The Pediatric Antiretroviral Pipeline

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.

Ones to Watch: The Innovator Pipeline

Since last year's report there have been a few changes:

• The pediatric investigational plan has begun with dolutegravir. (Shionogi/GSK/ViiV integrase inhibitor S/GSK-572).
• The cobicistat and Quad development plans were given a positive opinion by US and European Union (EU) regulatory agencies.
• The rilpivirine development plan is going ahead with the granule formulation.
• The dossier for the oral suspension of darunavir (boosted) for treatment-experienced children aged three to six years has been submitted to US and EU regulatory agencies.
• Raltegravir will be studied in neonates, first in a passive pharmacokinetic study and then dosed directly.

Nonnucleoside Reverse Transcriptase Inhibitors

• Etravirine: The recommended dose per weight band for children and adolescents aged six to 17 will be based on 5.2mg/kg bid. The company will present 24-week data from the PIANO study in experienced adolescents this year; 48 weeks of the trial will be completed in the last patient later this year.²³
• An IMPAACT 1090 protocol is in development and the first patient is expected to enroll this year.
• There is an upcoming submission for an indication for treatment experienced children and adolescents aged six to17 years and for the 25mg tablet.
• Rilpivirine: The PAINT trial is of treatment-naive adolescents, aged 12 to18 years, weighing more than 32kg and receiving 25mg qd plus a background regimen.
• TMC278-C220 is an open-label single-arm trial using the granule formulation, planned in children aged two to 12 years. This trial is taking a staggered approach and will study the drug in de-escalated age groups, down to two years of age.²⁴

Nucleotide Reverse Transcriptase Inhibitor

• Tenofovir DF: Although tenofovir was approved for adults in 2001 and is a preferred NRTI/nucleotide (Nt)RTI in international guidelines, pediatric development and approval has been slow. Bone toxicity and maturation concerns have been raised about using this drug in children.
• The 300mg tablet is approved for adolescents 12 to18 years old weighing more than 35kg in the United States. However, recently the European Medicines Agency (EMA) did not approve an indication for this age group. The decision was based on the GS-US-104-0321 trial of treatment-experienced adolescents, in which tenofovir performed no better than placebo, but this study was underpowered, and on concerns about bone toxicity.

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

Protease Inhibitors

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.

Younger children receiving atazanavir boosted with ritonavir are being studied in PACTG 1020A and PRINCE 1 and 2.^26,27

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.

Integrase Inhibitors

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.

CCR5 Receptor Antagonists

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.