Preclinical antileukemic activity, toxicology, toxicokinetics and formulation development of triptolide derivative MRx102.

PURPOSE: Triptolide induces cancer cell apoptosis by inhibiting RNA synthesis and signaling pathways like NF-κB. We compared triptolide prodrug MRx102 to triptolide to determine whether it displayed comparable efficacy and improved toxicology and toxicokinetic profiles.
METHODS: MV4-11 AML cells and cells from AML patients were analyzed for MRx102- and triptolide-induced cytotoxicity/apoptosis. MRx102 and triptolide were compared in toxicology/toxicokinetics studies in rat and dog using a new emulsion formulation.
RESULTS: MRx102 induced cytotoxicity in MV4-11 cells (IC50 = 15.2 nM, 7.29 nM for triptolide) and apoptosis in cells from AML patients (EC50 = 40.6 nM and 2.13 nM for triptolide). MRx102 and triptolide induced apoptosis in CD34+CD38- AML stem/progenitor cells with a similar difference in activity (EC50, MRx102 = 40.8 nM, triptolide = 2.14 nM). In a rat toxicology comparison using a new intravenous emulsion formulation, the MRx102 MTD was 4.5 mg/kg for males and 3 mg/kg for females; the triptolide MTD was 0.63 mg/kg for males and 0.317 mg/kg for females. The MRx102 NOAEL was 1.5-3.0 mg/kg, and the triptolide NOAEL was 0.05-0.15 mg/kg. Mean plasma concentrations for both MRx102 and triptolide decreased rapidly from a high C max following i.v. injection. Plasma triptolide levels stabilized at a consistent level through 2 h after MRx102 injection. Triptolide T 1/2,e values for MRx102-injected rats (~0.85 to ~3.7 h) were markedly greater than triptolide-injected rats (~0.15 to ~0.39 h), indicating more extended triptolide exposure with MRx102. MRx102 dog toxicology and toxicokinetics results are presented.
CONCLUSIONS: MRx102 was 20- to 60-fold safer than triptolide comparing rat NOAELs. This may be due to the improved toxicokinetic profile of MRx102 compared to triptolide using the emulsion formulation, with no high C max and more consistent early exposure to triptolide.