Bridging dolutegravir clinical viral response across doses and formulations using model-based exposure-response analysis in pediatrics.

OBJECTIVE:Dolutegravir (DTG) is a once-daily HIV-1 integrase inhibitor approved for the treatment of HIV-1 infection in adults and children from 4 weeks of age. The posology of DTG in children has been driven by exposure-matching relative to the adult dose for efficacy and safety. However, higher variability in pediatric exposures raises concern that efficacy may not be reliably extrapolated from adult trials. Therefore, we evaluated the relationship between DTG exposure and virologic response in children. DESIGN/METHODS:A population exposure-response analysis using logistic regression for virologic response was undertaken based on DTG exposure and covariate data from 146 pediatric participants with HIV-1 from age ≥4 weeks to <18 years treated for up to 48 weeks with DTG in IMPAACT P1093 study. RESULTS:None of the DTG exposure metrics were predictive of virologic response over the range of exposures in this analysis. Of the covariates tested, VL ≥100,000 copies/mL at enrolment was a significant predictor of virologic response showing a lower probability of achieving a virologic response of HIV-1 RNA <50 copies/mL compared to participants with VL <100,000 copies/mL at enrolment. Baseline VL was also a significant predictor at Week 48 whereby the probability of achieving a virologic response at Week 48 decreased with increasing baseline VL. CONCLUSIONS:This exposure-response analysis suggests that DTG exposures in children are all above the plateau of the exposure-response relationship. These results suggest that matching pediatric pharmacokinetic exposure parameters to those in adults is a reasonable approach for dose determination of DTG-containing formulations in pediatrics.