MICA: A bioequivalent study to WHO prequalify a new 15 mg primaquine tablet.
Lead Research Organisation:
University of Oxford
Department Name: Tropical Medicine
Abstract
Primaquine is an old drug and is recommended for treating malaria, a disease that affects millions of people who live mostly in tropical countries, by targeting different stages of its development.
The two main malaria species, Plasmodium falciparum and Plasmodium vivax, are transmitted to humans by infected mosquitoes which inject sporozoites when they bite humans. The sporozoites develop further in the liver and are injected back into the blood to infect red blood cells. In vivax malaria, some parasites stay in the liver as sleeping forms called hypnozoites, which periodically reactivate to set off new cycles of infection, called relapses.
The parasites in the red blood cells divide to cause illness but some are programmed to develop male and female sexual forms, called gametocytes. When mosquitoes feed, the gametocytes are taken up and undergo sexual reproduction to produce sporozoites.
Primaquine is recommended by the World Health Organization (WHO) to kill hypnozoites to prevent relapses, and block transmission in falciparum patients by killing gametocytes.
It's remarkable that primaquine is barely used by malaria control programmes to eliminate malaria even though it is so cheap. One key reason is that few drug companies show interest because profits are small and explains why we only have two tablet strengths on the market, 7.5 and 15 mg, that have been approved by stringent drug regulatory authorities. Such approval gives the public and malaria control programmes confidence that primaquine is of high quality.
Another issue is that children need small doses e.g. 2.5 and 5 mg and child-friendly formulations like granules or dispersible tablets but there are none so tablet fractions must be used which are inconvenient and inaccurate. Also, primaquine is very bitter and children don't that. What can be done to remedy this unhappy situation?
Our research group is striving to increase the number of approved primaquine tablets by WHO prequalification, equivalent to approval by a stringent drug regulatory authority. We have consulted the WHO on the necessary steps.
First, we must produce a generic 15 mg primaquine to high standards and conduct a bioequivalence study where by our test primaquine is given to healthy human adults, then, after it is no longer in the blood, reference 15 mg primaquine, produced by Sanofi. The concentrations of both primaquine formulations are compared and ours must be within 80-125% of the reference primaquine to be accepted by the WHO.
When bioequivalence is confirmed, we will prequalify 2.5, 3.75, 5, and 7.5 mg tablets by demonstrating in laboratory tests that they dissolve and have the same distribution of primaquine within the tablet as our prequalified generic 15 mg tablet. In parallel, we plan to work on developing tasteless granules and flavoured dispersible tablets to make swallowing much easier in children.
We have partnered with an enthusiastic, Indian drug company, IPCA, which will produce our high quality generic primaquine for the bioequivalence study (and future studies in patients) and help put together the dossier for submission to the WHO. Success in prequalifying primaquine is linked closely to our other work on designing the correct doses of primaquine for transmission blocking and preventing relapses and packaging so that one tablet equals one dose.
All we need our funds to carry out our work.
The two main malaria species, Plasmodium falciparum and Plasmodium vivax, are transmitted to humans by infected mosquitoes which inject sporozoites when they bite humans. The sporozoites develop further in the liver and are injected back into the blood to infect red blood cells. In vivax malaria, some parasites stay in the liver as sleeping forms called hypnozoites, which periodically reactivate to set off new cycles of infection, called relapses.
The parasites in the red blood cells divide to cause illness but some are programmed to develop male and female sexual forms, called gametocytes. When mosquitoes feed, the gametocytes are taken up and undergo sexual reproduction to produce sporozoites.
Primaquine is recommended by the World Health Organization (WHO) to kill hypnozoites to prevent relapses, and block transmission in falciparum patients by killing gametocytes.
It's remarkable that primaquine is barely used by malaria control programmes to eliminate malaria even though it is so cheap. One key reason is that few drug companies show interest because profits are small and explains why we only have two tablet strengths on the market, 7.5 and 15 mg, that have been approved by stringent drug regulatory authorities. Such approval gives the public and malaria control programmes confidence that primaquine is of high quality.
Another issue is that children need small doses e.g. 2.5 and 5 mg and child-friendly formulations like granules or dispersible tablets but there are none so tablet fractions must be used which are inconvenient and inaccurate. Also, primaquine is very bitter and children don't that. What can be done to remedy this unhappy situation?
Our research group is striving to increase the number of approved primaquine tablets by WHO prequalification, equivalent to approval by a stringent drug regulatory authority. We have consulted the WHO on the necessary steps.
First, we must produce a generic 15 mg primaquine to high standards and conduct a bioequivalence study where by our test primaquine is given to healthy human adults, then, after it is no longer in the blood, reference 15 mg primaquine, produced by Sanofi. The concentrations of both primaquine formulations are compared and ours must be within 80-125% of the reference primaquine to be accepted by the WHO.
When bioequivalence is confirmed, we will prequalify 2.5, 3.75, 5, and 7.5 mg tablets by demonstrating in laboratory tests that they dissolve and have the same distribution of primaquine within the tablet as our prequalified generic 15 mg tablet. In parallel, we plan to work on developing tasteless granules and flavoured dispersible tablets to make swallowing much easier in children.
We have partnered with an enthusiastic, Indian drug company, IPCA, which will produce our high quality generic primaquine for the bioequivalence study (and future studies in patients) and help put together the dossier for submission to the WHO. Success in prequalifying primaquine is linked closely to our other work on designing the correct doses of primaquine for transmission blocking and preventing relapses and packaging so that one tablet equals one dose.
All we need our funds to carry out our work.
Technical Summary
Primaquine (PQ) is fundamental to eliminating malaria by blocking the transmission of Plasmodium falciparum between humans and mosquitoes and killing P. vivax liver hypnozoites to prevent relapses, the main cause of the continuing vivax burden.
PQ is barely used by malaria control programmes (MCPs) for two main reasons: (i) G6PD deficiency testing, required before PQ radical cure is prescribed, is not widely available, and (ii) easy-to-use regimens of quality assured (QA) PQ tablets covering the age spectrum do not exist, thus excluding children, a key vulnerable group.
Cognizant of this substantial public health gap, the WHO called for the prequalification of 2.5, 3.75 and scored 5, 7.5 & 15 mg tablets and detailed the required process. Prequalification starts with prequalifying a scored generic 15 mg tablet through a bioequivalence (BE) study that: (i) uses the international PQ reference, the Sanofi 15 mg tablet, (ii) is conducted to WHO standards and passes WHO inspection, (iii) establishes bioequivalence, and (iv) is followed by dossier submission to the WHO.
Prequalifying the lower tablet strengths does not require more BE studies but is achieved by applying for biowaivers whereby these tablets are shown to be pharmaceutically equivalent (proportionality, dissolution properties) to the generic 15 mg tablet. Prequalification makes registration in malaria endemic countries easier and allows PQ bulk purchase and deployment using Global Fund money.
We seek funds for the BE study to engage IPCA, the industrial partner, through a MICA which provides the necessary legal framework for the planned work. Developing QAPQ as a public good dovetails with our current work of designing evidenced-based, allometrically scaled PQ regimens for transmission blocking and radical cure and bespoke to enhance patient adherence. Thus, increasing access to QAPQ will have a significant impact on malaria elimination.
PQ is barely used by malaria control programmes (MCPs) for two main reasons: (i) G6PD deficiency testing, required before PQ radical cure is prescribed, is not widely available, and (ii) easy-to-use regimens of quality assured (QA) PQ tablets covering the age spectrum do not exist, thus excluding children, a key vulnerable group.
Cognizant of this substantial public health gap, the WHO called for the prequalification of 2.5, 3.75 and scored 5, 7.5 & 15 mg tablets and detailed the required process. Prequalification starts with prequalifying a scored generic 15 mg tablet through a bioequivalence (BE) study that: (i) uses the international PQ reference, the Sanofi 15 mg tablet, (ii) is conducted to WHO standards and passes WHO inspection, (iii) establishes bioequivalence, and (iv) is followed by dossier submission to the WHO.
Prequalifying the lower tablet strengths does not require more BE studies but is achieved by applying for biowaivers whereby these tablets are shown to be pharmaceutically equivalent (proportionality, dissolution properties) to the generic 15 mg tablet. Prequalification makes registration in malaria endemic countries easier and allows PQ bulk purchase and deployment using Global Fund money.
We seek funds for the BE study to engage IPCA, the industrial partner, through a MICA which provides the necessary legal framework for the planned work. Developing QAPQ as a public good dovetails with our current work of designing evidenced-based, allometrically scaled PQ regimens for transmission blocking and radical cure and bespoke to enhance patient adherence. Thus, increasing access to QAPQ will have a significant impact on malaria elimination.
