Safety and Tolerability of PYR co-administered with PQP (fasted) in HV
Research type
Research Study
Full title
A randomised, double-blind, placebo controlled, parallel group study in healthy adult volunteers to determine the safety and tolerability of pyronaridine (PYR) co-administered with piperaquine (PQP) under fasted conditions
IRAS ID
307070
Contact name
Ulrike Lorch
Contact email
Sponsor organisation
Medicines for Malaria Venture
Eudract number
2021-005698-21
Clinicaltrials.gov Identifier
Duration of Study in the UK
0 years, 3 months, 3 days
Research summary
Summary of Research
The study is a clinical trial involving two medicines called pyronaridine (PYR) and piperaquine (PQP) which, in combination with artesunate (ART) and dihydroartemisinin (DHA) respectively, have been in clinical use for over 20 years to treat acute episodes of malaria.
PYR and PQP are both known to be well tolerated and provide effective treatment for
malarial infection when administered in their licensed combinations, but have not been administered together in combination before.
This new combination is being considered for development for malaria prevention (i.e. chemoprophylaxis) in sub-Saharan Africa and therefore, the trial participants will be exclusively
drawn from a population from that origin.The trial is a single centre (only to occur at Richmond Pharmacology), randomised, double-blind, placebo controlled, parallel group study in healthy adult male and female participants to determine the tolerability and safety of pyronaridine (PYR) co-administered with piperaquine (PQP) under fasted conditions. Participants will be dosed in a fasted state as this is known to improve the cardiac safety of PQP.
An initial sentinel cohort of ten participants is planned to commence the trial. Four participants will receive the combinations of PYR + PQP, two will receive PYR + placebo, two will receive PQP + placebo and two will receive the combined placebos. Provided the sentinel cohort doses are well tolerated and safe, the remaining 30 participants are planned to be enrolled and randomised to one of the four treatments in a 2:1:1:1 ratio.The total number (sentinel cohort + subsequent cohort) of participants receiving each combination of IMP/placebo once daily for three days is described below:
•Treatment 1 (N=16): PYR + PQP
•Treatment 2 (N = 8): PYR + placebo for PQP
•Treatment 3 (N = 8): placebo for PYR + PQP
•Treatment 4 (N = 8): placebo for PYR + placebo for PQPSummary of Results
This study was conducted to find out how safe and well tolerated the investigational products, piperaquine (PQP) and pyronaridine (PYR), are in humans when taken alone and in combination and whether they affect the heart’s electrical system. Both PQP and PYR have been in clinical use for over 20 years to treat acute malaria but have not previously been used in combination. In addition, the study looked at the pharmacokinetic profile (the calculation of how much of the medicines reach the bloodstream after they are swallowed and how long they stay in the body) of the investigational products when taken alone and in combination, and how, based on the participant genes, different people process the medicines.40 healthy male or female participants aged between 18-45 whose biological parents are black and of sub-Saharan origin were planned to be enrolled.
37 participants were enrolled, having met all of the protocol inclusion and exclusion criteria and were randomised to the following treatment groups:
15 participants were enrolled in Treatment group 1 (pyronaridine and piperaquine)
8 participants were enrolled in Treatment group 2 (pyronaridine + placebo for piperaquine)
8 participants were enrolled in Treatment group 3 (placebo for pyronaridine + piperaquine)
6 participants were enrolled in Treatment group 4 (placebo).All of the participants completed the study and blood samples were analysed for safety, tolerability and pharmacokinetics.
Duration of Treatment - A single dose (based on the weight of the participant) of pyronaridine or placebo, as well as a single dose of piperaquine or placebo, was administered orally to participants in a fasted state on the mornings of Day 1, Day 2 and Day 3 of the study.
Results
Taking pyronaridine and piperaquine daily for 3 days in a fasted state to healthy participants of African origin, at the doses normally prescribed for malaria treatment, was not associated with any unexpected safety or tolerability findings when compared with the two drugs when administered on their own.No serious adverse events or pregnancies were reported in this study.
Piperaquine administration was associated with an expected change (previously reported when using this product) in the heart's electrical system (prolonged QTc interval), this change was transitory and occurred at approximately the time that the maximum amount of piperaquine reached the blood stream. No intervention was required, and the participants heart rhythm returned to normal.
Previous reports of temporary increases in liver enzymes (proteins that speed up chemical reactions in the body) have been reported with pyronaridine use, and these were also observed in this study.
The number, timing, and severity of these increases in liver enzymes indicates that co-administration of piperaquine did not affect the results. Given the low number of participants in this study this conclusion needs to be taken with caution.The interpretation of the pharmacokinetic (how much of the medicines reach the bloodstream after they are swallowed and how long they stay in the body) is not conclusive for a formal evaluation of risk of Drug x Drug Interaction due to the low numbers of participants in each treatment group, coupled with significant variation (up to 25%) in the measurements taken on different days within a single participant.
There was an mild increase in the exposure of both pyronaridine (maximum increase on Day 2) and piperaquine (maximum increase on Day 1) when these products were taken together compared to when taken alone.
More studies will be needed to fully understand the reasons behind the pharmacokinetic changes that have been seen in this study when pyronaridine and piperaquine are taken together.
After completion of the study and analysis of safety and pharmacogenetic data, it was decided not to analyse blood samples for any genetic variations between participants that may have impacted the way medicines are processed in the body.
REC name
South Central - Berkshire B Research Ethics Committee
REC reference
21/SC/0374
Date of REC Opinion
5 Jan 2022
REC opinion
Further Information Favourable Opinion