Rapid resolution liquid chromatography-mass spectrometry determination of SAR97276 in monkey matrices. Pharmacokinetics in rhesus monkey infected by Plasmodium cynomolgi

Since several years, we developed a new class of antimalarial drugs targeting the phospholipid metabolism of the Plasmodium falciparum malaria parasite. The bis-thiazolium compound, SAR97276, is the lead compound and is now in clinical development. In this paper, we applied the fast rapid resolution liquid chromatography-mass spectrometry technique to the analysis of SAR97276 in monkey matrices. The sample pre-treatment procedure involved an acidic precipitation of proteins followed by solid-phase extraction. The monocationic compound, T2, was used as internal standard. A good separation was achieved on a Zorbax eclipse XDB C8 column (1.8 μm, 50 mm × 4.6 mm) with a mobile phase consisting of acetonitrile-trimethylamine-formate buffer (pH 3) gradient elution. The total run time was 8 min. Inter-assay precisions were <10% in plasma, and ≤12% in blood. Accuracies were 96.6-98.1% (plasma) and 94.5-103% (blood). Mean extraction efficiencies were >85% in plasma, and >75% in blood. The lower limits of quantitation were 3.3 μg/l in plasma and 3.3 μg/kg in blood. No matrix effect was observed. This newly developed method is sensitive, selective, reproducible, and stability indicating. It was used to analyse samples taken during a pharmacokinetic/pharmacodynamic study carried out in infected Rhesus monkey by Plasmodium cynomolgi as part of the ongoing development of SAR97276.