Efavirenz pharmacokinetics in HIV-1-infected children are associated with CYP2B6-G516T polymorphism

Akihiko Saitoh, Courtney V. Fletcher, Richard Brundage, Carmelita Alvero, Terrence Fenton, Karen Hsia, Stephen A. Spector

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

BACKGROUND: The CYP2B6-G516T polymorphism has been shown to alter plasma efavirenz (EFV) concentrations in adults. The impact of CYP2B6-G516T polymorphisms on EFV concentrations may be different in children because of differences in liver maturation and drug dosage. METHODS: The CYP2B6-G516T polymorphisms were analyzed in 71 HIV-1-infected children receiving highly active antiretroviral therapy (HAART) containing EFV for ≥6 months. EFV pharmacokinetics, toxicity profiles, and viral resistance data were also evaluated. RESULTS: The median oral clearance (CL/F) rate was significantly lower in children with the CYP2B6-516-T/T genotype (3.0 L/h/m, n = 13) than in children with the G/T genotype (5.7 L/h/m, n = 30; P = 0.02) or the G/G genotype (7.0 L/h/m, n = 31; P = 0.003). In children with the CYP2B6-516-G/G genotype, which is associated with higher expression of hepatic CYP2B6, the clearance rate was significantly higher in younger children (<5 years of age) than in older children (≥5 years of age) (9.7 L/h/m vs. 6.6 L/h/m; P = 0.03). No association was found between CYP2B6-G516T polymorphisms and virologic or immunologic responses, toxicity, or the development of viral resistance against EFV. CONCLUSIONS: CYP2B6-G516T polymorphisms significantly affect the CL/F rate of EFV in children. Changes in hepatic enzyme activity by age may need to be considered when evaluating the impact of genetic variants on antiretroviral pharmacokinetics in children.

Original languageEnglish (US)
Pages (from-to)280-285
Number of pages6
JournalJournal of Acquired Immune Deficiency Syndromes
Volume45
Issue number3
DOIs
StatePublished - Jul 1 2007

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efavirenz
HIV-1
Pharmacokinetics
Genotype
Liver
Cytochrome P-450 CYP2B6
Highly Active Antiretroviral Therapy

Keywords

  • Age
  • CYP2B6
  • Children
  • Efavirenz
  • Pharmacogenomics
  • Resistance

ASJC Scopus subject areas

  • Infectious Diseases
  • Pharmacology (medical)

Cite this

Efavirenz pharmacokinetics in HIV-1-infected children are associated with CYP2B6-G516T polymorphism. / Saitoh, Akihiko; Fletcher, Courtney V.; Brundage, Richard; Alvero, Carmelita; Fenton, Terrence; Hsia, Karen; Spector, Stephen A.

In: Journal of Acquired Immune Deficiency Syndromes, Vol. 45, No. 3, 01.07.2007, p. 280-285.

Research output: Contribution to journalArticle

Saitoh, Akihiko ; Fletcher, Courtney V. ; Brundage, Richard ; Alvero, Carmelita ; Fenton, Terrence ; Hsia, Karen ; Spector, Stephen A. / Efavirenz pharmacokinetics in HIV-1-infected children are associated with CYP2B6-G516T polymorphism. In: Journal of Acquired Immune Deficiency Syndromes. 2007 ; Vol. 45, No. 3. pp. 280-285.
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abstract = "BACKGROUND: The CYP2B6-G516T polymorphism has been shown to alter plasma efavirenz (EFV) concentrations in adults. The impact of CYP2B6-G516T polymorphisms on EFV concentrations may be different in children because of differences in liver maturation and drug dosage. METHODS: The CYP2B6-G516T polymorphisms were analyzed in 71 HIV-1-infected children receiving highly active antiretroviral therapy (HAART) containing EFV for ≥6 months. EFV pharmacokinetics, toxicity profiles, and viral resistance data were also evaluated. RESULTS: The median oral clearance (CL/F) rate was significantly lower in children with the CYP2B6-516-T/T genotype (3.0 L/h/m, n = 13) than in children with the G/T genotype (5.7 L/h/m, n = 30; P = 0.02) or the G/G genotype (7.0 L/h/m, n = 31; P = 0.003). In children with the CYP2B6-516-G/G genotype, which is associated with higher expression of hepatic CYP2B6, the clearance rate was significantly higher in younger children (<5 years of age) than in older children (≥5 years of age) (9.7 L/h/m vs. 6.6 L/h/m; P = 0.03). No association was found between CYP2B6-G516T polymorphisms and virologic or immunologic responses, toxicity, or the development of viral resistance against EFV. CONCLUSIONS: CYP2B6-G516T polymorphisms significantly affect the CL/F rate of EFV in children. Changes in hepatic enzyme activity by age may need to be considered when evaluating the impact of genetic variants on antiretroviral pharmacokinetics in children.",
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T1 - Efavirenz pharmacokinetics in HIV-1-infected children are associated with CYP2B6-G516T polymorphism

AU - Saitoh, Akihiko

AU - Fletcher, Courtney V.

AU - Brundage, Richard

AU - Alvero, Carmelita

AU - Fenton, Terrence

AU - Hsia, Karen

AU - Spector, Stephen A.

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N2 - BACKGROUND: The CYP2B6-G516T polymorphism has been shown to alter plasma efavirenz (EFV) concentrations in adults. The impact of CYP2B6-G516T polymorphisms on EFV concentrations may be different in children because of differences in liver maturation and drug dosage. METHODS: The CYP2B6-G516T polymorphisms were analyzed in 71 HIV-1-infected children receiving highly active antiretroviral therapy (HAART) containing EFV for ≥6 months. EFV pharmacokinetics, toxicity profiles, and viral resistance data were also evaluated. RESULTS: The median oral clearance (CL/F) rate was significantly lower in children with the CYP2B6-516-T/T genotype (3.0 L/h/m, n = 13) than in children with the G/T genotype (5.7 L/h/m, n = 30; P = 0.02) or the G/G genotype (7.0 L/h/m, n = 31; P = 0.003). In children with the CYP2B6-516-G/G genotype, which is associated with higher expression of hepatic CYP2B6, the clearance rate was significantly higher in younger children (<5 years of age) than in older children (≥5 years of age) (9.7 L/h/m vs. 6.6 L/h/m; P = 0.03). No association was found between CYP2B6-G516T polymorphisms and virologic or immunologic responses, toxicity, or the development of viral resistance against EFV. CONCLUSIONS: CYP2B6-G516T polymorphisms significantly affect the CL/F rate of EFV in children. Changes in hepatic enzyme activity by age may need to be considered when evaluating the impact of genetic variants on antiretroviral pharmacokinetics in children.

AB - BACKGROUND: The CYP2B6-G516T polymorphism has been shown to alter plasma efavirenz (EFV) concentrations in adults. The impact of CYP2B6-G516T polymorphisms on EFV concentrations may be different in children because of differences in liver maturation and drug dosage. METHODS: The CYP2B6-G516T polymorphisms were analyzed in 71 HIV-1-infected children receiving highly active antiretroviral therapy (HAART) containing EFV for ≥6 months. EFV pharmacokinetics, toxicity profiles, and viral resistance data were also evaluated. RESULTS: The median oral clearance (CL/F) rate was significantly lower in children with the CYP2B6-516-T/T genotype (3.0 L/h/m, n = 13) than in children with the G/T genotype (5.7 L/h/m, n = 30; P = 0.02) or the G/G genotype (7.0 L/h/m, n = 31; P = 0.003). In children with the CYP2B6-516-G/G genotype, which is associated with higher expression of hepatic CYP2B6, the clearance rate was significantly higher in younger children (<5 years of age) than in older children (≥5 years of age) (9.7 L/h/m vs. 6.6 L/h/m; P = 0.03). No association was found between CYP2B6-G516T polymorphisms and virologic or immunologic responses, toxicity, or the development of viral resistance against EFV. CONCLUSIONS: CYP2B6-G516T polymorphisms significantly affect the CL/F rate of EFV in children. Changes in hepatic enzyme activity by age may need to be considered when evaluating the impact of genetic variants on antiretroviral pharmacokinetics in children.

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KW - Resistance

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