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Efavirenz PKs Highly Variable and Driven by CYP2B6 Genotype in Youngsters
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13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona
Mark Mascolini
Efavirenz concentrations varied widely in a study of 13 US children and adolescents, depending on genotype of CYP2B6, the enzyme central to metabolism of this nonnucleoside [1]. Results of this study and ongoing research are critical because currently recommended doses often yield subtherapeutic efavirenz concentrations in youngsters, and because CYP2B6 genotype varies from person to person. Previous research linked CYP2B6 polymorphisms at G516T to high variability in efavirenz exposure among infants, children, and adolescents. In addition, developmental changes in growing youngsters may affect efavirenz metabolism and resulting concentrations.
This cross-sectional study involved 7 girls and 6 boys taking efavirenz in the Washington, DC area. Their median age was 12.8 years and ranged from 8.2 to 17.4. Median body mass index was 20.8 kg/m(2) and median weight 46.8 kg. Twelve participants were black and 1 was Hispanic.
All study participants had their CYP2B genotype determined when they enrolled. Six youngsters had the CYP2B6 516 GG genotype, 4 had the GT genotype, and 3 had the TT genotype. The investigators measured concentrations of efavirenz and its metabolites 8-hydroxy-EFV (E8F) and 8-hydroxy-EFV glucuronide (E8G) before dosing and 1, 2, 4, 6, 8, 12, and 24 hours after an observed intake of the standard recommended efavirenz dose. Eight study participants took 600 mg of efavirenz daily and 5 took 300 to 400 mg daily.
Median efavirenz area under the concentration-time curve (AUC) for the whole group was 62.3 mcg*h/mL (range 21.6 to 271.6), and median clearance was 0.21 L/h/kg (range 0.0466 to 0.460). Two participants had a subtherapeutic efavirenz 24-hour concentration (C24 below 1 mg/L), and both had the 516 GG genotype. The 3 youngsters with the 516 TT genotype had the three highest efavirenz AUCs (range 96.3 to 271.6 mcg*h/mL) and the three lowest efavirenz clearances (0.0466 to 0.113 L/h/kg).
Metabolite E8G concentrations were greater than metabolite E8F concentrations in all but one study participant. There was a trend to decreasing E8G/EFV ratio median values from 3.43 (0.00 to 9.45) with the GG genotype, to 2.83 (1.48 to 6.04) with the GT genotype, and to 1.03 (0.61 to 1.38) with the TT genotype (P = 0.075).
The E8G/EFV ratio and the E8T/EFV ratio correlated positively with efavirenz clearance (r = 0.79 and 0.74), but the E8F/EFV ratio did not correlate with clearance (r = 0.27). Age had no discernible impact on efavirenz clearance, probably because of the strong genotype impact. The highest E8T/EFV ratio occurred in participants with the GG genotype (median 8.97, 2.68 to 14.41), while the lowest ratio occurred in those with a TT genotype (median 1.04, 0.93 to 1.60) (P = 0.013).
The investigators concluded that efavirenz pharmacokinetics are highly variable in the children and adolescents they studied and that the CYP2B6 G516T genotype is directly related to efavirenz AUC and clearance in this group. They proposed that "ongoing study with repeated within-subject sampling will allow us to better investigate the impact of developmental changes on the metabolism of efavirenz in children and adolescents."
Although 8-hydroxylation of efavirenz has been proposed as a phenotypic probe to evaluate CYP2B6 activity, in this study extensive conversion of the E8F metabolite to the E8G metabolite limited the usefulness of this proposed probe.
Reference
1. Rakhmanina N, Gordish-Dressman H, Van Den Anker JN, Williams K, Rossi S, Capparelli EV. CYP2B6 activity in HIV-infected children and adolescents: pharmacokinetic evaluation of efavirenz and its 8-hydroxymetabolite. 13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona. Abstract O_09.
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