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

Carolyn Bolton Moore, Edmund V. Capparelli, Pearl Samson, Mutsa Bwakura-dangarembizi, Patrick Jean-philippe, Carol Worrell, Barbara Heckman, Lynette Purdue, Stephen A. Spector, Alex Benns, William Borkowsky, Amy Loftis, Elizabeth Hawkins, Carole Wallis, Ellen G. Chadwick, for the IMPAACT P1070 team

Research output: Contribution to journalArticle

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Abstract

OBJECTIVES:: To determine safety, efficacy and genotypic-specific dose requirements of EFV in children aged 3 - <36 months of age with HIV infection with or without TB co-infection. DESIGN:: IMPAACT P1070 was a 24 week prospective cohort trial of EFV (as open capsules) plus two nucleoside reverse transcriptase inhibitors in children with HIV infection 3-?<?36 months without tuberculosis (Cohort 1). METHODS:: CYP2B6 G516T genotype was determined and intensive PKʼs were performed at week 2. EFV dose was adjusted if outside the target area under the curve (AUC) 35 -180?mcghr/mL. PK and CYP2B6 G516T genotype data were used to model EFV exposures based on 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 versus 516GG/GT (median 490 vs 107 p?=?0.0001) with all 516TT above AUC target. Following an amendment that reduced the 516TT EFV dose by 75%, PK 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 sub-therapeutic AUCs in almost one third of participants with 516GG/GT and excessive AUCs in?>?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 out-perform other dosing approaches.

LanguageEnglish (US)
JournalAIDS
DOIs
StateAccepted/In press - Mar 18 2017

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efavirenz
Area Under Curve
HIV Infections
Genotype
Reverse Transcriptase Inhibitors
Coinfection
Nucleosides
Capsules
Cytochrome P-450 CYP2B6
Tuberculosis
Age Groups

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Moore, C. B., Capparelli, E. V., Samson, P., Bwakura-dangarembizi, M., Jean-philippe, P., Worrell, C., ... for the IMPAACT P1070 team (2017). CYP2B6 Genotype-directed dosing is required for optimal efavirenz exposure in children 3 to 36 months with HIV infection. AIDS. DOI: 10.1097/QAD.0000000000001463

CYP2B6 Genotype-directed dosing is required for optimal efavirenz exposure in children 3 to 36 months with HIV infection. / Moore, Carolyn Bolton; 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.; for the IMPAACT P1070 team.

In: AIDS, 18.03.2017.

Research output: Contribution to journalArticle

Moore, CB, Capparelli, EV, Samson, P, Bwakura-dangarembizi, M, Jean-philippe, P, Worrell, C, Heckman, B, Purdue, L, Spector, SA, Benns, A, Borkowsky, W, Loftis, A, Hawkins, E, Wallis, C, Chadwick, EG & for the IMPAACT P1070 team 2017, 'CYP2B6 Genotype-directed dosing is required for optimal efavirenz exposure in children 3 to 36 months with HIV infection' AIDS. DOI: 10.1097/QAD.0000000000001463
Moore CB, Capparelli EV, Samson P, Bwakura-dangarembizi M, Jean-philippe P, Worrell C et al. CYP2B6 Genotype-directed dosing is required for optimal efavirenz exposure in children 3 to 36 months with HIV infection. AIDS. 2017 Mar 18. Available from, DOI: 10.1097/QAD.0000000000001463
Moore, Carolyn Bolton ; 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. ; for the IMPAACT P1070 team. / CYP2B6 Genotype-directed dosing is required for optimal efavirenz exposure in children 3 to 36 months with HIV infection. In: AIDS. 2017
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abstract = "OBJECTIVES:: To determine safety, efficacy and genotypic-specific dose requirements of EFV in children aged 3 - <36 months of age with HIV infection with or without TB co-infection. DESIGN:: IMPAACT P1070 was a 24 week prospective cohort trial of EFV (as open capsules) plus two nucleoside reverse transcriptase inhibitors in children with HIV infection 3-?<?36 months without tuberculosis (Cohort 1). METHODS:: CYP2B6 G516T genotype was determined and intensive PKʼs were performed at week 2. EFV dose was adjusted if outside the target area under the curve (AUC) 35 -180?mcghr/mL. PK and CYP2B6 G516T genotype data were used to model EFV exposures based on 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 versus 516GG/GT (median 490 vs 107 p?=?0.0001) with all 516TT above AUC target. Following an amendment that reduced the 516TT EFV dose by 75\{%}, PK 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 sub-therapeutic AUCs in almost one third of participants with 516GG/GT and excessive AUCs in?>?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 out-perform other dosing approaches.",
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T1 - CYP2B6 Genotype-directed dosing is required for optimal efavirenz exposure in children 3 to 36 months with HIV infection

AU - Moore,Carolyn Bolton

AU - Capparelli,Edmund V.

AU - Samson,Pearl

AU - Bwakura-dangarembizi,Mutsa

AU - Jean-philippe,Patrick

AU - Worrell,Carol

AU - Heckman,Barbara

AU - Purdue,Lynette

AU - Spector,Stephen A.

AU - Benns,Alex

AU - Borkowsky,William

AU - Loftis,Amy

AU - Hawkins,Elizabeth

AU - Wallis,Carole

AU - Chadwick,Ellen G.

AU - for the IMPAACT P1070 team

PY - 2017/3/18

Y1 - 2017/3/18

N2 - OBJECTIVES:: To determine safety, efficacy and genotypic-specific dose requirements of EFV in children aged 3 - <36 months of age with HIV infection with or without TB co-infection. DESIGN:: IMPAACT P1070 was a 24 week prospective cohort trial of EFV (as open capsules) plus two nucleoside reverse transcriptase inhibitors in children with HIV infection 3-?<?36 months without tuberculosis (Cohort 1). METHODS:: CYP2B6 G516T genotype was determined and intensive PKʼs were performed at week 2. EFV dose was adjusted if outside the target area under the curve (AUC) 35 -180?mcghr/mL. PK and CYP2B6 G516T genotype data were used to model EFV exposures based on 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 versus 516GG/GT (median 490 vs 107 p?=?0.0001) with all 516TT above AUC target. Following an amendment that reduced the 516TT EFV dose by 75%, PK 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 sub-therapeutic AUCs in almost one third of participants with 516GG/GT and excessive AUCs in?>?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 out-perform other dosing approaches.

AB - OBJECTIVES:: To determine safety, efficacy and genotypic-specific dose requirements of EFV in children aged 3 - <36 months of age with HIV infection with or without TB co-infection. DESIGN:: IMPAACT P1070 was a 24 week prospective cohort trial of EFV (as open capsules) plus two nucleoside reverse transcriptase inhibitors in children with HIV infection 3-?<?36 months without tuberculosis (Cohort 1). METHODS:: CYP2B6 G516T genotype was determined and intensive PKʼs were performed at week 2. EFV dose was adjusted if outside the target area under the curve (AUC) 35 -180?mcghr/mL. PK and CYP2B6 G516T genotype data were used to model EFV exposures based on 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 versus 516GG/GT (median 490 vs 107 p?=?0.0001) with all 516TT above AUC target. Following an amendment that reduced the 516TT EFV dose by 75%, PK 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 sub-therapeutic AUCs in almost one third of participants with 516GG/GT and excessive AUCs in?>?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 out-perform other dosing approaches.

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