CYP2B6 genotype-directed dosing is required for optimal efavirenz exposure in children 3-36 months with HIV infection.
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.



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).



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.



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.



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.
aCentre for Infectious Disease Research in Zambia, Lusaka, Zambia bUniversity of Alabama at Birmingham, Birmingham, Alabama cUniversity of California San Diego, La Jolla dRady Children's Hospital, San Diego, California eHarvard T.H. Chan School of Public Health, Boston, Massachusetts, USA fUniversity of Zimbabwe, Harare, Zimbabwe gNational Institutes of Allergy and Infectious Diseases hEunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland iFrontier Science and Technology Research Foundation, Amherst jNew York University's School of Medicine, New York, New York kUNC Global Health and Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina lSocial and Scientific Systems Inc, Silver Springs, Maryland, USA mBARC-SA and Lancet Laboratories, Johannesburg, South Africa nNorthwestern University's Feinberg School of Medicine, Chicago, Illinois, USA.
Carolyn
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Bolton Moore
Edmund V
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Capparelli
Pearl
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Samson
Mutsa
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Bwakura-Dangarembizi
Patrick
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Jean-Philippe
Carol
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Worrell
Barbara
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Heckman
Lynette
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Purdue
Stephen A
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Spector
Alex
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Benns
William
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Borkowsky
Amy
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Loftis
Elizabeth
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Hawkins
Carole
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Wallis
Ellen G
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Chadwick
D000480:Alkynes; D048588:Benzoxazines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002675:Child, Preschool; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics*; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D007223:Infant; D008297:Male; D011446:Prospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics*
D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; C098320:efavirenz