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Safety and Pharmacokinetics of Elvitegravir in HIV-1 Infected Pediatric Subjects
Joseph M. Custodio1, Victor Musiime2, Aditya Gaur3, Elizabeth McFarland4, Wasana Prasitsuebsai5, Lize Hellstrom6, Xuelian Wei1, Rebecca Begley1, Srinivasan Ramanathan 1, Sean R. Bennett1
1 Gilead Sciences, Inc., Foster City, CA, United States. 2 Joint Clinical Research Centre, Kampala, Uganda. 3 St. Jude Children's Research Hospital, Memphis, TN, United States. 4 University of Colorado Denver, Aurora, CO, United States. 5 HIV - NAT, Bangkok, Thailand. 6 Be Part Yoluntu Centre, Cape Town, South Africa.
Background: Safe and effective pediatric antiretroviral therapies are needed. Elvitegravir (EVG), a once-daily integrase inhibitor, is indicated in treatment-experienced HIV-1 infected adults when administered with a ritonavir (r)-boosted protease inhibitor (PI/r). The safety and pharmacokinetics (PK) of EVG were evaluated in a completed lead-in phase of a study in 6 to <11 year old HIV-infected subjects upon addition to a PI/r-containing background regimen consisting of at least 2 fully-active agents.
Methods: Treatment-experienced subjects 6 to <11 years of age, weighing ≥17 kg with suppressed viremia (HIV-1 <50 c/mL) or failing a current antiretroviral regimen (HIV-1 RNA >1,000 c/mL) received EVG (adult or pediatric formulation) once daily in addition to their background regimen including either lopinavir/r or atazanavir/r. The adult EVG dose (85 mg) was administered in subjects >30 kg and reduced to 50 mg in subjects ≥17 kg to <30 kg. Intensive PK was performed on or after Day 10 (steady state). EVG exposure (primarily AUCtau) was compared to exposures in adults from EVG+PI/r Phase 3 trials by an analysis of variance using a mixed-effects model for parallel group design. Adverse events (AE) and routine laboratory tests were assessed.
Results: A total of 14 subjects (57% male, 14% Asian, 71% black and 14% white) were enrolled with a median age of 10 years (range: 6-11) and a median weight of 26 kg (range: 18-47). At baseline, mean CD4 count was 811 cells/µL; 13 of 14 subjects had HIV RNA <50 c/mL. There were no deaths or AEs leading to premature study drug discontinuation. No EVG-related SAEs were observed. No AE occurred in more than one subject. EVG PK is summarized in Table 1. The geometric mean ratio (GMR) of EVG AUCtau, Cmax, and Ctrough was 136%, 147%, and 129%, respectively, versus adult exposure. Importantly, mean EVG Ctau was ~11-fold above the in vitro protein-binding adjusted IC95 (44.5 ng/mL). Moreover, subjects >30 kg or ≥17 kg to <30 kg (receiving EVG 85 or 50 mg, respectively) showed EVG exposure associated with safety and efficacy based on extensive PK-pharmacodynamic analyses in adults. These study data are consistent with EVG PK in children >12 years of age.
Conclusions: Administration of EVG once daily with a PI/r in children 6 to <11 years old provides therapeutic EVG exposure with mean trough concentrations ~11-fold above IC95 and appears well tolerated. These results support continued evaluation of the efficacy and safety of EVG in pediatric populations.