|Table 4. Pediatric Drugs and Formulations Needed
||Drug||Formulation and Dose||Comments||Heat stable formulations of ritonavir and ritonavir-boosted PIs||Lopinavir/ritonavir||Sprinkle, 40/10mg||Will be equivalent to 0.5ml of liquid
||Ritonavir||Sprinkle or tablet (heat stable), 50mg|
Sprinkle (heat-stable), 25mg
|Urgently needed for super-boosting when PIs need to be dosed with rifampicin||NRTI backbone combinations as FDCs||Abacavir/lamivudine||Scored adult tablet, 300/150 mg||For children over 25kg
Scored tablet, 300/300mg
|Approval of tenofovir in over 12 years in the United States; there is currently no FDC for this age group||Triple FDCs with NNRTI or boosted PI*||Abacavir/lamivudine/nevirapine||Tablet, 60/30/50mg||Triple FDC to align with the dual FDC.||Abacavir/lamivudine/efavirenz||Copack||Dual FDC and efavirenz||Lamivudine/lopinavir/r/zidovudine||Copack||First line for NNRTI-exposed infants and children; second line for NNRTI-unexposed and older children||Abacavir/lamivudine/lopinavir/r||Copack||First line for NNRTI-exposed infants and children; second line for NNRTI-unexposed and older children|
Source: WHO Essential Medicines List
* It may not be possible to coformulate some combinations, as the individual drugs may have different dosing schedules. Dual blister packaging is preferred in these cases. Emtricitabine is considered interchangeable with lamivudine.
The working group also considered atazanavir, darunavir, etravirine, raltegravir, and tenofovir to be high priority. These drugs are currently approved for adolescents and adults but not for children. The development status and formulations of these drugs are described in Table 5.
As new antiretrovirals become approved, there will be more options for coformulations and copackaging.
Since last year's report there have been a few changes:
An additional study is ongoing to determine safety and efficacy in children below 12 years of age and under 35kg in weight, in which the 40mg/g oral powder is being evaluated.
A randomized open-label trial, 104-0352, is comparing switching stavudine or zidovudine to tenofovir versus continuing stavudine or zidovudine in virologically suppressed children. Children under 37kg receive the oral powder and those above this weight the 300mg tablet. This trial is ongoing.25
Atazanavir: The capsule formulation is approved for children in the United States aged six years and older who are treatment-naive and weigh 15kg or more and for treatment-experienced children weighing 25kg or more. In the EU it is approved for both treatment-naive and treatment-experienced children aged six years and older and weighing 15kg or more.
Darunavir: The 75mg tablet is approved when boosted with ritonavir for children over six years of age. The dossier for the oral suspension for treatment-experienced children has been submitted for approval at the following doses: darunavir/ritonavir 25/3mg/kg bid for children weighing 10 to <15kg and darunavir/ritonavir 375/50mg bid for those weighing 15 to <20kg. There is a waiver for children under three years of age.
Dolutegravir (S/GSK-572): The IMPAACT P1093 study will work with deescalated age bands of children down to six-week-old infants. The older children will receive tablets and the younger ones the pediatric formulation. A granule formulation is in development.28
Elvitegravir: The 183-0152 study was a phase IB open label nonrandomized trial in treatment-experienced adolescents receiving 150mg qd plus a PI-optimized background regimen. Of the 21 subjects enrolled in the 10-day PK study, 9 of 11 eligible subjects continued elvitegravir plus ritonavir-boosted PI-containing optimized background regimen and completed 48 weeks of treatment.
The pediatric committee of the EMA granted positive opinion toward the cobicistat and Quad pediatric investigational plan in April 2011.
The Quad study will start after a review of data for elvitegravir and cobicistat. Age-appropriate formulations are planned.
Raltegravir: IMPAACT 1060 is investigating this drug in de-escalated age bands. Data for children six to11 years of age and interim data for those two to five years of age, receiving the chewable formulation, have been presented. A dose of 6mg/kg (maximum 300mg) has been chosen. The chewable formulation has lower oral clearance than that of the adult tablet.29
Children under two years of age are now being enrolled in a study to determine the dose of the oral granule formulation.
IMPAACT P1097 is a washout (passive) pharmacokinetc and safety study. This is the first clinical trial of an investigational antiretroviral to look at neonatal pharmacokinetics. Raltegravir crosses the placenta well. It is metabolized primarily by an enzyme in the liver (UGT-1A1), that is immature in neonates. UGT pathways increase in activity hugely in the first weeks of life. This study is recruiting mothers already receiving raltegravir in pregnancy (the infants are not dosed directly). The infants will be sampled at intervals up to 30 to 36 hours after dosing.
After a review of pharmacokinetc and safety data from both trials the company is planning a study of infants born to HIV-positive mothers from immediately after the time of birth until their HIV status has been confirmed.
Maraviroc: The A4001031 study is ongoing in children two to 12 years old who are infected with the CCR5-tropic virus (virus variants that use the CCR5 receptor for entry).30
Use of this drug requires a tropism assay, as it will not work for people with the CXCR4-tropic virus or in mixed-virus (CCR5/CXCR4) populations.
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