E-DRUG: Why UNITAID matters for people living with HIV, TB, & malaria - market impact (3)
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Dear Chris and other e-druggers,
Thank you for your interest in DNDi's paediatric HIV project. We would like to take this opportunity to provide an update on our progress.
We know that many people are eagerly awaiting child-adapted ARV formulations for children with HIV/AIDS, as are we. Below we provide a short summary of some of the technical challenges we and our partners have encountered, which have caused some delays; a summary of where we are in the formulation development process; and an update on our plans to start rolling out better LPV/r-based treatments in an implementation study while we wait for the final "4-in-1" formulations to be available.
As a background, DNDi embarked on its paediatric HIV project after requests from organisations such as MSF, WHO, UNITAID to work on needed formulations for children living with HIV, a population that has been neglected by pharmaceutical companies. A paediatric HIV programme was set up at DNDi and experts were consulted to build a target product profile of the needed formulation in this population. In 2012 DNDi was awarded a grant by UNITAID to support this programme.
The objectives of this programme are to develop and deliver taste-masked, heat-stable lopinavir/ritonavir based formulations for infants and young children (ABC/3TC/LPV/r and AZT/3TC/LPV/r, also known as the "4-in-1s") and a standalone RTV booster to be added during TB/HIV co-treatment. The programme has been committed from the beginning to ensuring affordability and access so that these formulations can be made available rapidly to all HIV-positive children in need.
Reformulating LPV/r and RTV is not straightforward. This is why a partnership was formed with Cipla Ltd. (Indian generic manufacturer). An initial taste-masked formulation of LPV/r granules gave highly unpredictable LPV levels in adult volunteers and the formulation had to be abandoned. Following this, DNDi consulted various experts including AbbVie scientists who know the drugs well and worked closely with Cipla R&D team to develop more than 20 LPV/r based formulations, checked for chemical and physical stability and studied their bioavailability in animal models.
The challenges in working with LPV and RTV are well-known. These molecules are highly insoluble and do not cross the gastro-intestinal barrier easily (Biopharmaceutical Class IV). They taste very bitter thus cannot be made into a dispersible tablet and require melt extrusion technology to make the formulation heat-stable. Bioavailability can be severely lost when certain taste-masking agents are used.
Despite these technical challenges, our target product profile remains the same. We are not compromising the fact that the new 4-in-1s should be heat-stable, palatable and come in an easy to use fixed-dose combination (FDC).
Based on the review of all data available, we have decided to evaluate in the coming months the bioavailability of the two most promising formulations in healthy human volunteers (Phase I).
To support these objectives, DNDi has also worked on modelling and simulations of population pharmacokinetics (PK) in 2013 which integrated existing PK data of LPV, AZT, 3TC and ABC from the US, France and Africa in order to determine the optimal FDC to treat children across all weight bands. The results were adopted by the WHO paediatric ARV working group and published in Antiviral Therapy, an international, peer-reviewed journal. A pharmacokinetic study of LPV/r "super-boosting" in infants and young children co-infected with HIV and TB was started in South Africa in 2013 (recruitment ongoing, study registered at the Pan African Clinical Trial Registry with registration number PACTR201302000426554) to collect the needed PK data in young children to support the use of RTV super-boosting during TB/HIV co-infection.
While we work on the new 4-in-1s, and in order to ensure rapid access to better formulations for HIV infected children now, an implementation study entitled "Prospective study of Lopinavir based ART for HIV Infected children globally ( LIVING study)" (study registered with ClinicalTrials.gov NCT02346487) was designed with field conditions in mind and will provide early access to an alternative solid, heat stable formulation such as the LPV/r pellets developed by Cipla. Their feasibility and acceptability will be assessed. Countries engaged in this study are Kenya, Tanzania, Uganda, Zimbabwe, Malawi and South Africa. Others may follow. DNDi is also working with the civil society and communities living with HIV in an effort to raise awareness about early testing, diagnosis and treatment of HIV infection in infants and young children who have fallen out of the system.
We would like to thank all our partners and funders who are working with us or supporting us to achieve the objectives. We aim to be able to provide these much needed formulations as soon as they become available.
Please feel free to contact us should you have further questions of any sort. Thank you.
Marc Lallemant, MD, Head, Paediatric HIV Programme, DNDi
mlallemant@dndi.org
Janice Lee, MPharm, Project Manager, Paediatric HIV Programme, DNDi
jlee@dndi.org