Pharmacokinetics and safety of dolutegravir in children receiving rifampicin tuberculosis treatment in South Africa (ORCHID): a prospective cohort study

Background Data on the safety and pharmacokinetics of dolutegravir in children with HIV and tuberculosis are scarce. We aimed to determine the pharmacokinetics and safety of dolutegravir 50 mg twice daily in children receiving rifampicin, and to predict exposures for once-daily dolutegravir with rifampicin. Methods ORCHID is an open-label, sequential, prospective cohort study in children ( trough ), maximum concentration (C max ), and area under the concentration-time curve from dose to 24 h after dose (AUC 0-24 ) and population plasma pharmacokinetic parameters (ie, absorption rate constant, volume of distribution, and oral clearance) of dolutegravir film-coated tablet 50 mg twice daily in children with and without rifampicin, assessed in all participants with evaluable pharmacokinetic data (pharmacokinetic population). Secondary outcomes included pharmacokinetic parameters for the once-daily dolutegravir dosing option with rifampicin, simulated in the pharmacokinetic population. This study is registered at ClinicalTrials.gov, NCT04746547. Findings Between Aug 19, 2021, and Aug 17, 2023, we enrolled and followed up 13 children, with a median weight of 23·8 kg (IQR 21·7-24·8) and median age 10 years (range 5·9-13·0). Seven were male, six female, and 13 Black. Typical dolutegravir clearance was 0·584 L/h (95% CI 0·492-0·724), with an increase in clearance of 99·1% (73·2-120) with rifampicin. Median C trough was 1·45 mg/L (coefficient of variation 68%) for participants on twice-daily dolutegravir with rifampicin and 1·24 mg/L (70%) for participants on once-daily dolutegravir without rifampicin. Median viral load and CD4 count at baseline were 2·48 log 10 copies per mL (IQR 1·64-4·99) and 109 cells per μL (77-385), respectively. Viral load was less than 50 copies per mL in all 13 children completing week 24 and in 12 children at week 48. Four grade 3 adverse events, no grade 4 adverse events, and one serious adverse event (ie, hospitalisation) unrelated to study drug were reported, with no treatment discontinuations or switches due to adverse events. Simulated C trough values for dolutegravir 50 mg once daily if it were co-administered with rifampicin in children were similar to those reported in adults, with time below the target (0·064 mg/L) similarly short; 90% of adults and children either above the target or below the target for less than 2 h. Interpretation Twice-daily dolutegravir with rifampicin in children weighing 20-35 kg achieved therapeutic concentrations and was well tolerated with high rates of viral suppression. Simulations suggest that once-daily dolutegravir during rifampicin co-administration in children weighing 20-35 kg should be investigated in clinical studies. Funding National Institutes of Health and South African Medical Research Council.