Using Population Pharmacokinetic and Pharmacodynamic Analyses of Entecavir in Pediatric Subjects to Simplify Dosing Recommendations.

Background: Entecavir is an orally administered guanosine nucleoside analog with activity against hepatitis B virus (HBV) polymerase, which is approved for the treatment of chronic hepatitis B (CHB) infection in adults and children ≥2 years old (USA and EU).

Objective: To develop simplified entecavir dosing recommendations for young children infected with CHB.

Methods: Data from recent clinical trials were used to develop a population pharmacokinetic (PPK) model, which allowed us to estimate entecavir exposures in children and compare them to ranges known to be efficacious in adults. A population pharmacodynamic (PPD) model was generated to describe the concentration/effect relationship for entecavir in lamivudine treatment-naïve children. The PPK dataset comprised three pediatric cohorts: 2 to <6 years (n = 36); 6 to <12 years (n = 43); and 12 to <18 years (n = 74). Data from 177 adults were also included to enhance model stability and to aid in the covariate search.

Results: Entecavir concentration-time profiles were well-described by a two-compartment model with first-order absorption and first-order elimination. Age was not a statistically significant covariate after accounting for weight. For the PPD model, the HBV DNA concentration following entecavir exposure was adequately described using a direct effect inhibitory maximum effect (E ) model with additive residual error.

Conclusion: Model-estimated, steady-state entecavir area under the concentration-time curve, in both the original (15 weight groups) and simplified (eight weight groups) pediatric dosing regimens, provided entecavir exposures consistent with those observed to be efficacious in adults, and resulted in the simplified dose algorithm for pediatric patients that is approved for the current entecavir label.