ArticleCancer chemotherapy and pharmacology2026
Repurposing artesunate in acute myeloid leukemia: a pharmacokinetic rationale derived from antimalarial data.
Article in Cancer chemotherapy and pharmacology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundArtesunate (AS), a standard antimalarial, is a promising candidate for repurposing in Acute Myeloid Leukemia (AML) due to its ability to induce iron-dependent ferroptosis and apoptosis. However, a pharmacokinetic (PK) mismatch exists: while antimalarial dosing focuses on rapid parasite clearance via high-concentration peaks, AML cytotoxicity requires sustained exposure to the active metabolite, dihydroartemisinin (DHA). Currently, standard bolus dosing leads to rapid clearance (DHA t½ ≈ 1–2 h), creating a pharmacokinetic mismatch for oncology applications.Purpose: To develop a pharmacokinetic rationale for repurposing artesunate by defining an exposure-time framework that aligns its known pharmacology with the requirements for sustained cytotoxicity in AML.
methodsA pharmacokinetic model was developed for a 70 kg adult using published human data. The model integrated the rapid conversion of AS to DHA (f_conv = 0.9), respective volumes of distribution, and elimination rates(k_DHA = 0.462 h⁻¹). Three dosing strategies were simulated: intermittent bolus, a 6-hour infusion, and a 24-hour infusion. Exposure targets were anchored to a known Phase I Maximum Tolerated Dose (MTD) of 18 mg/kg.
resultsSimulations demonstrated that intermittent bolus dosing produces high, transient peaks (~11 µg/mL) followed by rapid sub-therapeutic troughs. In contrast, a 24-hour infusion (or a loading dose of 4.5 mg/kg followed by a 9 mg/kg maintenance infusion) achieved a stable DHA plateau within the ideal cytotoxic range of 0.5 - 1.5 µg/mL (≈1.6–4.8 µM) . Even when constrained by the aqueous instability of artesunate (10–12 hours), the model showed that segmented infusions could effectively maintain the required time-above-threshold.
conclusionThis study provides a pharmacokinetic rationale for transitioning from bolus to prolonged infusion strategies in AML. By reshaping the exposure profile to maintain steady low-micromolar DHA levels, artesunate can be optimized to trigger the oxidative and ferroptotic pathways necessary for antileukemic efficacy while remaining within established safety boundaries.
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