Simultaneous quantification of proposed anti-malarial combination comprising of lumefantrine and CDRI 97-78 in rat plasma using the HPLC-ESI-MS/MS method: application to drug interaction study

• Published in: Malaria journal Vol. 14; no. 1; p. 172
• Main Authors: Wahajuddin, Muhammad, Singh, Sheelendra P, Taneja, Isha, Raju, Kanumuri S R, Gayen, Jiaur R, Siddiqui, Hefazat H, Singh, Shio K
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 22-04-2015; BioMed Central
• Subjects: Animals; Antimalarials - blood; Antimalarials - pharmacokinetics; Blood Chemical Analysis - instrumentation; Blood Chemical Analysis - methods; Bridged Bicyclo Compounds, Heterocyclic - blood; Bridged Bicyclo Compounds, Heterocyclic - pharmacokinetics; Chromatography, High Pressure Liquid; Drug Combinations; Ethanolamines - blood; Ethanolamines - pharmacokinetics; Fluorenes - blood; Fluorenes - pharmacokinetics; Male; Phenanthrenes - blood; Phenanthrenes - pharmacokinetics; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Canada; India
• DOI: 10.1186/s12936-015-0684-5
• EISSN: 1475-2875

Lumefantrine is the mainstay of anti-malarial combination therapy in most endemic countries presently. However, it cannot be used alone owing to its long onset time of action. CDRI 97-78 is a promising trioxane-derivative anti-malarial candidate that is currently being investigated as a substitute for artemisinin derivatives owing to their emerging resistance.
In the present study, a sensitive, simple and rapid high-performance liquid chromatography coupled with positive ion electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) method was developed for the simultaneous determination of lumefantrine and CDRI 97-78's metabolite, 97-63, in rat plasma using halofantrine as an internal standard. Lumefantrine and 97-63 were separated on a Waters Atlantis C18 (4.6×50 mm, 5.0 μm) column under isocratic condition with mobile phase consisting of acetonitrile: methanol (50:50, v/v) and ammonium formate buffer (10 mM, pH 4.5) in the ratio of 95:5 (v/v) at a flow rate of 0.65 mL/min.
The method was accurate and precise within the linearity range 3.9-500 ng/mL for both lumefantrine and 97-63 with a correlation coefficient (r2) of ≥0.998. The intra- and inter-day assay precision ranged from 2.24 to 7.14% and 3.97 to 5.90%, and intra- and inter-day assay accuracy was between 94.93 and 109.51% and 96.87 and 108.38%, respectively, for both the analytes. Upon coadministration of 97-78, the relative bioavailability of lumefantrine significantly decreased to 64.41%.
A highly sensitive, specific and reproducible high-throughput LC-ESI-MS/MS assay was developed and validated to quantify lumefantrine and CDRI 97-78. The method was successfully applied to study the effect of oral co-administration of lumefantrine on the pharmacokinetics of 97-78 in male Sprague-Dawley rats and vice versa. Co-administration of 97-78 significantly decreased the systemic exposure of lumefantrine.