Dolutegravir (DTG, S/GSK1349572) is recommended as first-line treatment for HIV-infected adults and children 6 yrs and older due to its potency, high barrier to resistance, convenience and tolerability. A 5mg dispersible tablet (DTG-DT) formulation for children is being evaluated in IMPAACT P1093 (NCT01302847), an ongoing phase I/II open-label dose-finding study. The first DTG-DT dosing tested did not meet target drug exposures. Here we present the intensive pharmacokinetic (PK), 4-week safety and efficacy data of higher dosing for DTG-DT in children ages 6 mo to <6 yr.
Enrollment was stratified into two age cohorts of 10 children (≥6 mo to <2 yr and ≥2 to <6 yr). DTG-DT was dosed once daily by WHO weight-band (6 to <10kg: 15mg, 10 to <14kg: 20mg, 14 to <20kg: 25mg). Children received DTG-DT alone or added to stable-failing or empiric initial background regimens. PK sampling was completed between days 5-10 under fasting conditions. Background regimens were optimized based on enrollment HIV genotypes. Safety, tolerability, and plasma HIV-1 RNA levels were assessed through 4 weeks. Based on adult data, exposure targets were geometric mean (GM) (range) AUC24h of 46 (37-134) mg.h/L and C24h of 995 (697-2260) ng/mL.
Twenty children (10 female) with median (range) age 22 months (6, 71), and weight 9.4 kg (6.5, 17.5) were studied. Median baseline CD4+ cell % and HIV-1 RNA levels were 27.3 (IQR: 22.0, 36.9) and 4.3log10 (c/mL) (IQR: 3.3, 5.3). For age cohorts of ≥6 mo to <2 yr and ≥2 to <6 yr, the GM(CV%) AUC24h(CV%) was 70.2 (49.6) mg.h/L and 59.0 (62.2) mg.h/L, C24h was 1094(70.4) ng/mL and 791 (105) ng/mL, and Cmax was 5702(37) ng/mL and 5181 (44) ng/mL, respectively. C24h levels varied from 104 to 4579 ng/mL (figure). DTG was well tolerated, with no drug-related Grade 3 or 4 AEs or discontinuations. HIV-1 RNA levels were <400 c/mL in 16/20 and <50 c/ml in 8/20 participants after 4 weeks of treatment, with median decrease from BL of 2.38 log10 (c/mL) (IQR: 1.36, 3.11).
The tested dosing of DTG-DT met pre-specified AUC24h and C24h targets for age-cohorts children 6 mo to <6 yr old, even with moderate intra-participant variability. DTG was virologically potent and well tolerated through week 4. With the additional PK, long-term safety and efficacy data currently being collected, these novel results will form the basis of safe and efficacious WHO weight-band dosing recommendations for DTG-DT in children.