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Clinical Trial
. 2022 May;9(5):e332-e340.
doi: 10.1016/S2352-3018(22)00044-3.

Pharmacokinetics, safety, tolerability, and antiviral activity of dolutegravir dispersible tablets in infants and children with HIV-1 (IMPAACT P1093): results of an open-label, phase 1-2 trial

Theodore D Ruel  1 , Edward P Acosta  2 , Jessica P Liu  3 , Kathryn P Gray  4 , Kathleen George  5 , Nicole Montañez  5 , Stephanie Popson  6 , Ann M Buchanan  7 , Mattie Bartlett  6 , Dale Dayton  8 , Patricia Anthony  9 , Cynthia Brothers  7 , Cynthia Vavro  7 , Rajendra Singh  10 , Lucy Koech  11 , Tichaona Vhembo  12 , Blandina T Mmbaga  13 , Jorge A Pinto  14 , Els F M Dobbels  15 , Moherndran Archary  16 , Kulkanya Chokephaibulkit  17 , Pradthana Ounchanum  18 , Jaime G Deville  19 , Rohan Hazra  20 , Ellen Townley  21 , Andrew Wiznia  22 ; IMPAACT P1093 team
Collaborators, Affiliations
Clinical Trial

Pharmacokinetics, safety, tolerability, and antiviral activity of dolutegravir dispersible tablets in infants and children with HIV-1 (IMPAACT P1093): results of an open-label, phase 1-2 trial

Theodore D Ruel et al. Lancet HIV. 2022 May.

Abstract

Background: Safe and potent antiretroviral medications in child-friendly formulations are needed to treat young children living with HIV-1. We aimed to select dosing for a dispersible tablet formulation of dolutegravir that achieved pharmacokinetic exposures similar to those in adults, and was safe and well tolerated in young children.

Methods: International Maternal Pediatric Adolescent AIDS Clinical Trial (IMPAACT) P1093 is a phase 1-2 ongoing multicentre, open-label, non-comparative study of dolutegravir. A 5 mg dispersible tablet formulation of dolutegravir was studied in children aged 4 weeks to less than 6 years old, weighing at least 3 kg, with HIV RNA of greater than 1000 copies per mL and no previous treatment with integrase strand transfer inhibitor recruited from IMPAACT clinical research sites in Africa, the Americas, and Asia. Doses were selected on the basis of intensive pharmacokinetic evaluation on days 5-10, with safety and tolerability assessed up to 48 weeks. The primary objectives of this study are to evaluate the pharmacokinetics of dolutegravir in combination with optimised background therapy and to establish the dose of dolutegravir that achieves the targeted 24-h trough concentration and 24-h area under the curve for infants, children, and adolescents with HIV-1, to establish the safety and tolerability of dolutegravir at 24 and 48 weeks, and to select a dose that achieves similar exposure to the dolutegravir 50 mg once daily dose in adults. This analysis included participants treated with the proposed dose of dolutegravir dispersible tablets in two stages for each of three age cohorts. This trial is registered at ClinicalTrials.gov (NCT01302847) and is ongoing.

Findings: We recruited 181 participants from April 20, 2011, to Feb 19, 2020; of these, 96 received dolutegravir dispersible tablets. This analysis included 73 (35, 48% female) participants who received the final proposed dose with median (range) age of 1 year (0·1 to 6·0), weight (minimum-maximum) of 8·5 kg (3·7 to 18·5), plasma HIV-1 RNA concentration of 4·2 log10 copies per mL (2·1 to 7·0), and CD4% of 24·0% (0·3 to 49·0); 64 (87·7%) were treatment-experienced. The selected dose within each age cohort (≥2 years to <6 years, ≥6 months to <2 years of age and ≥4 weeks to <6 months) achieved geometric mean trough (ng/mL) of 688, 1179, and 1446, and 24 h area-under-the-curve (h·mg/L) of 53, 74, and 65, respectively. No grade 3 or worse adverse events were attributed to dolutegravir.

Interpretation: In this study, the proposed once daily dosing of dolutegravir dispersible tablets provided drug exposures similar to those for adults, and was safe and well tolerated. These data support the use of dolutegravir dispersible tablets as first-line or second-line treatment for infants and children aged less than 6 years living with HIV-1.

Funding: National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Mental Health, and ViiV Healthcare-GlaxoSmithKline.

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Conflict of interest statement

Declaration of interests MA and JAP have served on the advisory board for ViiV Healthcare. JAP has received research funding from GlaxoSmithKline (through his institution). RS held stock and was an employee of GlaxoSmithKline. CV, CB, and AMB hold stock and are employees of ViiV Healthcare, the manufacturer of dolutegravir. All other authors declare no competing interests.

Figures

Figure 1.
Figure 1.
Participant flow chart Doses were evaluated in Stage I by examining intensive pharmacokinetic and safety results through one month; in Stage II, additional participants were enrolled to assess safety through 48 weeks. This analysis included only participants who received the dispersible tablet formulation.
Figure 2.
Figure 2.
Dolutegravir steady state concentrations a) cohort ≥ 2 years to < 6 years; b) ≥ 6 months to < 2 years, c) ≥ 4 weeks to < 6 months; d) composite of all three cohorts with triangles for ≥ 2 years to < 6 years, circles for ≥ 6 months to < 2 years, and square for ≥ 4 weeks to < 6 months. The solid line connects geometric mean values at each time point and the dashed line represents the EC90 of 300 ng/mL. For d) the solid line connects the geometric means for each cohort, and the dashed line represents the target of 995 ng/mL.
Figure 3.
Figure 3.
Proportion of participants with HIV RNA<400 copies/mL and <50 copies/mL
See this image and copyright information in PMC

Comment in

References

    1. UNAIDS. Children living with HIV lagging behind adults in access to treatment. March 8, 2021. ed; 2021.
    1. World Health Organization. Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV: interim guidelines. Supplement to the 2016 consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. 2018.
    1. U.S. Food and Drug Administration. New Drug Applicatino: 204790. 2013. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview... (accessed March 10 2021).
    1. Viani RM, Alvero C, Fenton T, et al. Safety, Pharmacokinetics and Efficacy of Dolutegravir in Treatment-experienced HIV-1 Infected Adolescents: Forty-eight-week Results from IMPAACT P1093. Pediatr Infect Dis J 2015; 34(11): 1207–13. - PMC - PubMed
    1. Pediatric HIV Infection: Drug Product Development for Treatment Guidance for Industry. Food and Drug Administration; 2019.

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