Background:
Indication for dolutegravir, dosed at 50 mg daily, have been extended to children 20-35kg. There are, however, limited data on safety and pharmacokinetics of twice daily 50 mg dolutegravir in children with HIV and tuberculosis (TB) co-infection.
Methods:
We conducted an open-label, sequential non-randomised prospective study in children initiated on a rifampicin-based TB regimen and dolutegravir twice daily (BD) during TB treatment and once daily (OD) after stopping rifampicin (NCT04746547). Plasma samples were collected in steady-state at pre-dose, and at 1, 2, 3, 4, 6, and 12 or 24h post-dose and assayed with a validated LC-MS/MS method. Non-compartmental pharmacokinetic (PK) analyses were conducted using the ncappc package in R.The area under the concentration-time curve (AUC) was calculated using the linear-up log-down trapezoidal method. Extrapolation was done from the last measurement to 12 or 24h, using the elimination rate constant. Participants underwent frequent clinical and safety visits. Viral load was measured at weeks 8, 12, 24 and 48.
Results:
We enrolled 13 children between August 2021 and September 2022 and report the preliminary analysis of all data collected up to November 2022; Median (IQR) age 10 (9-11) range [5-13] years; 54% males; 100% black race. The median (IQR) viral load and CD4 at baseline were 2.5 (1.6-5.0) log10-copies/mL and 108.5 (76.5-385.2) cells/μl. Viral load was undetectable in all children completing the week 12 and 24 visits. There were two grade 3 adverse events and no SAEs. Data from 12 children were included in the preliminary PK analysis, contributing 12 profiles on twice daily dolutegravir and rifampicin and 2 profiles on once daily dolutegravir (total of 114 dolutegravir plasma concentration values). Median trough concentration (CTau) was 1.60 and 1.49 mg/L, while AUC0-24 was 33.55 and 36.67 h*mg/L for participants on BID dolutegravir with rifampicin and OD dolutegravir, respectively. All CTau were > 0.3 mg/L. Results are summarized in Table 1.
Conclusions:
Preliminary data from children 20-35kg receiving twice-daily dolutegravir during TB treatment suggest this dosing is well-tolerated and achieves similar PK values to daily treatment for HIV-alone. VL suppression data are, similarly, promising.
Table 1. Dolutegravir (DTG) pharmacokinetic parameters and their unit presented for visit 1 and visit 2 in Median (Min, Max)