Data from Thailand demonstrated non-inferiority of abacavir (ABC) and 3TC once daily compared to a twice daily regimen in children.10
ABC and 3TC are approved for once daily use in adolescents aged 12 and above and adults, but not yet in younger children.
Previous studies in European and African children found similar PK for once and twice daily ABC and 3TC.
This was a single-arm, open- label, crossover study, conducted in 30 Thai children and adolescents aged <18 years, weighing >14 kg, viral load <50 copies/mL, and HLA B5701 negative. ABC and 3TC daily doses by weight were 300 and 150 mg for 14 to <20 kg, 450 and 300 mg for 20 to <25 kg, and 600 and 300 mg for >25 kg.
The study used originator ABC and 3TC scored tablets. Intensive PK sampling was performed following14 days of each dose. GMR (90% CI) of AUC0-24 and Cmax were compared.
At baseline, participants were a median age 8.8 years (IQR 6.6-11.3) years, weight 21.9 kg (IQR 11.9-30.6) kg and CD4 count 841(IQR 580-1073) cells/mm3.
ABC and 3TC was given with EFV (60%), LPV/r (37%), or NVP (3%). No children had SAEs or laboratory abnormalities during the PK study.
GM of AUC0-24 for once and twice daily ABC were 14.43 and 10.65 mg·h/L, which gave a GMR 1.36, (90% CI 1.19-1.55). For 3TC, these values were 17.70 and 18.11 mg·h/L, GMR 0.98 (90% CI 0.84-1.14).
GMR of ABC Cmax for once and twice daily was 2.84 mg/L (90% 2.28-3.53); 3TC was 1.69 mg/L (1.35-2.09).
ABC AUC0-24 once daily was higher overall but lower in the 14 to 20 kg weight band. 3TC AUC0-24 once and twice daily was bioequivalent -- there was higher 3TC exposure in Thai children compared to historical data in children and adults but no toxicities were observed.
The study demonstrated the non-inferiority of once daily ABC and 3TC compared to twice daily and provides further support for this dosing regimen in children.
A generic dispersible fixed dose combination (FDC) of 3TC/NVP/AZT for children is bioequivalent to the originator liquids.11
Mylan (formerly Matrix) tested dissolution of 3TC/NVP/AZT 30/50/60 mg FDC tablets in 0.1N HCl /Type II/75 rpm/900mL media. Bioequivalence was tested in 48 healthy adults aged 18 to 50 under fasting conditions. Originator liquids were used as reference: Epivir solution, Viramune suspension and Retrovir syrup.
The tablet has a short disintegration time and disperses quickly in water -- after 10 minutes, 98 to 100 of the API was dissolved.
In the bioequivalence study all participants were randomised to receive a single dose of either the FDC or reference products during period 1 and then the other after a washout period of 21 days. Very intensive sampling was performed up to 72 hours. The relative bioequivalence is shown in table 3.
|Table 3: Relative Bioequivalence (% of Reference) of 3TC/NVP/AZT Tablets to Originator Liquids|
|3TC||105.51(95.49 -115.54)||98.42(90.69 -106.15)||98.59(91.15-106.03)|
|NVP||102.52(98.18 - 106.86)||100.55(99.07 - 102.04)||--|
|AZT||99.37(91.16 - 107.58)||101.12(97.83 - 104.41)||101.27(98.09-104.46)|
The study found the time/concentration curves for the dispersible tablet and the reference products were indistinguishable, demonstrating equal bioavailability.
Data from PRINCE 1 has taken its time -- adult ATV approval was in 2003 and for older children 2008. Presumably data from the combined sets from PRINCE 1 and 2 will eventually be submitted for approval. Whether there will be generic heat stable versions of ATV/r for children remains to be seen.
DRV/r might also be a good second line option for children over three who started on NNRTIs if suitable heat stable generics were available.
As with adults maraviroc will be far to complicated to use for all but a few treatment experienced children in rich countries.
According to this model, the risk of EFV toxicities seems quite high with WHO weight band dosing. This is not ideal particularly with double the proportion in the toxic range in the higher weight band, i.e., older children and adolescents who are most likely to receive it.
The Thai data for ABC and 3TC once daily reinforces that from ARROW and the PENTA studies. ViiV are submitting ARROW and PENTA data for a once daily indication for children (particularly with a view to producing a scaled down paediatric once daily FDC of dolutegravir plus these two NRTIs).
Finally, indisputable bioequivalency data for the only paediatric FDC recommended in the new WHO guidelines that is currently available.
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