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Piperaquine-dihydroartemisinin combination is the latest addition to the repertoire of ACTs recommended by the World Health Organization (WHO) for treatment of falciparum malaria. Due to the increasing resistance to artemisinin derivatives, CSIR-CDRI has developed a prospective short acting, trioxane antimalarial derivative, CDRI 97-78. In the present study, a liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) method for the simultaneous quantification of piperaquine (PPQ) and 97-63, the active metabolite of CDRI 97-78 found in vivo, was developed and validated in 100 μL rat plasma using halofantrine as internal standard. PPQ and 97-63 were separated using acetonitrile:methanol (50:50, v/v) and ammonium formate buffer (10 mM, pH 4.5) in the ratio of 95:5(v/v) as mobile phase under isocratic conditions at a flow rate of 0.65 mL/min on Waters Atlantis C18 (4.6 × 50 mm, 5.0 µm) column. The extraction recoveries of PPQ and 97-63 ranged from 90.58 to 105.48%, while for the internal standard, it was 94.27%. The method was accurate and precise in the linearity range 3.9-250 ng/mL for both the analytes, with a correlation coefficient (r) of ≥ 0.998. The intra- and inter-day assay precision ranged from 2.91 to 8.45% and; intra- and inter-day assay accuracy was between 92.50 and 110.20% for both the analytes. The method was successfully applied to study the effect of oral co-administration of PPQ on the pharmacokinetics of CDRI 97-78 in Sprague-dawley rats and vice versa. The co-administration of CDRI 97-78 caused significant decrease in AUC0-∞ of PPQ from 31.52 ± 2.68 to 14.84 ± 4.33 h*µg/mL. However, co-administration of PPQ did not have any significant effect on the pharmacokinetics of CDRI 97-78., (Copyright © 2015 John Wiley & Sons, Ltd.)

The pharmacokinetic compatibility of short-acting CDRI candidate antimalarial trioxane derivative, 99-411, was tested with long-acting prescription antimalarials, lumefantrine and piperaquine. LC-ESI-MS/MS methods were validated for simultaneous bioanalysis of lumefantrine and 99-411 and of piperaquine and 99-411 combinations. The interaction studies were performed in rats using these validated methods. The total systemic exposure of 99-411 increased when administered with either lumefantrine or piperaquine. However, co-administration of 99-411 significantly decreased the systemic exposure of piperaquine by half-fold while it had no effect on the kinetics of lumefantrine. 99-411, thus, seemed to be a good alternative to artemisinin derivatives for combination treatment with lumefantrine. To explore the reason for increased plasma levels of 99-411, an in situ permeability study was performed by co-perfusing lumefantrine and 99-411. In presence of lumefantrine, the absorption of 99-411 was significantly increased by 1.37 times than when given alone. Lumefantrine did not affect the metabolism of 99-411 when tested in vitro in human liver microsomes. Additionally, ATPase assay suggest that 99-411 was a substrate of human P-gp, thus, indicating the probability of interaction at the absorption level in humans as well.

Malaria is the leading parasitic disease in emerging countries. Therapeutic drug monitoring of antimalarial drugs is becoming increasingly important due to their spreading resistance. Measuring systemic antimalarial drug concentrations is also vital for safety and PK evaluations during clinical development. The dried blood spot (DBS) technique is a convenient alternative sample-collection method to venipuncture, especially in resource -limited areas where the clinical studies of antimalarials are usually carried out. Various bioanalytical methods for antimalarial drug estimation utilizing DBS sampling have been reported. This review discusses the applicability and relevance of DBS in quantitative assessment of antimalarial drugs, the advantages and drawbacks of DBS, and the difficulties encountered during its implementation.

Lumefantrine has been reported to be mainly bio-transformed by cytochrome P450 isozyme 3A4 to desbutyl-lumefantrine (DLF) in human liver microsomes. Since CYP3A is expressed in a sex specific manner in rats, it could be expected that the pharmacokinetics of lumefantrine would be changed in male rats compared with those in female rats. The pharmacokinetics of lumefantrine and its active metabolite DLF were evaluated after intravenous (0.5 mg/kg) and oral (20 mg/kg) administration of lumefantrine to male and female Sprague-Dawley rats. The quantitative bioanalysis was carried out by the liquid chromatography tandem mass spectrometry method. After intravenous and oral administration of lumefantrine the area under the curve (AUC) of lumefantrine was significantly higher in female rats than that in male rats, whereas the AUC of DLF was significantly lower in female rats in comparison with male rats. This lower AUC of DLF in female rats could have been due to reduced metabolism of lumefantrine in female rats. The bioavailability (%F) of lumefantrine was 1.66 times higher in male rats than that in female rats., (Copyright © 2012 John Wiley & Sons, Ltd.)

Objectives: The aim of the study was to predict human intestinal permeability and the fraction absorbed of an oral dose of a promising trioxane anti-malarial drug (CDRI 99/411) using the single-pass intestinal perfusion technique (SPIP) in rats., Methods: Effective permeability coefficients (P eff) in anaesthetized rats were determined for marker compounds and the trioxane derivative 99/411. Drug solution in perfusion buffer was perfused through intestine with a flow rate of 0.2 ml/min and samples were taken from an outlet tubing at different time points up to 120 min. Drug concentrations in samples were determined using RP-HPLC., Key Findings: The effective permeability coefficient values of marker compounds obtained in rats were compared with published data for human intestinal permeability (P eff (human)) and human fraction absorbed (F(a) (human)) to establish an in-house model. Strong correlations were found between rat and human values for markers (P eff (human) = 1.039 P eff (rat) - 0.1815; R2 = 0.970 and F(a) (human) = 0.15621n (P eff (rat) + 0.7232; R2 = 0.927). Subsequently the human permeability and fraction dose absorbed in human were predicted for 99/411 using the obtained rat permeability value and established correlations. P eff in human predicted from the model was found to be 7.05 x 10(-4) cm/s and F(a) value in human was predicted around 1., Conclusions: Considering the high correlation of rat Peff values with those of human reported values, it can be concluded that the developed in-house model is reliable and can be used preliminarily, to predict human permeability and fraction dose absorbed of any test compound. From predicted results, 99/411 was found to have high permeability and possibly complete absorption in human.

A simple, sensitive and rapid method for the analysis of lumefantrine in rat plasma using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) was developed. Detection was performed by positive ion electrospray ionization (ESI) in multiple reaction monitoring (MRM) mode. The method included a chromatographic run of 5 min using a C(18) analytical column and the calibration curve was linear over the concentration range of 2-500 ng/mL with a correlation coefficient (r) of 0.996 or better. The intra- and inter-day assay precision ranged from 1.5 to 7.5% and 5.5 to 7.7%, respectively, and intra- and inter-day assay accuracy was between 91.3-109.7% and 97.0-104.7%, respectively. The method was successfully applied for the pharmacokinetic study in rats.