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Background <p>Artesunate (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.</p> Methods <p>A 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.</p> Results <p>Simulations 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.</p> Conclusion <p>This 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.</p>

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Repurposing artesunate in acute myeloid leukemia: a pharmacokinetic rationale derived from antimalarial data

  • 期刊论文

  • 发表日期：

    2026年4月29日

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  • Woei Jye Ong

摘要

Background

Artesunate (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.

Methods

A 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.

Results

Simulations 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.

Conclusion

This 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.