title: Breast milk pharmacokinetics of efavirenz and breastfed infants' exposure in genetically defined subgroups of mother-infant pairs: an observational study.
abstract: BACKGROUND
  The antiretroviral drug efavirenz is widely used during breastfeeding. Evaluating its safety requires an understanding of its breast milk pharmacokinetics, level of breastfed infants' exposure, and potential influence of polymorphisms in drug disposition genes.
  
  
  METHODS
  For this observational study, we investigated plasma and breast milk pharmacokinetics of efavirenz and breastfed infants' exposure in human immunodeficiency virus positive nursing mothers and their breastfed infants. We also evaluated potential variability due to genetic polymorphisms in CYP2B6, NR1I3, CYP2A6, ABCB1, ABCB5, and ABCG2.
  
  
  RESULTS
  CYP2B6 516G>T was independently associated with efavirenz concentrations in maternal plasma, breast milk, and infant plasma (n = 134). When stratified based on CYP2B6 516G>T (n = 29 ; 11 GG, 10 GT and 8 TT), efavirenz pharmacokinetic parameters in plasma and breast milk differed significantly between patient groups. The median time-averaged milk-to-plasma concentration ratio was 1.10 (range: 0.57-1.71). The estimated maximum infant efavirenz dose from breast milk was 809 µg/kg/day (215-2760) and pediatric dose weight-adjusted exposure index was 4.05% (1.08-13.8). Infant plasma concentrations did not change significantly during the dosing interval, 157 ng/mL (28.6-1360) in pooled analysis and 315 ng/mL (108-1360) in CYP2B6 516TT group. Infant plasma concentrations were highest up to 8 days of age at 1590 ng/mL (190-4631) and decreased by about 90% in the age stratum day 9 to 3 months. No efavirenz related toxicity was reported.
  
  
  CONCLUSIONS
  Most breastfed infants are exposed to <10% of the weight-adjusted therapeutic pediatric dose, the safety threshold for exposure to maternal drugs from breast milk.
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, United Kingdom Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Nigeria.
authors.forename: Adeniyi
authors.initials: A
authors.lastname: Olagunju
authors.affiliation: Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Nigeria.
authors.forename: Oluseye
authors.initials: O
authors.lastname: Bolaji
authors.affiliation: Liverpool Bioanalytical Facility, Department of Molecular and Clinical Pharmacology, University of Liverpool, United Kingdom.
authors.forename: Alieu
authors.initials: A
authors.lastname: Amara
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, United Kingdom.
authors.forename: Catriona
authors.initials: C
authors.lastname: Waitt
authors.affiliation: Liverpool Bioanalytical Facility, Department of Molecular and Clinical Pharmacology, University of Liverpool, United Kingdom.
authors.forename: Laura
authors.initials: L
authors.lastname: Else
authors.affiliation: Department of Paediatrics and Child Health, Obafemi Awolowo University, Ile-Ife, Nigeria.
authors.forename: Ebunoluwa
authors.initials: E
authors.lastname: Adejuyigbe
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, United Kingdom.
authors.forename: Marco
authors.initials: M
authors.lastname: Siccardi
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Back
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, United Kingdom.
authors.forename: Saye
authors.initials: S
authors.lastname: Khoo
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
mesh_terms: D000293:Adolescent; D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000032:analysis* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D048588:Benzoxazines / Q000032:analysis* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001942:Breast Feeding; D000090702:Constitutive Androstane Receptor; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016014:Linear Models; D008895:Milk, Human / Q000737:chemistry* / Q000378:metabolism; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D055815:Young Adult
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D000090702:Constitutive Androstane Receptor; D003521:Cyclopropanes; C000716327:NR1I3 protein, human; D065702:Cytochrome P-450 CYP2B6; C098320:efavirenz
keywords: CYP2B6 516G>T; breast milk; efavirenz; infant exposure; pharmacokinetics