Pharmacokinetics and Toxicity Assessment of Artesunate and Its Metabolite, Dihydroartemisinin, in NOD Scid Gamma Mice

Artesunate (ART) is an FDA-approved antimalarial drug and is currently being repurposed for various solid tumor treatments. However, there are no safety or pharmacokinetic (PK) studies in mice exploring its potential application in murine brain tumor models. This study aims to delineate the tolerability and PK of ART in healthy NOD scid gamma (NSG) mice to inform future efficacy studies. The maximum tolerated dose (MTD) of ART following intraperitoneal (IP) administration was determined by a single-dose escalation method. PK and brain penetration of ART and its active metabolite, dihydroartemisinin (DHA), were analyzed using an optimized LC-MS/MS bioanalytical method, following single oral and IP doses (100 mg/kg). A 350 mg/kg IP dose was well tolerated with no evidence of systemic and organ-specific toxicities. Bioanalytical assay results were linear (R2 > 0.99) over a range of 5–1000 ng/mL. An optimized extraction method employing low sample volume improved analyte recovery from brain homogenate by 2-fold. PK studies showed rapid absorption with short elimination half-lives (t1/2: 8–22 min) and higher systemic and brain exposure for ART and DHA following IP administration over oral dosing. We conclude that ART is well-tolerated at high doses (350 mg/kg, IP) in NSG mice, although repeated doses may be necessary for therapeutic efficacy in brain tumors given its rapid elimination kinetics.