allowed us to estimate the potential for CYP3A inhibition to contribute to adverse events related to HIV protease inhibitor-quetiapine coadministration. We identified excess sedation following coadministration of quetiapine and an HIV protease inhibitor in 3 reports without obvious confounders. In prescription claims data, 0.4% of quetiapine patients were dispensed a concurrent ritonavir prescription. The quetiapine dose was not reduced on ritonavir initiation in 90% of therapy episodes. Available data indicate to us that all HIV protease inhibitors combined with ritonavir are likely to be strong CYP3A inhibitors. We predicted that ritonavir would increase quetiapine exposure comparable to the strong CYP3A inhibitor ketoconazole. The current dosing recommendations for use of quetiapine with strong CYP3A inhibitors (ie, 6-fold lower quetiapine dose) are appropriate and should be followed when quetiapine is coadministered with HIV protease inhibitors.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"59 4","pages":"500-509"},"PeriodicalIF":2.9,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1345","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36685774","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}

{"title":"Pharmacokinetic Interactions of Rolapitant With Cytochrome P450 3A Substrates in Healthy Subjects.","authors":"Xiaodong Wang,&nbsp;Jing Wang,&nbsp;Sujata Arora,&nbsp;Lorraine Hughes,&nbsp;Jennifer Christensen,&nbsp;Sharon Lu,&nbsp;Zhi-Yi Zhang","doi":"10.1002/jcph.1339","DOIUrl":"https://doi.org/10.1002/jcph.1339","url":null,"abstract":"<p><p>Rolapitant (Varubi) is a neurokinin-1 receptor antagonist approved for the prevention of chemotherapy-induced nausea and vomiting. Rolapitant is primarily metabolized by the cytochrome P450 3A4 (CYP3A4) enzyme. Unlike other neurokinin-1 receptor antagonists, rolapitant is neither an inhibitor nor an inducer of CYP3A4 in vitro. The objective of this analysis was to examine the pharmacokinetics of rolapitant in healthy subjects and assess drug-drug interactions between rolapitant and midazolam (a CYP3A substrate), ketoconazole (a CYP3A inhibitor), or rifampin (a CYP3A4 inducer). Three phase 1, open-label, drug-drug interaction studies were conducted to examine the pharmacokinetic interactions of orally administered rolapitant with midazolam, rolapitant with ketoconazole, and rolapitant with rifampin. The pharmacokinetic profiles of midazolam and 1-hydroxy midazolam metabolites were essentially unchanged when coadministered with rolapitant, indicating the lack of a clinically relevant inhibition or induction of CYP3A by rolapitant. Coadministration of ketoconazole with rolapitant had no effects on rolapitant maximum concentration and resulted in an approximately 20% increase in the area under the concentration-time curve of rolapitant, suggesting that strong CYP3A inhibitors have minimal inhibitory effects on rolapitant exposure. Repeated administrations of rifampin appeared to reduce rolapitant exposure, resulting in a 33% decrease in maximum concentration and 87% decrease in area under the concentration-time curve from time zero to infinity. Coadministration of rolapitant did not affect the exposure of midazolam. Rifampin coadministration resulted in lower concentrations of rolapitant, and ketoconazole coadministration had no or minimal effects on rolapitant exposure. Rolapitant was safe and well tolerated when coadministered with ketoconazole, rifampin, or midazolam. No new safety signals were reported compared with previous studies of rolapitant.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"59 4","pages":"488-499"},"PeriodicalIF":2.9,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1339","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36718343","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}