At the close of 2015, we would like to take this opportunity to update you on the status of DNDi’s paediatric HIV 4-in-1 formulation development programme.
DNDi’s research and development (R&D) programme aims to develop two improved child-friendly lopinavir/ritonavir (LPV/r)-based fixed dose combinations (4-in-1s) and develop a strategy to counteract the negative drug-drug interaction between lopinavir/ritonavir (LPV/r) and rifampicin during TB/HIV co-infection in children.
In 2011, we began to explore various formulation options, including prodrugs of LPV and RTV, nanosuspension and nanoparticles of LPV and RTV as well as LPV/r pellets developed by Cipla Ltd in collaboration with partners (MRC and clinical trial sites in Uganda), tested in the CHAPAS-2 study. The CHAPAS 2 results demonstrated good bioavailability of the LPV/r pellets in comparison with LPV/r syrup in children less than one year old, as well as in comparison with AbbVie’s heat stable LPV/r tablets in children aged four and above. The acceptability of the LPV/r pellets was good in the younger cohort but taste remained an issue with the older cohort. Based on these results, DNDi decided to support an additional comparative bioavailability and acceptability study of the pellets versus the liquid formulation in children aged one to four years old. Nonetheless, the LPV/r pellets still represent an improvement over the liquid formulation because they are heat stable, do not contain alcohol and other toxic excipient, are logistically easier to manage, dose, and administer.
The dossier of LPV/r pellets was submitted by Cipla Ltd. to the US Food and Drug Administration (US FDA) in 2013 and received US FDA tentative approval in May 2015.
Due to the urgency to use a better adapted formulation of LPV/r for the treatment of infants and young children in resource limited settings, DNDi decided to introduce Cipla’s LPV/r pellets in the field through implementation studies in various countries. The focus is on assessing acceptability of the formulation (ease of administration, instructions for use across different age groups, acceptability by children, caregivers, and healthcare workers) and the feasibility of using it in real life settings. These studies will provide early access to the pellets and knowledge gained will be important for treatment scale up at the country level, adoption by programs and faster product registration. The trial has started in Kenya, and we plan to extend it as soon as possible to several additional countries. The aim is for the study to support and help to accelerate the registration process, including through the WHO Prequalification Programme. It equally aims to support change of policy/treatment guidelines at country level.
In the meantime, DNDi continues its collaboration with Cipla Ltd. on improving the taste-masking of solid formulations of LPV/r and to combine LPV/r with two NRTI pairs (AZT/3TC or 3TC/ABC) in a single dosage form (fixed dose combination). Cipla Ltd. is responsible for the pharmaceutical development work (formulation screening, process development and analytics), product registration and conduct of Phase I, healthy human volunteer bioavailability studies, while DNDi manages clinical development including the implementation studies referred to above, using the LPV/r pellets developed by Cipla Ltd. While these studies provide early access to the pellets, they will be switched to the 4-in-1 formulations as soon as they are available.
A first Phase I study using a well taste masked LPV/r granules formulation was performed in healthy human volunteers in 2013. You may remember that this study showed a very large variability of Cmax and AUC’s as well as low bioavailability, approximately half of that of the reference LPV/r syrup.
The challenges of working with LPV and RTV are well-known. These molecules are highly insoluble, lipophilic and do not cross the gastro-intestinal barrier easily (Biopharmaceutical Class IV). The individual active ingredients interact with each other and with the transport and metabolism enzymes of the gut and the liver. They taste very bitter thus cannot be made into a dispersible tablet and require melt extrusion technology to enhance solubility.
Following these Phase I results, DNDi and Cipla Ltd. teams decided to evaluate different formulations of LPV/r focusing on bioavailability, stability and taste masking before moving forward to human studies. Various taste-masked granule formulations were tested while keeping coated LPV/r pellet formulations as backup options. A series of about 40 LPV/r formulations were tested in pre-clinical models to confirm bioavailability before proceeding to Phase I studies.
As of November 2015, six taste masked LPV/r formulations have been identified which could demonstrate good bioavailability. The quality of the taste masking needs to be confirmed for a few of the formulations. Three LPV/r formulations have already been tested in Phase I studies in comparison with the reference LPV/r syrup. The results showed high bioavailability of all three formulations compared to the LPV/r syrup.
This is where we are today, and are in the process of selecting the most promising formulation for further development. While the plan is to immediately switch out the ARVs currently being tested in the implementation studies to introduce the 4-in-1s, we may have to conduct a Phase II/III before being able to file for their registration.
We have also progressed on the super boosting strategy by which extra RTV is added to the existing LPV/r formulation to achieve a 1:1 ratio between LPV and RTV during TB treatment containing rifampicin was based on scant data and needed to be validated. DNDi worked with investigators from South Africa to design a pharmacokinetic study involving 90 children with the objective to show that under super boosting, LPV/r levels are similar to those obtained after HIV/TB co-therapy. Recruitment into the study commenced in January 2013 and an interim analysis was performed in 2015 and presented at a Paediatric HIV Workshop held in Vancouver in July 2015. While we still need to complete the analysis, interim results were very encouraging. We are currently completing the follow-up and analysis of this study, and plan to conduct a similar study using LPV/r pellets from Cipla Ltd. and ritonavir oral powder from AbbVie in South Africa.