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A phase 1, placebo controlled, randomised, single ascending dose study and a volunteer infection study to characterize the safety, pharmacokinetics and antimalarial activity of the Plasmodium phosphatidylinositol 4-kinase inhibitor MMV390048.


ABSTRACT:

Background

MMV390048 is the first Plasmodium phosphatidylinositol 4-kinase inhibitor to reach clinical development as a new antimalarial. We aimed to characterize the safety, pharmacokinetics and antimalarial activity of a tablet formulation of MMV390048.

Methods

A two-part, phase 1 trial was conducted in healthy adults. Part one was a double-blind, randomised, placebo-controlled, single ascending dose study consisting of three cohorts (40, 80, 120 mg MMV390048). Part two was an open-label volunteer infection study using the Plasmodium falciparum induced blood-stage malaria model consisting of two cohorts (40, 80 mg MMV390048).

Results

Twenty four subjects were enrolled in part one (n=8 per cohort, randomised 3:1 MMV390048:placebo) and 15 subjects were enrolled in part two (n=7 and n=8; 40 and 80 mg cohort respectively). One subject was withdrawn from part 2 (80 mg cohort) before dosing and was not included in analyses. No serious or severe adverse events were attributed to MMV390048. The rate of parasite clearance was greater in subjects administered 80 mg compared to those administered 40 mg (clearance half-life 5·5 h [95% CI: 5·2-6·0] vs 6·4 h [95% CI: 6·0-6·9]; P=0·005). Pharmacokinetic/pharmacodynamic modeling estimated a minimal inhibitory concentration of 83 ng/mL, a minimal parasiticidal concentration that would achieve 90% of the maximum effect of 238 ng/mL, and predicted a single 120 mg dose would achieve an adequate clinical and parasitological response with 92% certainty.

Conclusions

The safety, pharmacokinetics, and pharmacodynamics of MMV390048 support its further development as a partner drug of a single-dose combination therapy for malaria.

SUBMITTER: McCarthy JS 

PROVIDER: S-EPMC7744986 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Publications

A Phase 1, Placebo-controlled, Randomized, Single Ascending Dose Study and a Volunteer Infection Study to Characterize the Safety, Pharmacokinetics, and Antimalarial Activity of the Plasmodium Phosphatidylinositol 4-Kinase Inhibitor MMV390048.

McCarthy James S JS   Donini Cristina C   Chalon Stephan S   Woodford John J   Marquart Louise L   Collins Katharine A KA   Rozenberg Felix D FD   Fidock David A DA   Cherkaoui-Rbati Mohammed H MH   Gobeau Nathalie N   Möhrle Jörg J JJ  

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20201201 10


<h4>Background</h4>MMV390048 is the first Plasmodium phosphatidylinositol 4-kinase inhibitor to reach clinical development as a new antimalarial. We aimed to characterize the safety, pharmacokinetics, and antimalarial activity of a tablet formulation of MMV390048.<h4>Methods</h4>A 2-part, phase 1 trial was conducted in healthy adults. Part 1 was a double-blind, randomized, placebo-controlled, single ascending dose study consisting of 3 cohorts (40, 80, 120 mg MMV390048). Part 2 was an open-label  ...[more]

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