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PK AND 4-WEEK OUTCOMES OF DOLUTEGRAVIR DISPERSIBLE TABLETS IN HIV-INFECTED CHILDREN
Theodore Ruel1, Edward P. Acosta2, Rajendra P. Singh3, Carmelita Alvero4, Kathleen George5, Stephanie Popson6, Mattie Bartlett6, Ann Buchanan7, Cindy Brothers7, Lucy Koech8, Tichaona Vhembo9, Rohan Hazra10, Ellen Townley11, Andrew Wiznia12
1University of California San Francisco, San Francisco, CA, USA,2University of Alabama at Birmingham, Birmingham, AL, USA,3GlaxoSmithKline, King of Prussia, PA, USA,4Harvard T.H. Chan School of Public Health, Boston, MA, USA,5FHI 360, Durham, NC, USA,6Frontier Science & Technology Research Foundation, Inc, Amherst, NY, USA,7ViiV Healthcare, Research Triangle Park, NC, USA,8Walter Reed Project–Kericho, Kericho, Kenya,9University of Zimbabwe, Harare, Zimbabwe,10National Institute of Child Health and Human Development, Bethesda, MD, USA,11NIAID, Bethesda, MD, USA,12Albert Einstein College of Medicine, Bronx, NY, USA
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.