Browsing by Author "Zimmer B"

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    Establishing Dosing Recommendations for Efavirenz in HIV/TB-Coinfected Children Younger Than 3 Years.
    (2019-Aug-01) Bwakura Dangarembizi M; Samson P; Capparelli EV; Moore CB; Jean-Philippe P; Spector SA; Chakhtoura N; Benns A; Zimmer B; Purdue L; Jackson C; Wallis C; Libous JL; Chadwick EG; Department of Paediatrics and Child Health, University of Zimbabwe College of Health Sciences, Harare, Zimbabwe.; Rady Children's Hospital, San Diego, CA.; IMPAACT Operations Center, FHI360, Durham, NC.; BARC-SA and Lancet Laboratories, Johannesburg, South Africa.; National Institutes of Allergy and Infectious Diseases, Bethesda, MD.; Division of Infectious Diseases, Department of Pediatrics, University of California, San Diego, La Jolla, CA.; Harvard T.H. Chan School of Public Health, Center for Biostatistics in AIDS Research, Boston, MA.; Eunice Kennedy Shriver National Institute for Child Health and Human Development, National Institutes of Health, Bethesda, MD.; Department of Pediatrics, Texas Children's Hospital Baylor College of Medicine, Houston, TX.; Northwestern University's Feinberg School of Medicine, Chicago, IL.; Frontier Science and Technology Research Foundation, Amherst, NY.; Centre for Infectious Disease Research in Zambia, Lusaka, Zambia.; University of Alabama at Birmingham, Birmingham, AL.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)
    BACKGROUND: CYP2B6 516 genotype-directed dosing improves efavirenz (EFV) exposures in HIV-infected children younger than 36 months, but such data are lacking in those with tuberculosis (TB) coinfection. METHODS: Phase I, 24-week safety and pharmacokinetic (PK) study of EFV in HIV-infected children aged 3 to <36 months, with or without TB. CYP2B6 516 genotype classified children into extensive metabolizers (516 TT/GT) and poor metabolizers [(PMs), 516 TT]. EFV doses were 25%-33% higher in children with HIV/TB coinfection targeting EFV area under the curve (AUC) 35-180 μg × h/mL, with individual dose adjustment as necessary. Safety and virologic evaluations were performed every 4-8 weeks. RESULTS: Fourteen children from 2 African countries and India with HIV/TB enrolled, with 11 aged 3 to <24 months and 3 aged 24-36 months, 12 extensive metabolizers and 2 PMs. Median (Q1, Q3) EFV AUC was 92.87 (40.95, 160.81) μg × h/mL in 8/9 evaluable children aged 3 to <24 months and 319.05 (172.56, 360.48) μg × h/mL in children aged 24-36 months. AUC targets were met in 6/8 and 2/5 of the younger and older age groups, respectively. EFV clearance was reduced in PM's and older children. Pharmacokinetic modeling predicted adequate EFV concentrations if children younger than 24 months received TB-uninfected dosing. All 9 completing 24 weeks achieved viral suppression. Five/14 discontinued treatment early: 1 neutropenia, 3 nonadherence, and 1 with excessive EFV AUC. CONCLUSIONS: Genotype-directed dosing safely achieved therapeutic EFV concentrations and virologic suppression in HIV/TB-coinfected children younger than 24 months, but further study is needed to confirm appropriate dosing in those aged 24-36 months. This approach is most important for young children and currently a critical unmet need in TB-endemic countries.
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    Impact of CYP2B6 genotype, tuberculosis therapy, and formulation on efavirenz pharmacokinetics in infants and children under 40 months of age.
    (2022-Mar-15) Nikanjam M; Tran L; Chadwick EG; Bwakura-Dangarembizi M; Bolton Moore C; Samson P; Spector SA; Chakhtoura N; Jean-Philippe P; Frenkel L; Zimmer B; Benns A; Libous J; Capparelli EV; Maternal and Pediatric Infectious Disease Branch (MPIDB), Eunice Kennedy Shriver National Institute for Child Health and Human Development, National Institutes of Health.; Department of Paediatrics and Child Health, University of Zimbabwe College of Health Sciences, Harare, Zimbabwe.; Frontier Science and Technology Research Foundation, Amherst, New York.; Division of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina.; Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, California.; Department of Pediatrics, University of Washington, Seattle, Washington.; Department of Pediatrics, Northwestern University's Feinberg School of Medicine, Chicago, Illinois, USA.; 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.; Division of AIDS, National Institutes of Allergy and Infectious Diseases, Bethesda, Maryland, USA.; Centre for Infectious Disease Research in Zambia, Lusaka, Zambia.; Centre for Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama.; IMPAACT Operations Center, FHI360, Durham, North Carolina, USA.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)
    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.