Background: Dolutegravir (DTG) 5mg dispersible tablets (DT) are small, child-friendly and allow easy scaling. We describe a pharmacokinetic (PK) substudy of DT DTG in children weighing 6-< 20kg dosed by WHO weight bands (WB) conducted within ODYSSEY, an ongoing phase-III trial of DTG (NCT02259127).
Methods: Children weighing 6-< 10kg, 10-< 14kg, 14-< 20kg received DTG 5mg DT at 15, 20, and 25mg QD, respectively. At steady-state, 24-hour PK profiles (7 samples) were constructed after DTG intake. DTG plasma concentrations were measured by UPLC-MS/MS; Phoenix64 was used for non-compartmental analysis. Results were compared to historical PK parameters from adults taking 50mg DTG filmcoated tablets (FCT) QD or BID, previous ODYSSEY PK data and published data from IMPAACTP1093.
Results: 28 children [29 PK curves] from Zimbabwe and Uganda were included in the analysis. PK results (table 1) from WBs 10-< 14kg and 14-< 20kg were similar to PK data from children receiving same DT doses in IMPAACTP1093, and GM Ctrough values were similar to children 20-< 40kg in ODYSSEY on DTG FCT 50mg and adults on 50mg DTG FCT QD. In children 14-< 20kg, exposures were ~1.8-2-fold higher on 25mg DT than 25mg FCT, similar to relative bioavailability of DT/FCT in adults. Our data from the 6-< 10kg WB showed lower GM exposure to DTG compared to IMPAACTP1093 with high variability, and 3 of 8 children had observed Ctrough below EC90 (0.32mg/L).
Conclusions: DTG DT in children weighing 10-< 20kg, dosed QD in WHO WBs achieves similar Ctrough to adults and older children on the adult DTG dose and young children on DT in IMPAACTP1093. Some children in the 6-< 10kg WB had Ctrough levels below EC90, and PK profiles showed high variability in this WB. Further PK data collection in children 3-< 10kg is ongoing and all children are followed up for safety.

 Odyssey Lower weightband PK substudiesReference adults
WHO weightband6-<10kg10-<14kg14-<20kg≥40kg≥40kg/50mg FCT BID
DTG dose and (N)15mg DT (8)20mg DT (8)25mg DT (13)50mg FCT (10)a50mg FCT BID (12b; 24c)
Age (years)1.3 (0.6-3.0)3.0 (1.6-4.2)6.0(4.9-8.5)34 (22-53)48 (31-59)b; 47 (33-68)c
Weight (kg)7.6 (6.7-9.7)11.5 (10.0-12.6)18.0 (14.9-19.9)--
Dose/weight (mg/kg)2.0 (1.5-2.2)1.7 (1.6-2.0)1.4 (1.3-1.7)--
Ctrough (mg/L); %below EC900.43 (207); 37.5%0.77 (62); 0%0.85 (67); 0%0.83 (26)a2.41 (77)b; 2.72 (70)c
AUC0-24h (mg*h/L)46.3 (90)76.0 (25)69.6 (30)43.4 (20)a92.7 (55)b; 93.4 (50)c
Cmax (mg/L)5.3 (58)8.0 (25)7.1 (21)3.3 (16)a5.6 (49)b; 5.4 (40)c
Pharmacokinetic parameters are expressed as geometric mean with coefficient of variation (%), median (range) for age, weight and dose/weight. Doses represent once daily doses, unless otherwise specified. FCT, film-coated tablet; DT, dispersible tablet; BID, twice daily. aFasted HIV-positive adults. bFasted healthy HIV-negative adults. cHIV-positive treatment experienced adults, fed state not specified.
[Table 1]