Plasma efavirenz concentrations and the association with CYP2B6-516G >T polymorphism in HIV-infected Thai children.
BACKGROUND
Concerns have been raised about the possibility of subtherapeutic efavirenz (EFV) plasma levels in children with the current dosing guideline. Single nucleotide polymorphisms of the hepatic cytochrome P450 isoenzyme 2B6 (CYP2B6) gene have been associated with high interindividual variations in EFV plasma concentrations. Our objective was to determine the adequacy of EFV dosing and explore the influence of CYP2B6-516G>T polymorphisms on EFV plasma concentrations in Thai HIV-infected children.


METHODS
A total of 63 HIV-infected children receiving EFV for > or =4 weeks were assessed. Children received EFV daily doses on the basis of body weight bands. Between 12 to 16 h after EFV intake, a blood sample was drawn to measure the EFV plasma concentration and to determine the CYP2B6-516G>T polymorphism using HPLC and direct gene sequencing, respectively.


RESULTS
The median age (range) was 12.3 years (3.1-18.7). The mean (+/-sd) EFV plasma concentration was 3,138 ng/ml (3,313). Eight (13%), 45 (71%) and 10 (16%) children had an EFV concentration <1,000 ng/ml, 1,000-4,000 ng/ml and >4,000 ng/ml, respectively. CYP2B6-516 G/G, G/T and T/T genotypes were found in 48%, 41% and 11% children, respectively. The CYP2B6-516G>T allele frequency was 31.75%. The mean (+/-sd) EFV concentration for children with G/G, G/T and T/T genotypes were 1,604 ng/ml (729), 2,635 ng/ml (1,199) and 11,582 ng/ml (2,972), respectively (P<0.001). A correlation between EFV concentrations >4,000 ng/ml and psychiatric side effects was observed (P=0.02), but there was no association with rash, hepatotoxicity or central nervous system disturbances.


CONCLUSIONS
Current EFV dosing guidelines provide adequate plasma drug concentrations in Thai HIV-infected children. CYP2B6-516G>T polymorphisms significantly affect the drug metabolism of EFV in children.
Puthanakit
Thanyawee
T
Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand.
Tanpaiboon
Pranoot
P
Aurpibul
Linda
L
Cressey
Tim R
TR
Sirisanthana
Virat
V
D000293:Adolescent; D000480:Alkynes; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D048588:Benzoxazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D011110:Polymorphism, Genetic; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013785:Thailand
D000480:Alkynes; D000890:Anti-Infective Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; C098320:efavirenz