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Impact of CYP2B6 genotype, tuberculosis therapy, and formulation on efavirenz pharmacokinetics in infants and children under 40 months of age.
Nikanjam, Mina; Tran, Lana; Chadwick, Ellen G; Bwakura-Dangarembizi, Mutsa; Bolton Moore, Carolyn; Samson, Pearl; Spector, Stephen A; Chakhtoura, Nahida; Jean-Philippe, Patrick; Frenkel, Lisa; Zimmer, Bonnie; Benns, Alex; Libous, Jennifer; Capparelli, Edmund V.
Afiliación
  • Nikanjam M; Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, California.
  • Tran L; Division of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina.
  • Chadwick EG; Department of Pediatrics, Northwestern University's Feinberg School of Medicine, Chicago, Illinois, USA.
  • Bwakura-Dangarembizi M; Department of Paediatrics and Child Health, University of Zimbabwe College of Health Sciences, Harare, Zimbabwe.
  • Bolton Moore C; Centre for Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama.
  • Samson P; Centre for Infectious Disease Research in Zambia, Lusaka, Zambia.
  • Spector SA; Statistical and Data Management Center (SDMC) Harvard T.H. Chan School of Public Health, Center for Biostatistics in AIDS Research/Frontier Science Foundation, Boston, Massachusetts.
  • Chakhtoura N; Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, California.
  • Jean-Philippe P; Maternal and Pediatric Infectious Disease Branch (MPIDB), Eunice Kennedy Shriver National Institute for Child Health and Human Development, National Institutes of Health.
  • Frenkel L; Division of AIDS, National Institutes of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
  • Zimmer B; Department of Pediatrics, University of Washington, Seattle, Washington.
  • Benns A; Frontier Science and Technology Research Foundation, Amherst, New York.
  • Libous J; Frontier Science and Technology Research Foundation, Amherst, New York.
  • Capparelli EV; IMPAACT Operations Center, FHI360, Durham, North Carolina, USA.
AIDS ; 36(4): 525-532, 2022 03 15.
Article en En | MEDLINE | ID: mdl-34873089
OBJECTIVE: Dosing efavirenz (EFV) in children less than 3 years of age is challenging due to large variability in drug levels. This study evaluated differences in pharmacokinetics with tuberculosis (TB) therapy, formulation, age, and CYP2B6 genotype. DESIGN: Pharmacokinetic data from three IMPAACT/PACTG studies (P382, P1021, and P1070) for children initiating therapy less than 40 months of age were evaluated. METHODS: Pharmacokinetic data were combined in a population pharmacokinetic model. Exposure from the 2-week pharmacokinetic visit was compared with changes in viral RNA between the Week 0 and Week 4 visits. RESULTS: The model included 103 participants (19 on TB therapy). CYP2B6 516 genotype information was available for 82 participants (TT: 15, GT: 28, GG: 39). Median age at the first pharmacokinetic visit was 17.0 months (range: 2.0-39.0 months). Liquid formulation led to a 42% decrease in bioavailability compared with opened capsules. TB therapy (isoniazid and rifampin) led to a 29% decreased clearance, however Monte Carlo simulations demonstrated the majority of participants on TB therapy receiving standard EFV dosing to be in the target area under the curve range. Clearance was 5.3-fold higher for GG than TT genotype and 3.3-fold higher for GT than TT genotype. Age did not have a significant effect on clearance in the final model. Initial viral RNA decay was lower for patients in the lowest quartile of exposures (area under the curves) than for higher quartiles (P = 0.013). CONCLUSION: EFV dosing should account for CYP2B6 516 genotype and formulation, but does not require adjustment for concurrent TB therapy.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tuberculosis / Infecciones por VIH / Fármacos Anti-VIH Tipo de estudio: Prognostic_studies Límite: Child / Humans / Infant Idioma: En Revista: AIDS Asunto de la revista: SINDROME DA IMUNODEFICIENCIA ADQUIRIDA (AIDS) Año: 2022 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tuberculosis / Infecciones por VIH / Fármacos Anti-VIH Tipo de estudio: Prognostic_studies Límite: Child / Humans / Infant Idioma: En Revista: AIDS Asunto de la revista: SINDROME DA IMUNODEFICIENCIA ADQUIRIDA (AIDS) Año: 2022 Tipo del documento: Article Pais de publicación: Reino Unido