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

Muhammad Wahajuddin,Hefazat H Siddiqui,Isha Taneja,Shio K Singh,Sheelendra P Singh,Jiaur R Gayen,Kanumuri Sr Raju

doi:10.1186/s12936-015-0684-5

Abstract

BackgroundLumefantrine 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.MethodsIn 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.ResultsThe 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%.ConclusionsA 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-015-0684-5) contains supplementary material, which is available to authorized users.

Highlights

Lumefantrine is the mainstay of anti-malarial combination therapy in most endemic countries presently
The combination of a short-acting and a longacting drug is apt for treatment of malaria cases since the short-acting partner kills most of the circulating parasites while the long-acting drug clears the remaining more slowly, preventing recrudescence
Recently reports of artemisinin resistance have emerged from the Greater Mekong Subregion of Myanmar, Cambodia, Thailand, and Vietnam with increased parasite clearance times [1,4]

Summary

Introduction

Lumefantrine is the mainstay of anti-malarial combination therapy in most endemic countries presently. 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. Artemether-lumefantrine (AL) is a first-line artemisinin combination therapy (ACT) recommended by WHO for the treatment of uncomplicated Plasmodium falciparum malaria [1]. Lumefantrine (LUME) (previously known as benflumetol) was synthesized in the 1970s by the Academy of Military Medical Sciences in Beijing, China. It is a racemic fluorene derivative, named 2-dibutylamino-1-[2,7-dichloro-9-(4-chlorobenzylidene)- 9H-fluoren-4-yl]-ethanol [2,3]. It is the long-acting partner drug of the artemisinin derivative artemether, in this ACT. Recently reports of artemisinin resistance have emerged from the Greater Mekong Subregion of Myanmar, Cambodia, Thailand, and Vietnam with increased parasite clearance times [1,4]

Methods

Results

Conclusion