CYP2B6 genotype-directed dosing is required for optimal efavirenz exposure in children 3–36 months with HIV infection. (15th May 2017)

• Record Type: Journal Article
• Authors: Bolton Moore, Carolyn; Capparelli, Edmund V.; Samson, Pearl; Bwakura-Dangarembizi, Mutsa; Jean-Philippe, Patrick; Worrell, Carol; Heckman, Barbara; Purdue, Lynette; Spector, Stephen A.; Benns, Alex; Borkowsky, William; Loftis, Amy; Hawkins, Elizabeth; Wallis, Carole; Chadwick, Ellen G.
• Is Part Of: AIDS. Volume 31:Number 8(2017)
• Publication Date: 2017-05-15
• Subjects: children -- CYP2B6 G516T genotype -- efavirenz -- HIV -- pharmacokinetics -- treatment; AIDS (Disease) -- Periodicals; Acquired Immunodeficiency Syndrome; AIDS (Disease); Periodicals; Periodicals; 616.9792005
• DOI: 10.1097/QAD.0000000000001463
• Languages: English
• ISSNs: 0269-9370

Abstract

Abstract : Objectives: To determine safety-specific, efficacy-specific and genotypic-specific dose requirements of efavirenz (EFV) in children aged 3 to less than 36 months with HIV infection. Design: IMPAACT P1070 was a 24-week prospective cohort trial of EFV (as open capsules) and two nucleoside reverse transcriptase inhibitors in children with HIV infection 3 to less than 36 months without tuberculosis (Cohort 1). Methods: CYP2B6 G516T genotype was determined, and intensive pharmacokinetics was performed at week 2. EFV dose was adjusted if outside the target area under the curve (AUC) 35–180 μg*h/ml. Pharmacokinetic and CYP2B6 G516T genotype data were used to model EFV exposures based on Food and Drug Administration (FDA)-approved doses. Results: Forty-seven participants, median age 19 months, initiated the study regimen with 24 weeks median follow-up; 38 516GG/GT and 9 516TT genotypes. Initially, median EFV AUC was higher in 516TT vs. 516GG/GT (median 490 vs. 107 μg*h/ml; P = 0.0001) with all 516TT above AUC target. Following an amendment that reduced the 516TT EFV dose by 75%, pharmacokinetic modeling predicted that 83% of participants met the AUC target (31/38 516GG/GT, 8/9 516TT). In contrast, modeling using P1070 data predicted that FDA-approved doses would produce subtherapeutic AUCs in almost one-third of participants with 516GG/GT and excessive AUCs in more than 50% with 516TT genotypes. Conclusion: CYP2B6 G516T genotype strongly influences EFV exposures in this age group. Genotype-directed dosing yields therapeutic EFV concentrations and appears to outperform other dosing approaches. Abstract : Supplemental Digital Content is available in the text