Abstract Body

Weight band pharmacokinetic (PK) substudies within the ongoing phase III ODYSSEY-trial evaluate PK and safety of simplified weight band-based dosing of dolutegravir (DTG) for children on first-line and second-line antiretroviral therapy (ART). This substudy assessed PK and safety of DTG adult film-coated tablets (FCT) and pediatric dispersible tablets (DT) in children weighing 20 to <25kg who make up a high proportion of children living with HIV. DT have higher bioavailability compared to FCT in adults (ratio 1.5-1.8).

Steady state 24h DTG PK profiles in fasted children taking once-daily DTG 50mg FCT or 30mg DT (6x5mg) were recorded ≥7 days after switch from DTG 25mg FCT. Blood was sampled at t=0, 1, 2, 3, 4, 6 and 24h and DTG plasma concentrations were measured with a validated UPLC-MS/MS method. Non-compartmental PK analysis was performed to calculate PK parameters (WinNonlin 8.1). Results were compared to those in HIV-positive adults taking DTG 50mg FCT once/twice daily, and children 20 to <25kg on 25mg FCT once daily (Table). Safety was evaluated at 2, 4, 12, and then every 12 weeks.

15 African children were enrolled in Zimbabwe and Uganda (Table). The 50mg FCT (n=7) and 30mg DT (n=8) doses both resulted in geometric mean (GM) Ctrough values comparable to adults on DTG 50mg FCT once-daily and were higher compared to children 20 to <25kg on 25mg FCT. GM AUC0-24h for both doses was in-between values observed in adults taking DTG 50mg once daily and 50mg twice daily. GM Cmax on both doses exceeded adult GM values for DTG 50mg once and twice daily. DTG 50mg FCT in this weight band provided a lower GM Cmax compared to 30mg DT. After median (IQR) follow-up of 11.9 (4.0-11.9) and 5.1 (3.0-11.8) weeks on 50mg FCT and 30mg DT respectively, no children experienced grade 3/4, serious adverse events or discontinued DTG.

Daily DTG 50mg FCT and 30mg DT provide similar and appropriate PK profiles for children 20 to <25kg. Short-term safety data are reassuring and, provided ongoing longer-term safety is acceptable, these results support use of either 50mg FCT or DTG 30mg DT in this weight band. Adult DTG 50mg FCT could offer a practical and accessible dosing strategy for children weighing 20 to <25kg allowing rapid alignment of WHO-preferred ART regimens for adults and children ≥20kg in low- and middle-income countries.