Pharmacokinetics of a Dolutegravir Pediatric Granule Formulation in Healthy Adult Subjects
P Patel1, I Song1, J Borland1, S Chen1, A Peppercorn1, T Wajima2, T Funaki2, N Fujita2, J Hughes3, and Stephen Piscitelli*1
1GlaxoSmithKline, Res Triangle Park, NC, US; 2Shionogi & Co Ltd, Osaka, Japan; and 3GlaxoSmithKline, Ware, UK
Background: Dolutegravir (DTG) is an integrase inhibitor currently in Phase 3 that delivers predictable plasma exposures without the need for a booster. This study evaluated the PHARMACOKINETICS of a granule formulation developed as an alternative to tablets for use in pediatric populations.
Methods: Single-center, randomized, open-label, 5-way crossover study in healthy adult subjects. Subjects received a single dose of DTG 50mg as the Phase 3 tablet and in 10g of granule administered 1) direct to mouth; 2) with purified water; 3) with water containing high cation concentrations; or 4) with a milk-based infant formula. Study treatments were separated by 7 days. Safety evaluations and serial PHARMACOKINETICS samples were collected during each treatment period. Non-compartmental PHARMACOKINETICS analysis was performed; geometric least squares (GLS) mean ratios and 90% confidence intervals (CI) were generated for treatment comparison. Palatability was assessed by a questionnaire.
Results: Preliminary data demonstrate that the plasma DTG exposures in all granule treatment arms exceeded those of the tablet formulation (Table). PHARMACOKINETICS was similar when DTG was mixed with purified or cation-containing water. Inter-subject variability was modest with CV% for AUC of 31-43%. DTG was well tolerated with no withdrawals due to AEs. Taste was rated as acceptable for all treatments.
Conclusions: The exposure of DTG following administration of the granule formulation alone, with different types of water and with formula exceeded that of the tablet, demonstrating DTG granule can be given without restriction on the type of liquid, or can be administered directly to mouth (e.g., when potable water is not available). These data support the further evaluation of the DTG granule formulation in an ongoing study in pediatric HIV-infected subjects (IMPAACT P1093) as an alternative to tablet.