Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Brief Report: Suboptimal Lopinavir Exposure in Infants on Rifampicin Treatment Receiving Double-dosed or Semisuperboosted Lopinavir/Ritonavir: Time for a Change

“…Moreover, increasing the dosing interval of dolutegravir from once daily to twice daily was shown to be safe and sufficient to overcome its interaction with rifampicin in children with HIV/TB coinfection. 22 However, pharmacokinetic data were available for only 3 children <6 year old, and no evaluable data were available for infants less than 1 year old. 22 More data are needed to confirm twice-daily dolutegravir dosing in infants with HIV/TB.…”

“… 22 However, pharmacokinetic data were available for only 3 children <6 year old, and no evaluable data were available for infants less than 1 year old. 22 More data are needed to confirm twice-daily dolutegravir dosing in infants with HIV/TB.…”

Twice-Daily Dosing of Dolutegravir in Infants on Rifampicin Treatment: A Pharmacokinetic Substudy of the EMPIRICAL Trial

“…Dolutegravir and dolutegravir-glucuronide pharmacokinetic parameters were determined with noncompartmental pharmacokinetic analysis using WinNonlin (Phoenix 64 v8.3, Certara) and were described as geometric mean with an associated coefficient of variance. Similar to previous studies, pharmacokinetic profiles were considered nonevaluable if the predose minimum concentration of dolutegravir was more than 15 times lower than the end-of-dose interval C trough , suggesting potential nonadherence [ 11 , 20 , 21 ]. The first concentration below the LLOQ at the end of the curve was set to half the LLOQ.…”

“…Rifampicin, an essential component of TB treatment, interacts substantially with dolutegravir by increasing dolutegravir metabolism through induction of UGT1A1, UGT1A9, and CYP3A4, resulting in a reduction in dolutegravir area under the plasma concentration-time curve (AUC), maximum concentration (C max ), and trough concentration (C trough ) by 54%, 43%, and 72% in healthy adults, respectively [ 9 ]. Adapting the dolutegravir dosing interval from once daily (OD) to twice daily (BID) was safe and effective in both adults and children [ 10 , 11 ]. However, only limited data were available for children on dolutegravir dispersible tablets (DTs), and no pharmacokinetic data were available for infants who weighed less than 14 kg in whom the maturation of metabolic enzyme activity may not yet be fully complete [ 11 , 12 ].…”

“…Adapting the dolutegravir dosing interval from once daily (OD) to twice daily (BID) was safe and effective in both adults and children [ 10 , 11 ]. However, only limited data were available for children on dolutegravir dispersible tablets (DTs), and no pharmacokinetic data were available for infants who weighed less than 14 kg in whom the maturation of metabolic enzyme activity may not yet be fully complete [ 11 , 12 ]. Ontogeny of UGT1A1 primarily occurs within the first 3–6 months of life, whereas CYP3A4 reaches adult levels in children aged between 1 and 5 years [ 13 ].…”