دورية أكاديمية
أعرض في EDS

Impact of Genetic Variants in ABCG2 , NR1I2 , and UGT1A1 on the Pharmacokinetics of Dolutegravir in Children.

التفاصيل البيبلوغرافية
العنوان: Impact of Genetic Variants in ABCG2 , NR1I2 , and UGT1A1 on the Pharmacokinetics of Dolutegravir in Children.
المؤلفون: Spector SA; University of California San Diego, La Jolla, CA.; Rady Children's Hospital San Diego, San Diego, CA., Brummel SS; Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, MA., Chang A; Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, MA., Wiznia A; Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, NY., Ruel TD; University of California, San Francisco, San Francisco, CA; and., Acosta EP; University of Alabama at Birmingham, Birmingham, AL.
مؤلفون مشاركون: for IMPAACT P1093 Team
المصدر: Journal of acquired immune deficiency syndromes (1999) [J Acquir Immune Defic Syndr] 2024 Mar 01; Vol. 95 (3), pp. 297-303.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: Lippincott Williams & Wilkins, Inc Country of Publication: United States NLM ID: 100892005 Publication Model: Print Cited Medium: Internet ISSN: 1944-7884 (Electronic) Linking ISSN: 15254135 NLM ISO Abbreviation: J Acquir Immune Defic Syndr Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Hagerstown, MD : Lippincott Williams & Wilkins, Inc., c1999-
مواضيع طبية MeSH: HIV Infections*/drug therapy , HIV Infections*/genetics , Oxazines* , Piperazines*, Child ; Humans ; Female ; Child, Preschool ; Male ; Pregnane X Receptor/genetics ; Genotype ; Heterocyclic Compounds, 3-Ring ; Pyridones ; RNA ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics ; Neoplasm Proteins/genetics
مستخلص: Background: Dolutegravir plasma concentrations and pharmacokinetic (PK) parameters in children display considerable variability. Here, the impact of genetic variants in ABCG2 421C>A (rs2231142), NR1I2 63396 C>T (rs2472677), and UGT1A1 (rs5839491) on dolutegravir PK was examined.
Methods: Children defined by age and administered dolutegravir formulation had AUC 24 at steady state, C max and C 24h determined. Associations between genetic variants and PK parameters were assessed using the dominant inheritance model.
Results: The 59 children studied had a median age of 4.6 years, log 10 plasma HIV RNA of 4.79 (copies/mm 3 ), and CD4 + lymphocyte count of 1041 cells/mm 3 ; 51% were female. For ABCG2 , participants with ≥1 minor allele had lower adjusted mean AUC difference (hr*mg/L) controlling for weight at entry, cohort and sex (-15.7, 95% CI: [-32.0 to 0.6], P = 0.06), and log 10 C max adjusted mean difference (-0.15, 95% CI: [-0.25 to -0.05], P = 0.003). Participants with ≥1 minor allele had higher adjusted mean AUC difference (11.9, 95% CI: [-1.1 to 25.0], P = 0.07). For UGT1A1 , poor metabolizers had nonsignificant higher concentrations (adjusted log 10 C max mean difference 11.8; 95% CI: [-12.3 to 36.0], P = 0.34) and lower mean log 10 adjusted oral clearance -0.13 L/h (95% CI: [-0.3 to 0.06], P = 0.16). No association was identified between time-averaged AUC differences by genotype for adverse events, plasma HIV RNA, or CD4 + cell counts.
Conclusions: Dolutegravir AUC 24 for genetic variants in ABCG2 , NR1l2 , and UGT1A1 varied from -25% to +33%. These findings help to explain some of the variable pharmacokinetics identified with dolutegravir in children.
Competing Interests: The authors have no funding or conflicts of interest to disclose.
(Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
References: BMC Infect Dis. 2021 Jan 4;21(1):5. (PMID: 33446115)
J Acquir Immune Defic Syndr. 2014 Nov 1;67(3):310-5. (PMID: 25162819)
J Antimicrob Chemother. 2020 May 1;75(5):1259-1266. (PMID: 32011683)
J Infect Dis. 2022 Nov 1;226(9):1616-1625. (PMID: 35512135)
Chem Biol Interact. 2015 Dec 5;242:203-10. (PMID: 26462791)
Pharmacogenomics. 2014 Jan;15(1):9-16. (PMID: 24329186)
J Pediatric Infect Dis Soc. 2020 Apr 30;9(2):159-165. (PMID: 30951600)
Mem Inst Oswaldo Cruz. 2017 Apr;112(4):269-274. (PMID: 28327790)
Tumour Biol. 2016 Jan;37(1):791-8. (PMID: 26250462)
Lancet HIV. 2022 May;9(5):e332-e340. (PMID: 35489377)
J Acquir Immune Defic Syndr. 2010 Dec 15;55(5):536-49. (PMID: 20861742)
J Pharmacol Exp Ther. 2020 Jul;374(1):38-43. (PMID: 32303561)
Int J Cancer. 2012 Dec 15;131(12):2920-8. (PMID: 22473764)
Curr Res Pharmacol Drug Discov. 2021 Aug 08;2:100044. (PMID: 34909672)
J Int AIDS Soc. 2022 Nov;25(11):e25970. (PMID: 36377082)
Antimicrob Agents Chemother. 2022 Jan 18;66(1):e0164521. (PMID: 34694878)
Mol Cancer Ther. 2002 Jun;1(8):611-6. (PMID: 12479221)
J Chromatogr B Analyt Technol Biomed Life Sci. 2014 Jan 15;945-946:225-32. (PMID: 24361860)
J Antimicrob Chemother. 2019 Jan 1;74(1):149-156. (PMID: 30272231)
معلومات مُعتمدة: UM1 AI068632 United States AI NIAID NIH HHS; U01 AI068616 United States AI NIAID NIH HHS; UM1 AI068616 United States AI NIAID NIH HHS; UM1 AI106716 United States AI NIAID NIH HHS; UM1 AI069536 United States AI NIAID NIH HHS
المشرفين على المادة: DKO1W9H7M1 (dolutegravir)
0 (Pregnane X Receptor)
0 (Heterocyclic Compounds, 3-Ring)
0 (Pyridones)
63231-63-0 (RNA)
0 (ABCG2 protein, human)
0 (ATP Binding Cassette Transporter, Subfamily G, Member 2)
0 (Neoplasm Proteins)
0 (Oxazines)
0 (Piperazines)
تواريخ الأحداث: Date Created: 20240105 Date Completed: 20240228 Latest Revision: 20240610
رمز التحديث: 20240610
مُعرف محوري في PubMed: PMC10922521
DOI: 10.1097/QAI.0000000000003358
PMID: 38180896
قاعدة البيانات: MEDLINE
الوصف
تدمد:1944-7884
DOI:10.1097/QAI.0000000000003358