Pharmacokinetics and safety of dispersible and immediate release FDC abacavir/dolutegravir/lamivudine in children with HIV weighing '¥14 kg: preliminary results from IMPAACT 2019
BACKGROUND: Pediatric-friendly fixed dose combination (FDC) formulations for children with HIV are limited. IMPAACT 2019 is a Phase I/II, multi-site, open-label dose confirmation study examining the pharmacokinetics (PK), safety, and tolerability of immediate-release (IR) and a novel dispersible tablet (DT) formulation of abacavir (ABC)/dolutegravir (DTG)/lamivudine (3TC). Here we report preliminary PK and Week 4 safety results for IR and DT ABC/DTG/3TC FDC once-daily in children weighing â?¥14 kg.
METHODS: Children <12 years were enrolled across five weight bands (WB) in Botswana, South Africa, Thailand, and the United States. The study design is summarized in Figure 1. Data for WB3, WB4, and WB5 are presented.
RESULTS: Demographic and PK results are summarized in Table 1. Two grade 2 events in one child in WB4 and one grade 1 event in WB5 were related to DTG. One child in WB3 experienced a grade 3 eGFR decrease and serum creatinine increase (with values in normal range) unrelated to study drug. All AEs resolved without intervention and no children discontinued study treatment due to AEs.
| Characteristic | WB 3 (n=7) | WB4 (n=7) | WB5 (n=7) |
| Demographics | |||
| Sex at birth, n(%) Female Male | 4 (57%) 3 (43%) | 3 (43%) 4 (57%) | 3 (43%) 4 (57%) |
| Age (year), median (range) | 7.4 (5.8-9.6) | 8.0 (6.4-8.9) | 10.3 (9.3-11.3) |
| Weight (kg), median (range) | 18.8 (16.5-19.5) | 21.6 (19.8-24.4) | 28.0 (25.9-37.1) |
| Treatment-experienced, n(%) | 7 (100%) | 7 (100%) | 7 (100%) |
| PK Results (Geometric Mean [CV%]) | |||
| DTG AUC0-24h (µgâ??h/mL) | 71.5 (23.5%) | 84.5 (26.3%) | 71.8 (13.9%) |
| DTG C24h (µg/mL) | 0.79 (44.2%) | 1.35 (95.6%) | 0.98 (27.9%) |
| ABC AUC0-24h (µgâ??h/mL) | 15.1 (40.3%) | 17.3 (19.2%) | 25.7 (14.6%) |
| 3TC AUC0-24h (µgâ??h/mL) | 13.0 (15.6%) | 14.5 (16.5%) | 21.7 (26.2%) |
CONCLUSIONS: PK targets were met for IR and DT ABC/DTG/3TC in children â?¥14kg and these formulations were well-tolerated. Additional data in children <14 kg and long-term safety/tolerability data are forthcoming. These findings provide reassurance for the dosing of these FDC formulations in children â?¥14 kg and are expected to support global efforts to expand the availability of pediatric-friendly DTG-containing FDCs in alignment with WHO WB dosing.
K. Brooks * (1), J. Kiser (1), P. Samson (2), Y. Rani (2), S. Ward (2), T. Cressey (3,4), H. Cassim (5), J.G. Deville (6), G.R. Masheto (7), P.L. Ponatshego (7), A. Coletti (8), K. Lypen (8), I. Mustich (8), B. Heckman (9), M. Lojacono (9), R. Bowman (9), D. Yin (10), E. Townley (10), S. Majji (11), E.P. Acosta (12), K.J. Ryan (12), A.M. Buchanan (13), C.H. Brothers (13), H. Chandasana (14), H. Rabie (15), P. Flynn (16), on behalf of the IMPAACT 2019 Study Team
(1) University of Colorado-Anschutz Medical Campus, Department of Pharmaceutical Sciences, Aurora, United States, (2) Frontier Science & Technology Research Foundation (FSTRF), Brookline, United States, (3) Chiang Mai University, Chiang Mai, Thailand, (4) Chiangrai Prachanukroh Hospital, Chiang Rai, Thailand, (5) University of the Witwatersrand, Johannesburg, South Africa, (6) University of California-Los Angeles, Los Angeles, United States, (7) Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana, (8) FHI 360, Durham, United States, (9) Frontier Science & Technology Research Foundation (FSTRF), Amherst, United States, (10) Division of AIDS, NIAID, Rockville, United States, (11) Eunice Shriver National Institute of Child Health and Human Development, Bethesda, United States, (12) University of Alabama-Birmingham, Birmingham, United States, (13) ViiV Healthcare, Research Triangle Park, United States, (14) GlaxoSmithKline, Collegeville, United States, (15) University of Stellenbosch, Stellenbosch, South Africa, (16) St. Jude Childrenâ??s Research Hospital, Memphis, United States