Dolutegravir: 48-Week Results in Children Age 6 to 12 Years Old
March 5, 2016
Dolutegravir (DTG) is safe and effective in children age 6-12 years, according to results presented at CROI 2016.1
IMPAACT P1093 is an ongoing phase 1/2, multicentre, open-label, pharmacokinetic (PK), dose finding and safety study of DTG plus optimised background regimen (OBR) in infants, children and adolescents.2 The evaluation takes a staggered approach and participants are studied in de-escalated, age-defined cohorts.
In adolescents (12-18 years), paediatric weight band dosing of approximately 1 mg/kg once daily gave comparable PK exposures to those seen in adults receiving 50 mg once daily. Data for this age group were included in the adult regulatory filings and DTG is approved for children age 12 and above in over 50 countries.3
Twenty-four week PK, safety and efficacy data from the 6-12 years age group has recently been submitted to the FDA.4 The IMPAACT investigators reported 48-week results at CROI 2016.
Participants were ART-experienced but integrase inhibitor (INI)-naive, with viral load >1000 copies/mL. They were either on a failing ART regimen for at least 12 weeks or off ART for four weeks. Participants were only eligible if they had at least one other fully active drug for the OBR.
In stage 1 of the study, DTG was added to the failing ART regimen and the OBR optimised after intensive PK (day 5-10). In stage 2, participants received DTG and OBR when they joined the study. The primary endpoint was virologic suppression to <400 copies/mL at 48 weeks (FDA snapshot algorithm); <50 copies/mL was a secondary endpoint.
A total of 23 children were enrolled (11 stage 1 and 12 stage 2) and 21 (93.3%) completed 48 weeks. Baseline demographics were: 70% male, 52% black, 17% white, 13% Asian, and 26% Latino. Median age was 10 years and weight was 30 kg (range 18-54). Median viral load was 5 log10 copies/mL (IQR 4.5-5.5), median CD4 count 645 cells/mm3 (IQR 466-732) and CD4 per cent was 24% (IQR 14.3-28.7). Participants had received ART for a median of 9.3 years (IQR 6.4-10.4) before study entry. Sites were in the United States, South Africa and Thailand.
Of 23 participants: 6 weighed >40 kg, 6 weighed 30-40 kg, 8 weighed 20-30 kg and 3 weighed 15-20 kg. They received DTG doses of: 50 mg, 35 mg, 25 mg and 20 mg respectively, with the exception of one participant in the >40 kg weight band who received 70 mg (greater than the adult 50 mg dose). The study used tablets of 10 mg, 25 mg and 50 mg (already approved adult and adolescent formulation).
Previously reported DTG geometric mean (CV%) for PK parameters were: AUC24 50.46 ug*h/mL (63%) and C24 0.92 ug/mL (89%).3
At 48 weeks, 78.3% of participants had viral load <400 copies/mL and 74% <50 copies/mL. The median change in CD4 per cent from baseline was +9% (IQR 7-14%).
The investigators found DTG to be generally well tolerated with no discontinuations due to adverse events. They reported no DTG-related adverse events.
IMPAACT P1093 is continuing to evaluate infants and young children 4 weeks of age and above.
ViiV Healthcare (the originator manufacturer of DTG) filed two reduced strength tablets (10 mg and 25 mg) for the 6 to 12 years age group with the FDA at the end of last year.
The two cohorts in the youngest age groups (6 months to 2 years and 4 weeks to 6 months) started with a granules in suspension formulation but use of this will stop once the 5 mg dispersible tablet formulation is available on site.5,6
Only the dispersible tablets will be available commercially. These will be strawberry cream flavoured. The primary completion date for the whole study is May 2018.2
Every paediatric expert consultation has identified DTG as a priority for children in low- and middle-income countries. Generic versions of DTG are already on the way for adults.7 The development of appropriate generic formulations of DTG for children should follow as swiftly as the originator manufacturer, generic manufacturers, and regulators can do so.
Several issues have been raised concerning DTG specifically and paediatric drug development in general and some were discussed at a Themed Discussion at CROI 2016 aptly titled: "New drugs for kids: what's taking so long?"8,9
The discussion included the problems with the age-staggered approach that results in delays in approval and availability of new drugs, particularly in the youngest age group where options are lacking. WHO uses a weight band dosing approach and it would make sense to investigate weight band dosing in paediatric antiretroviral development from the beginning, optimising the use of PK data and modeling. In P1093, with the dispersible tablet in the younger cohorts, the investigators are trying to capture enough data to inform weight bands.
Moving away from the age-staggered approached to weight bands it could also be possible to open multiple cohorts simultaneously, if formulations are available, which would speed up availability of new drugs for infants and children considerably.
Unless stated otherwise, all references are to the Programme and Abstracts of the Conference on Retroviruses and Opportunistic Infections (CROI), 22-25 February 2016, Boston, USA.
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