There is an urgent need for new drugs to treat HIV-1 infected children globally. Dolutegravir (DTG; S/GSK1349572) is a first-line agent for the treatment of HIV-1 infected adults due to its potency, high barrier to resistance, and tolerability; it promises a similar role in children. IMPAACT P1093 is an ongoing phase 1/2 open-label pharmacokinetic (PK) and dose finding study of DTG in age-defined pediatric cohorts (4 weeks to <18 years of age). Pediatric doses that provide DTG exposure comparable to that observed from 50 mg once daily in adults with acceptable safety and tolerability will be selected for each age cohort.
Children ≥2 and <6 years old received DTG granules-in-suspension at doses of ~0.8 mg/kg once daily. At enrollment, DTG was either started as monotherapy or added to a stable-failing regimen. Intensive PK evaluations were completed after oral administration of weight-based dose between days 5-10; background regimen was then optimized. Safety, tolerability, and plasma HIV RNA levels were assessed at 4 weeks. Based on adult data, target individual exposures were AUC24h range of 37-67 mg*hour/L (primary) and C24h range of 0.77-2.26 mg/L (secondary).
Ten children (5 female) with median (range) age 4 years (2-5), and weight 14.6kg (9.9-17.1) were studied. Median baseline (BL) CD4+ cell % and HIV-1 RNA levels were 28.0 (IQR: 22.0, 31.4) and 4.8 log10(c/mL) (IQR:4.7-5.3), respectively. Mean (range) DTG dose was 0.87 mg/kg (0.58 to 1.06). DTG demonstrated moderate intersubject PK variability. The geometric mean (CV%) AUC24h and C24h were 44.7 (36%) mg*hour/L and 0.51 (68%) mg/L, respectively. HIV-1 RNA levels were < 400 c/mL in 8/10 and < 50 c/ml in 6/10 after 4 weeks of treatment, with median (range) change from BL of -3.1 log10(c/mL) (-3.4 to -2.1). DTG was well tolerated with no Grade 3 or Grade 4 AEs and no discontinuations due to AEs.
DTG granules-in-suspension administered at ~0.8 mg/kg once daily in this cohort of children ≥2 to <6 years old achieved the target AUC24h; C24h was below the target but above the pharmacodynamic threshold reported in adults. DTG was virologically potent and well tolerated through week 4. These novel data will form the basis for dosing of DTG as dispersible tablets to be studied in this and younger age cohorts.