Advertisement
Advertisement

Read Now: News and Research From IDWeek 2014

Antiretrovirals, Doses and Formulations for Children

July/August 2013

 < Prev  |  1  |  2  |  3 

Once-Daily Abacavir and 3TC

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.

Advertisement

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.


Fixed-Dose Combination: 3TC/NVP/AZT

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
  Cmax AUC(0-t) AUC (0-inf)
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.


Comment

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.


References

  1. Expanding ARV options for children: first line and beyond. Session MOAB01.
  2. Strehlau R et al. PRINCE1: Safety and efficacy of ATV powder and RTV liquid in HIV-1-infected ART-naive and experienced infants and children 3 months to 6 years of age. 5th International Workshop on HIV Pediatrics. 28-29 June 2013, Kuala Lumpur. Oral abstract. O_2.
  3. Strehlau R et al. PRINCE 1: 48 week safety and efficacy of atazanavir powder and ritonavir liquid in HIV-1-infected antiretroviral treatment-naive and -experienced infants and children 3 months to 6 years of age. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 30 June - 3 July 2013, Kuala Lumpur. Poster abstract TULBPE22.
  4. Violari A et al. Safety and efficacy of darunavir/ritonavir in treatment-experienced pediatric patients aged 3 to < 6 Years: week 48 analysis of the ARIEL trial. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 30 June - 3 July 2013, Kuala Lumpur. Oral abstract MOAB0102.
  5. Chokephaibulkit K et al. Pharmacokinetics and 24-weeks efficacy of once daily darunavir/ritonavir in virologic suppressed HIV-infected Thai children: a pilot study. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 30 June - 3 July 2013, Kuala Lumpur. Poster abstract MOPE047.
  6. Giaquinto C et al. Safety and efficacy of maraviroc in CCR5-tropic HIV-1-infected children aged 2 to < 18 years. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 30 June - 3 July 2013, Kuala Lumpur. Oral abstract MOAB0103.
  7. Vourvahis M et al. Update from Study A4001031: maraviroc pharmacokinetics in CCR5-tropic HIV-1-infected children aged 2 to < 18 years. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 30 June - 3 July 2013, Kuala Lumpur. Poster abstract MOPE044.
  8. Homkam N et al. Plasma efavirenz concentrations in HIV-infected children in Thailand: comparison between FDA and WHO 2010 dosing guidelines. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 30 June - 3 July 2013, Kuala Lumpur. Oral abstract MOAB0104.
  9. Puthanakit T et al. A randomized study comparing low dose versus standard dose lopinavir/ritonavir among HIV-infected children with virological suppression. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 30 June - 3 July 2013, Kuala Lumpur. Oral abstract MOAB0101.
  10. Punyahotra P et al. Pharmacokinetics of abacavir and lamivudine once- versus twice-daily in HIV-infected Thai children. 5th International Workshop on HIV Pediatrics. 28-29 June 2013, Kuala Lumpur. Oral abstract. O_3.
  11. Bhushan A et al. The pediatric dispersible tablet with a FDC of 3TC/NVP/AZT is bioequivalent to the combination of Retrovir syrup, Epivir solution and Viramune suspension providing simplified adaptable dosing for pediatric patients. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 30 June - 3 July 2013, Kuala Lumpur. Poster abstract MOPE046.

Links to other websites are current at date of posting but not maintained.

 < Prev  |  1  |  2  |  3 



This article was provided by HIV i-Base. It is a part of the publication HIV Treatment Bulletin. Visit HIV i-Base's website to find out more about their activities, publications and services.
 

No comments have been made.
 

Add Your Comment:
(Please note: Your name and comment will be public, and may even show up in
Internet search results. Be careful when providing personal information! Before
adding your comment, please read TheBody.com's Comment Policy.)

Your Name:


Your Location:

(ex: San Francisco, CA)

Your Comment:

Characters remaining:

Advertisement