IMPAACT P1093 is an ongoing phase 1/2 open-label pharmacokinetic (PK) and dose finding study of dolutegravir in age-defined paediatric cohorts: 4 weeks to <18 years of age. Doses that provide dolutegravir exposure comparable to that from 50 mg once daily in adults with acceptable safety and tolerability are selected for each age group.
Dolutegravir is approved for children and adolescents aged 6 years and above, weighing at least 30 kg. Theodore Ruel and colleagues from P1093 presented 4 week results from an interim analysis of the 2 to <6 years cohort.
In this study children received dolutegravir granules-in-suspension at doses of ~0.8 mg/kg mg/kg once daily. Children were ART-experienced but INSTI-naive at enrolment. They had been on a failing regimen for up to 12 weeks or off ART for at least 4 weeks. PK targets, based on adult data, were geometric means of: AUC24h range of 37-67 mg*hour/L (primary) and C24h range of 0.77-2.26 mg/L (secondary).
Intensive PK performed on 10 participants was used to determine the dose. The dolutegravir granules-in-suspension was evaluated at ~0.8 mg/kg once daily -- based on data from the older P1093 cohorts.
PK was completed after oral administration of weight-based dose between days 5-10, after which the background regimen was optimised. Safety, tolerability, and viral load were assessed at 4 weeks, and the study is ongoing to 48 weeks.
At baseline the children (5 female and 5 male) were a median: age 4.3 years (IQR 3.6-4.6); weight 15.5 kg (13.8-15.9); CD4 count 1323 cells/mm3 (IQR 763-2441); CD4 percent 28.0%(IQR 22.0-31.4) and viral load 4.8 log10 copies /mL (IQR 4.7-5.3).
Mean dolutegravir dose was 0.87 mg/kg (range 0.58-1.06). The geometric mean (CV%) AUC24h was 44.7 (36%) mg*hour/L and C24h was 0.51 (68%) mg/L. C24h was below the target but above the pharmacodynamic threshold reported in adults. There was considerable variability among the participants.
Viral load was <400 copies/mL in 8/10 participants and <50 copies/mL in 6/10 after 4 weeks of treatment. There were no Grade 3 or Grade 4 adverse events and no discontinuations due
to adverse events.
The granules-in-suspension formulation will not be commercially available but these data will form the basis for dolutegravir dosing as dispersible tablets to be studied in this and younger age cohorts, which are now enrolling.
Ruel T et al. Dolutegravir pharmacokinetics, safety and efficacy in HIV+ children 2 to <6 years old. CROI 2017. 13-17 February 2017. Seattle, Washington. Poster abstract 806.