Preclinical Antimalarial Combination Study of M5717, a Plasmodium falciparum Elongation Factor 2 Inhibitor, and Pyronaridine, a Hemozoin Formation Inhibitor

Abstract

Antimalarial drug resistance in the Plasmodium falciparum parasite poses a constant challenge for drug development. To mitigate this risk, new antimalarial medicines should be developed as fixed-dose combinations. Assessing the pharmacodynamic interactions of potential antimalarial drug combination partners during early phases of development is essential in developing the targeted parasitological and clinical profile of the final drug product. Here, we have studied the combination of M5717, a P. falciparum translation elongation factor 2 inhibitor, and pyronaridine, an inhibitor of hemozoin formation. Our test cascade consisted of in vitro isobolograms as well as in vivo studies in the P. falciparum severe combined immunodeficient (SCID) mouse model. We also analyzed pharmacokinetic and pharmacodynamic parameters, including genomic sequencing of recrudescent parasites. We observed no pharmacokinetic interactions with the combination of M5717 and pyronaridine. M5717 did not negatively impact the rate of kill of the faster-acting pyronaridine, and the latter was able to suppress the selection of M5717-resistant mutants, as well as significantly delay the recrudescence of parasites both with suboptimal and optimal dosing regimens.

<p>Recent Progress in the Development of New Antimalarial Drugs with Novel Targets</p>

“…Similarly, M5717 (previously DDD107498), a selective inhibitor of the 80S ribosome interacting PfEF2, is currently in phase 1 study, validating the potential of the PfEF2as an effective target for antimalarial drugs. 88,90…”

<p>Antimalarial Drug Resistance and Novel Targets for Antimalarial Drug Discovery</p>

“…Drugs currently in Phase I, II and III trials for blood-stage treatments of malaria includes KAE609 (cipargamin) inhibit Na+-TPase 4 ion channel, 116 KAF156/GNF156/(Cyclic amine resistance unknown mechanism of locus (PfCARL) inhibitor), 117 Albitiazolium/SAR9727/(Inhibit the transport of choline into the parasite), 118 DSM265 (Inhibit dihydroorotate dehydrogenase enzyme), 119 Methylene Blue (Prevents haem polymerisation by inhibiting P. falciparum glutathione reductase), 120 Sevuparin/DF02/(Anti-adhesive polysaccharide derived Blocks merozoite invasion and sequestration), 121 MMV048 (Inhibiting the parasite enzyme phosphoinositol 4-kinase enzyme), 122 MMV390048 (Phosphatidylinositol 4-kinase (PfPI4K) inhibitor), 123 Fosmidomycin + piperaquine (DOXP pathway), Artefenomel (oz439) + Piperaquine (Synthetic endoperoxide), 124 OZ277+ Piperaquine (Inhibit Pf-encoded sarcoplasmic endoplasmic reticulum calcium ATPase), P218 (PfDHFR inhibitor), 125 M5717/DDD498/(Protein-making machinery of the malaria parasite, liver- stage P. falciparum), 126 SJ733 (The P-type Na+–ATPase transporter), 116 and Spiroindolone (cipargamin) inhibits PfATP4, a parasite plasma membrane Na+-ATPase that regulates sodium (maintains low-level Na + in the cytosol) and osmotic homeostasis. Cipargamin is used in the treatment of falciparum and vivax malaria.…”

Malaria PK/PD and the Role Pharmacometrics Can Play in the Global Health Arena: Malaria Treatment Regimens for Vulnerable Populations

“…Standard 48 hour in vitro parasite sensitivity experiments with synchronized parasite cultures are likely a poor surrogate for drug efficacy over a 1–2 week treatment duration with drug combinations. In vitro systems to assess P. falciparum drug sensitivity and a mouse model with P. berghei (rodent specific parasite species) allowed for a pipeline of new antimalarial drug candidates, but mechanistic PK/PD models based on preclinical data have overpredicted clinical benefits 94‐96 . Recent developments have focused on creating a mouse model able to sustain P. falciparum infections and now a humanized mouse model engrafted with human erythrocytes exists 97 .…”

“…In vitro systems to assess P. falciparum drug sensitivity and a mouse model with P. berghei (rodent specific parasite species) allowed for a pipeline of new antimalarial drug candidates, but mechanistic PK/PD models based on preclinical data have overpredicted clinical benefits. 94 , 95 , 96 Recent developments have focused on creating a mouse model able to sustain P. falciparum infections and now a humanized mouse model engrafted with human erythrocytes exists. 97 Unfortunately, this advanced model still overpredicts the clinical benefit of drug candidates.…”