Developing paediatric primaquine (DPP)

There are no quality-assured paediatric-friendly primaquine (PQ) formulations approved to international standards and this greatly limits malaria elimination because primaquine is used as radical cure of Plasmodium vivax and P. ovale and transmission-blocking of P. falciparum. Therefore, its therapeutic reach is global. Furthermore, the DPP study goes an extra mile to ensure children find these tablets palatable. The prequalification pathway must commence with prequalifying a scored generic 15 mg primaquine tablet by performing a bioequivalence study against the Sanofi 15 mg reference tablet in adult healthy volunteers according to WHO standards. Assuming bioequivalence is confirmed, a dossier will be submitted to the WHO to prequalify the scored 15 mg tablet. This will be followed by a line extension, that is, prequalifying all the lower tablet strengths (2.5 – 7.5 mg) requested by the WHO. This is done by showing their proportionality with reference to the 15 mg tablet and applying for biowaivers leading to prequalification. In parallel, we will undergo preliminary work on primaquine granules and conduct gustatory sensory studies to ascertain the best flavours that mask primaquine’s bitter taste and select the two best to produce clinical batches for the two field trials. These trials will assess the efficacy, tolerability, pharmacokinetics and acceptability of daily primaquine as radical cure of vivax-infected Ethiopians of all ages and single low-dose primaquine for transmission-blocking in children < 5 years old in Burkina Faso with falciparum malaria. In Ethiopia, several primaquine-containing prototype blisters will be evaluated for user-friendliness by patients and carers.  Following prequalification, we will register primaquine starting with countries in the WHO accelerated system and develop post-marketing pharmacovigilance, partnering with National Malaria Control Programmes and regulatory authorities. The study also provides a network for mutual support, capacity building covering drug development and malaria and developing primaquine as a public good. In the first two years of the project implementation phase, the study is moving forward though some deviations from the original plan were necessary mostly due to the restrictions posed by the COVID-19 pandemic. With travel becoming easier, the coordination team was able to travel in August 2022 to both IPCA and Bilcare, in India, to Ethiopia to visit the AHRI teams in Addis Ababa and Arba Minch (the field site). These visits were not only necessary and also very helpful for clarifying the administrative, technical and operational requirements of the project, reviewing work plans and timelines, and discussings pressing issues, challenges, and ways to strengthen future collaboration.  In total, 15 different products must be manufactured by IPCA, which is a challenging demand, while the company is still recovering from the effects of the COVID-19 pandemic. This has resulted in production delays across a range of their activities and a clear way for the flavoured tablets is being discussed with the company. The ‘taste-masking’ and the ‘granules and packaging’ components have made significant progress. Results have shed new light that will impact the development plan of the flavoured paediatric primaquine tablets. Thanks to additional funds from Oxford University (Medical and Life Sciences Translational Fund), work began on finalising the formulation of primaquine-flavoured granules. Sensory studies were performed to assess the bitterness level of different solutions of primaquine and the results show that the 15 mg tablet dry mix had the same level of bitterness as the 7.5 mg dry mix, implying that the 7.5 mg tablet mix requires the same amount of flavouring blend as the 15 mg tablet to obtain a sufficiently good taste-masking effect. Consequently, the 7.5 mg flavoured tablets cannot be prepared proportionally from the 15 mg flavoured tablet, i.e. the 15 mg flavoured tablet cannot be used to obtain the biowaiver for the lower tablet strengths. The lower strengths will have to be manufactured proportionally from the 7.5 mg flavoured tablet. The ‘bioequivalence’ study in Ethiopia will compare 2 tablets of 7.5 mg flavoured primaquine against the 15 mg Sanofi primaquine tablet, this change required a study protocol amendment, which was approved by OxTREC in April 2022 and by the AHRI IRB in September 2022. Regarding the vivax ‘radical cure’ field trial, approvals were secured from the OxTREC, AHRI IRB and national EC committee. The manufacture of all the primaquine tablets with certificates of analysis started in early 2023, and once obtained, the team will apply for the import permit from the Ethiopian FDA. The preparation of treatment cards has been discussed in-person with Bilcare and it will be coordinated jointly with IPCA. The ‘transmission blocking’ study in Burkina Faso has been approved by the local EC committee, and insurance cover is in place. The team can only apply for the import permit after the primaquine clinical batches have been produced and their certificates of analysis are available. The regulatory authorities meet 4 times/year. The study timeline is mostly dependent on the availability of primaquine tablets and the malaria season (June to December). Data Management, quality and monitoring activities for all 3 clinical trials are progressing and we plan site visits when we have firm dates for study execution. The Communication, Dissemination and Exploitation work has focused on promoting the project (by presentations and posters) at various international meetings.

DPP project website

Drug-based Strategies
P. vivax
Vulnerable Populations

Sep 2020 — Apr 2025

$3.84M

Burkina Faso
Ethiopia
France
United Kingdom