Dose Selection of Dolutegravir (DTG, S/GSK1349572) in Pediatric Studies
Ivy Song (1), Stephen Piscitelli (2), Toshihiro Wajima (3), Edward Acosta (4)
(1) Clinical Pharmacology Modeling & Simulation, (2) Clinical Pharmacology, GlaxoSmithKline, RTP, NC, USA; (3) Shionogi & Co., Ltd., Osaka, Japan; (4) School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Objectives: DTG is an unboosted, once daily integrase inhibitor currently in late stage clinical development for the treatment of HIV infection in adults. Evaluation of DTG in the pediatric population is now warranted necessitating the need for dosing recommendations. This analysis presents various methods used for the selection of dosing strategies and initial doses in an upcoming study in HIV-infected children and adolescents.
Methods: Target exposure of DTG was determined using pooled adult pharmacokinetic (PK) data obtained in Phase II. Initial dose(s) in various age ranges were proposed and justified based on review of approved pediatric doses versus adult doses of currently marketed antiretroviral agents as well as the predicted exposure in pediatric subjects through allometric scaling of adult PK parameters. Monte Carlo simulation was also performed to predict exposure at the proposed doses by weight band and to demonstrate the simulated exposure matches the pre-determined target exposure.
Results: Upon review of recommended dosing regimens of approved antiretroviral agents, the preferred dosing strategy in children was to dose DTG at fixed doses by weight band using either an adult tablet formulation or an alternative pediatric formulation. This approach generally makes prescribing much easier for clinicians and is expected to provide convenience and enhance compliance in pediatric subjects on HIV therapy. The following once daily doses were proposed for 6-18 years old children based on allometric scaling and Monte Carlo simulation: 50mg for subjects with weight of ³ 40 kg; 35 mg for 30-<40kg; 25mg for 20-<30kg; and 20mg for 15-<20kg. Dosing in children younger than 6 years old has more weight cut-offs and will require a pediatric-friendly formulation to allow more dosing flexibility relative to the tablet formulation.
Conclusions: Fixed doses by weight band were selected for the planned pediatric study. In order to provide more flexible dosing, three different tablet strengths (10, 25, and 50mg) were recommended and are available to support the proposed dosing strategy in 6-18 years old children. The selected dosing strategy will serve as initial doses and real-time PK will be collected for area-under-the-curve targeted dose optimization.
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