Dolutegravir dosing for children with HIV weighing less than 20 kg: pharmacokinetic and safety substudies nested in the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Abstract

Background: Dolutegravir-based antiretroviral therapy is a preferred first-line treatment for adults and children living with HIV; however, very little pharmacokinetic data for dolutegravir use are available in young children. We therefore aimed to evaluate dolutegravir dosing and safety in children weighing 3 kg to less than 20 kg by assessing pharmacokinetic parameters and safety data in children taking dolutegravir within the ODYSSEY trial.

Methods: We did pharmacokinetic substudies nested within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial. We enrolled children from seven research centres in South Africa, Uganda, and Zimbabwe. Children weighing 3 kg to less than 14 kg received 5 mg dispersible tablets of dolutegravir according to WHO weight bands: 5 mg for children weighing 3 kg to less than 6 kg and younger than 6 months, 10 mg for children weighing 3 kg to less than 6 kg and aged 6 months or older, 15 mg for children weighing 6 kg to less than 10 kg, and 20 mg for children weighing 10 kg to less than 14 kg. Children weighing 14 kg to less than 20 kg received a 25 mg film-coated tablet once per day early in the trial or 25 mg dispersible tablets (five 5 mg tablets once per day) later in the trial. A minimum of eight children per weight band or dose was targeted for 24 h pharmacokinetic profiling at steady state. The primary pharmacokinetic parameter was the trough concentration 24 h after observed dolutegravir intake (C_trough). Pharmacokinetic targets were based on adult dolutegravir C_trough and the 90% effective concentration (EC₉₀; ie, 0·32 mg/L). Safety was evaluated in eligible children consenting to pharmacokinetic substudies.

Findings: Between May 25, 2017, and Aug 15, 2019, we enrolled 72 children aged between 3 months and 11 years. 71 children were included in the safety population and 55 (76%) of 72 children contributed 65 evaluable pharmacokinetic profiles. Geometric mean C_trough in children on dispersible tablets in weight bands between 3 kg and less than 20 kg ranged between 0·53-0·87 mg/L, comparable to the adult geometric mean C_trough of 0·83 mg/L. Variability was high with coefficient of variation percentages ranging between 50% and 150% compared with 26% in adults. C_trough below EC₉₀ was observed in four (31%) of 13 children weighing 6 kg to less than 10 kg taking 15 mg dispersible tablets, and four (21%) of 19 weighing 14 kg to less than 20 kg taking 25 mg film-coated tablets. The lowest geometric mean C_trough of 0·44 mg/L was observed in children weighing 14 kg to less than 20 kg on 25 mg film-coated tablets. Exposures were 1·7-2·0 times higher on 25 mg dispersible tablets versus 25 mg film-coated tablets. 19 (27%) of 71 children had 29 reportable grade 3 or higher adverse events (13 serious adverse events, including two deaths), none of which were related to dolutegravir.

Interpretation: Weight-band dosing of paediatric dolutegravir dispersible tablets provides appropriate drug exposure in most children weighing 3 kg to less than 20 kg, with no safety signal. 25 mg film-coated tablets did not achieve pharmacokinetic parameters in children weighing 14 kg to less than 20 kg, which were comparable to adults, suggesting dosing with dispersible tablets is preferable or a higher film-coated tablet dose is required.

Funding: Paediatric European Network for Treatment of AIDS Foundation, ViiV Healthcare, and UK Medical Research Council.

Figure 1

Substudy trial profiles (A) Participants weighing 14 kg to less than 20 kg. (B) Participants weighing 3 kg to less than 14 kg. ART=antiretroviral therapy. DT=dispersible tablet. FCT=film-coated tablet. *One participant weighing 14 kg to less than 20 kg did a pharmacokinetic assessment on 25 mg FCT while taking co-medication was excluded but subsequently returned for a pharmacokinetic assessment on 25 mg FCT without co-medication. †Including two participants who had been excluded from the first substudy because of co-medication or wrong dose. ‡Nine children had intrasubject comparison in the first substudy. §One child completed pharmacokinetic profiles in two weight bands (6 kg to <10 kg receiving 15 mg DT, and 10 kg to <14 kg receiving 20 mg DT). ¶One participant younger than 6 months weighing 3 kg to less than 6 kg did a pharmacokinetic assessment on the wrong dose (10 mg DT) and was excluded. This participant subsequently returned for a pharmacokinetic assessment at the correct dose of 5 mg DT. ||Results for this one child are presented in the appendix (p 3).

Figure 2

Mean plasma concentrations versus time profiles for all doses by weight band and formulation DT=dispersible tablet. EC₉₀=the effective concentration at which 90% of maximal viral inhibition is achieved in a 10-day monotherapy study. FCT=film-coated tablet. *Children younger than 6 months. †Published geometric mean trough concentrations of adult reference values for 50 mg once per day and twice per day.

Figure 3

Individual dolutegravir C_trough, AUC_{0–24 h}, and C_max in children weighing 3 kg to less than 20 kg taking DT or FCT The horizontal black lines indicate geometric means per dose. The shaded area indicates concentrations below dolutegravir in-vivo EC₉₀. The dashed lines indicate published geometric mean adult reference values for 50 mg onc per day (lower lines) and twice per day (upper lines). DT=dispersible tablet. FCT=film-coated tablet. AUC_{0–24 h}=area under the concentration-time curve from 0 to 24 h. C_trough=trough concentration. C_max=maximum concentration. EC₉₀=the effective concentration at which 90% of maximal viral inhibition is achieved in a 10-day monotherapy study. *Children younger than 6 months.