Acute myeloid leukemia (AML) accounts for the majority of acute leukemia cases in adults and remains a major clinical challenge (Bhansali et al., 2023), and is associated with a poor prognosis, with a 5-year survival rate of only about 30%–35% (Kantarjian et al., 2021). Among the molecular alterations in AML, FLT3 mutations are common, occurring in approximately 30% of newly diagnosed cases (Abdel-Aziz et al., 2023). The two primary types of FLT3 mutations are internal tandem duplication (ITD) mutations and tyrosine kinase domain (TKD) mutations, with reported frequencies of 30% (Vela et al., 2020; Helbig et al., 2020) and 7%–10% (Fedorov et al., 2023), respectively. FLT3-ITD is an important prognostic biomarker (Daver et al., 2019). As indicated by the 2022 European LeukemiaNet (ELN) risk stratification, patients with FLT3-ITD-positive AML are categorized as an intermediate-risk subtype (D€ Ohner et al., 2022). Targeted inhibition of FLT3 has emerged as a promising strategy in precision medicine. FLT3 inhibitors have been developed to improve treatment outcomes in high-risk AML patients, with Gilteritinib, a second-generation type I FLT3 inhibitor, being the FDA-approved monotherapy for relapsed/refractory (R/R) AML harboring FLT3 mutations (Perl, 2019). It is the first FLT3 inhibitor to be approved for monotherapy, and ex vivo studies have demonstrated that gilteritinib markedly suppresses the colony-forming capacity of FLT3-ITD–positive leukemia samples, especially in those with a high allelic ratio (AR ≥ 0.5) (Cucchi et al., 2018). Meanwhile, multiple novel agents are currently undergoing clinical development to further improve treatment efficacy and safety.

HEC73543 is a second generation, highly specific, orally administered FLT3 inhibitor, innovatively developed by Dongguan HEC Biopharmaceutical R&D Co. (Liu et al., 2025), with global intellectual property rights. It is designed for FLT3-ITD mutation AML patients, either as monotherapy or in combination with other therapeutic agents. HEC73543 is an oral tablet. It is a weak base (pKa 8.02) with high lipophilicity (logP 4.98) and exhibits very low aqueous solubility, food might affect its rate and extent of absorption by altering the luminal conditions in the human gastrointestinal tract (Budha et al., 2012). Therefore, a food-effect study is necessary to evaluate the potential impact of fed conditions on the systemic exposure of HEC73543. Before the present study, a single-agent Phase I clinical pharmacodynamic trial is ongoing, but results remain incomplete. After oral administration of HEC73543, 15 metabolites have been detected in human plasma, with the parent drug and the metabolite M3 being predominant. Urine and feces have not yet been analyzed. Nonclinical pharmacokinetic findings suggest that HEC73543 can be metabolized via CYP3A4. To our knowledge, this is the first report on the pharmacokinetics of HEC73543 in humans. We believe that publishing these data will contribute important foundational knowledge to support the ongoing clinical development of HEC73543 and provide useful references for researchers and clinicians working on FLT3-targeted therapies.

This study evaluated the PK effect of a high-fat meal on HEC73543. Compared to the fasted condition, a high-fat meal markedly enhanced the bioavailability of HEC73543, with C_max and AUC 0 – ∞ increasing 1.21-fold and 1.55-fold, respectively. Similarly, M3 exhibited 0.77-fold and 0.90-fold increase in C_max and AUC 0 – ∞ , following a comparable trend to the parent drug. These findings indicate that food intake increased the exposure to both the HEC73543 and its metabolites. Notably, t_1/2 remained unchanged, indicating that the primary effect of food was to enhance absorption rather than alter drug elimination. The reduction in CL/F was primarily attributed to the increased bioavailability of HEC73543 in the fed group, rather than a decrease in intrinsic clearance. The significant increase in AUC under high-fat meal conditions can be explained by several physiological factors: 1. Increased bile salt secretion: postprandial bile salt secretion enhances the solubility of lipophilic drugs, promoting their absorption by forming bile salt-drug micelles (Charman et al., 1997). Given that HEC73543 has high lipophilicity (logP = 4.98), its solubility is likely improved in the presence of bile salts. 2. Increased splanchnic blood flow: following food intake, splanchnic blood flow increases, which may enhance oral drug transport and absorption efficiency. Enhanced hepatic blood flow may promote drug uptake from the portal circulation, as would escaping first-pass metabolism (Yan, 2017). 3. Limited impact of pH changes. Despite HEC73543 being a weak base (pKa = 8.02), this study results suggest that pH changes did not significantly affect its absorption.

In addition, we observed high variability in PK parameters, with wide 90% CIs, such as for AUC 0 – ∞ (90% CI: 198.10–328.80%). The relatively wide CIs can be attributed to several factors. First, food effect studies involve two distinct physiological states (fed vs. fasted), and inter-subject differences in gastric pH, gastric emptying time, bile salt secretion, and intestinal motility can all impact drug absorption and metabolism. Second, the pharmacokinetic properties of HEC73543, particularly the pronounced increase in drug exposure under fed conditions, may amplify inter-individual differences in absorption and metabolism, thereby contributing to the observed variability. Third, as this is a first-in-human food-effect study with a modest sample size (n = 20 per group), it was sufficiently powered to detect a significant food effect but may not have fully accounted for inter-individual PK variability.

The impact of food on the PK profiles of FLT3 inhibitors varies. A high-fat meal slightly decreased the absorption of gilteritinib in healthy subjects, with GLSM ratios (fed/fasted %) were 74.0% for Cmax, 91.0% for AUC₇₂, 93.8% for AUC 0 – ∞ , and 94.6% for AUC_0–t (James et al., 2020). For midostaurin, co-administration with a standard or high-fat meal lowered C_max by 20%–27%, delayed T_max by 2.5–3 h, and increased AUC exposure by 1.2- to 1.6-fold compared to fasting condition (Kim, 2017). Quizartinib exhibited similar PK profiles under fasted and fed conditions. GLSM ratios (%) for fed/fasted were 91.58% (Cmax), 105.39% (AUC_0-t), and 108.39% ( AUC 0 – ∞ ) (Li et al., 2020). These differences may arise from variations in molecular structure, solubility, metabolic characteristics, and bile salt-mediated absorption mechanisms. Given the significant food effect observed with HEC73543, food intake should be considered when optimizing its administration strategy.

The safety assessments were comparable under both high-fat meal and fasted conditions. Most AEs were CTCAE Grade 1 or 2, and all adverse events resolved by the end of the study. Although the overall incidence of TRAEs was comparable between the two groups, the incidence of ≥Grade 2 TRAEs in the fed group (30%) was slightly higher than that in the fasted group (5%). Notably, three cases of Grade 2 oral ulceration were reported in the fed group. This may be mechanistically associated with FLT3 inhibition. FLT3 is a receptor tyrosine kinase expressed not only in leukemic cells but also in normal hematopoietic stem cells and mucosal epithelial progenitor cells. Inhibition of FLT3 may impair mucosal cell proliferation and repair, potentially compromising the mucosal barrier and contributing to the development of oral ulcerations. Therefore, enhanced monitoring of oral mucosal adverse events is warranted in future clinical studies, particularly under conditions associated with increased drug exposure. Although no QTcF abnormalities were observed in our food-effect study, the conclusion is constrained by the characteristics of the study population (healthy volunteers), the single-dose design, and the relatively small sample size. A comprehensive assessment of QTc liability should incorporate evidence from other clinical and nonclinical studies to determine whether a dedicated thorough QT (TQT) study is required in future development.

This study provides valuable insights into the food effect on the pharmacokinetic profile of HEC73543. However, several limitations should be acknowledged. First, the small sample size may limit the generalizability of the findings. Second, the present study was conducted exclusively in healthy Chinese adults, and HEC73543 has not yet been evaluated in clinical trials outside of China. Therefore, further studies involving diverse populations are necessary. Third, this study only evaluated a high-fat meal, while food effects may vary depending on fat content, future studies should explore moderate and low-fat meal conditions to further refine dietary recommendations.

Food intake significantly affects the PK profile of HEC73543, enhancing bioavailability and increasing systemic exposure to both HEC73543 and its metabolite M3.