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Dolutegravir for younger children: results from the ODYSSEY trial

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Dolutegravir (DTG) dosed according to World Health Organisation (WHO) weight bands in children weighing 10 kg to 20 kg, achieved similar concentrations to adults and older children. But pharmacokinetic (PK) profiles showed high variability in the 6 kg to 10 kg weight band group.

These findings, from a nested PK sub study of the ODYSSEY trial, from researchers at Radboud University Medical Centre, Nijmegen, Netherlands; University College London Medical Research Council Clinical Trials Unit; Baylor College of Medicine, Kampala, Uganda; University of Zimbabwe Clinical Research Centre, Harare; Joint Clinical Research Centre, Kampala; Joint Clinical Research Centre, Mbarara, Uganda; Klerksdorp-Tsepong Hospital Complex, Matlosana, South Africa; Chris Hani Baragwanath Hospital, Perinatal HIV Research Unit (PHRU), Soweto, South Africa; University of Padova, Italy; Hospital 12 de Octubre, Madrid, Spain, using the ViiV Healthcare 5 mg dispersible tablet (DT) formulation, were presented at IAS 2019.

ODYSSEY is a phase 3, randomised, non-inferiority trial comparing DTG-based ART to first- and second-line standard of care in children and adolescents.

Data were shown from children weighing 6 kg to < 20 kg. Children weighing 6 kg to <10kg, 10 kg to <14 kg and 14 kg to < 20 kg received DTG DT at 15 kg (3 tablets), 20 mg (4 tablets) and 25 mg (5 tablets) once-daily dosing, respectively.

DTG DT is approximately 1.6 to 2 times more bioavailable than the adult film coated tablets (FCT).

Target reference values were those achieved in adults receiving DTG 50 mg once-daily and twice-daily with Ctrough being the primary target: 0.83 mg/L (CV 26%) and 2.72 mg/L (CV 70%). The investigators also evaluated individual levels above target EC90 (0.32 mg/L) and/or IC90 (0.06 mg/L).

Sampling was at steady state (at least 7 days) and fasted in children over 10 kg and, where possible, younger children.

Of 41 children enrolled from Zimbabwe, Uganda and South Africa, 34 had evaluable PK curves and were included in the analysis: 11, 10 and 13 in the 6 kg to <10 kg, 10 kg to <14 kg and 14 kg to <20 kg weight bands respectively. The youngest participant was 6 months old and the oldest 2.5 years.

The analysis found that DTG DT in children weighing 10 kg to <14 kg and 14 kg to <20kg, dosed once daily, according to WHO weight bands, achieved similar Ctrough to adults.

But children in the 6 to <10 kg weight band had lower geometric mean (GM) Ctrough, more frequent levels below EC90 (4/11) and PK profiles showed high variability.

Results were also similar to those seen in older children and the IMPAACT P1093 study.

Further PK data collection is ongoing in children in the 3 kg to <6 kg weight band receiving 5 mg if less than and 10 mg if more than 6 months of age. Both ODYSSEY and IMPAACT P1093 PK data will be included in submissions to US Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

Generic manufacturers are developing dispersible scored 10 mg DTG tablets to accommodate WHO paediatric weight bands with fewer tablets/formulations.

Abstract
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.

Authors
H Waalewijn, PDJ Bollen, C Moore, A Kekitiinwa, P Amuge, H Mujuru, E Chidziva, V Musiime, E Kaudha, A Lugemwa, S Makumbi, A Violari, E Variava, S Ali, C Giaquinto, P Rojo, A Colbers, D Gibb, D Ford, A Turkova, D Burger

I-Base material
IAS 2019 abstract


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