Pharmacokinetics of Efavirenz in 2-3 years old children: a high dose of 25 mg/kg per day [PublishAheadOfPrint]

Background: The MONOD ANRS 12206 trial was designated to assess simplification of a successful LPV-based antiretroviral treatment in young HIV-infected children using efavirenz (25 mg/kg/day) to preserve the protease inhibitors class before the age of 3. In this sub-study, EFV concentrations were measured to check the consistency of a 25 mg/kg EFV dose and to compare it with the 2016 FDA recommended dose.

Methods: Fifty-two children underwent blood sampling for pharmacokinetic study at 6-month and 12-month after switching to EFV. We applied a Bayesian approach to derive EFV pharmacokinetic parameters using the NONMEM nonlinear mixed-effect modeling program. The proportion of mid interval concentrations (C_12h) in the EFV therapeutic pharmacokinetic thresholds (1-4 mg/L) was assessed according to different dose regimens (25 mg/kg in the MONOD study versus the 2016 FDA recommended dose).

Results: With both 25 mg/kg/day or 2016 FDA recommended EFV dose, simulations show that the majority of C_12h were within the therapeutic ranges (62.6% vs 62.8%). However, there were more children underexposed with the 2016 FDA recommended dose: 11.6% vs. 1.2%. Conversely, there were more concentrations above the threshold of toxicity with a 25 mg/kg dose (36.2% vs. 25.6%) with C_12h up to 15 mg/L. Only one child/52 was switched back to LPV because of persistent sleeping disorders, but was within therapeutic ranges.

Conclusions: A high EFV dose of 25 mg/kg per day in children under 3 years old achieved satisfactory therapeutic effective levels. However, the 2016 FDA recommended EFV dose appeared to provide more acceptable therapeutic safe profiles.

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