| The objectives of this work are to develop a sensitive liquid chromatograph-mass spectrometry (LC-MS) assay for antimalarial artesunate (ARTS) and its active metabolite dihydroartemesinin (DHA); determine the pKa, solubility and stability of ARTS in acidic solution; evaluate the pharmacokinetic of ARTS and DHA in a phase I clinical trial; to determine effect of food, and pyronaridine on ARTS bioavailability, and develop a population pharmacokinetic model for ARTS and DHA.;A sensitive LC–MS method was developed for ARTS using solid phase extraction. The analysis requires 0.5 mL of plasma and has detection limit of 1 ng/mL. The pKa of the drug estimated using potentiometric titration at 37°C was 4.68. At pH of 1.31, the t1/2 for ARTS degradation in aqueous solution was 11.5 minutes, however at neutral pH t 1/2 was 323.3 minutes. Free acid solubility was estimated to be 168.2 μg/mL.;A phase I clinical trial was conducted in 98 healthy volunteers. Subjects were given oral doses of 2-5 mg/kg ARTS. Model independent analysis was used for the determination of pharmacokinetic parameters, and mixed linear model of analysis was used for the determination of effect of food and treatment. A population pharmacokinetic model for ARTS and DHA was developed using NONMEM.;In the single dose studies, linear increase of AUC and Cmax in a range of 2-4 mg/kg dose was observed, while in multiple dose studies, a linear increase was observed in a range of 2-5 mg/kg. Pharmacokinetics of ARTS was not affected by presence of pyronaridine, while food appears to increase tmax and MRT both for ARTS and DHA. One-compartment pharmacokinetics with first order absorption and linear elimination model was used to describe ARTS and DHA plasma concentration data. Population-based pharmacokinetic modeling using NONMEM indicated that gender was the only covariate found to effect clearance of DHA and none of the covariates tested were found to affect ARTS pharmacokinetic parameters. A simultaneous one-compartment model was also developed for ARTS and DHA and validated using bootstrap analysis. Population estimates of volume of distribution, clearance and absorption rate obtained for ARTS were 1090 L, 1200 L/hr and 2.85 1/hr, respectively. |
