Pharmacokinetic and safety profiles of MIT-001, a novel ferroptosis in

Introduction

Reactive oxygen species (ROS) are chemically reactive molecules that arise from the incomplete reduction of oxygen.¹ ROS are generated from extracellular sources, such as NADPH oxidases (NOXs), or from the mitochondrial respiratory chain.² At controlled levels, ROS function as signaling molecules that regulate cellular pathways.² However, an imbalance between ROS production and antioxidant defenses leads to elevated ROS levels, causing oxidative injury that damages lipids, proteins, and DNA, ultimately resulting in cell death.³

Oxidative injury caused by ROS induces the release of intracellular high-mobility group box 1 (HMGB1), a pro-inflammatory mediator of necrosis.⁴ ROS also activate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a transcription factor that upregulates pro-inflammatory molecules, including tumor necrosis factor (TNF) and NOX2.² Abnormally elevated ROS production during chemotherapy or radiotherapy triggers pro-inflammatory signaling cascades, further exacerbates oxidative stress, and leads to mucosal epithelial cell damage accompanied by necrotic ulcerative lesions, as observed in oral mucositis (OM).⁵

MIT-001, also known as NecroX-7 or LC28-0126, is a novel small-molecule inhibitor of ferroptosis and necrosis that functions as a mitochondria-targeted ROS scavenger, with therapeutic potential for treating oxidative stress- or ferroptosis-related diseases (Figure 1).⁶ By inhibiting the expression of HMGB-1 and suppressing NF-κB activity, MIT-001 has demonstrated the potential to reduce inflammation and prevent necrotic cell death in nonclinical studies.^7–9 It decreases the secretion of inflammatory cytokines, such as monocyte chemoattractant protein 1, TNF-α, and interleukin-1β, and inhibits NOX activity by modulating the Ncf1 and Rac2 genes, which encode NOX activators.^10,11

Figure 1 Chemical structure of MIT-001.

OM is a frequent complication of cancer treatment, resulting from excessive ROS production in cells damaged during chemotherapy or radiotherapy.^5,12–15 MIT-001 is expected to prevent or mitigate the severity of OM by suppressing inflammation associated with elevated ROS levels.⁷ Phase 2 clinical trials (ClinicalTrials.gov identifier: NCT04651634, NCT05493800) are currently underway to evaluate the efficacy of MIT-001 in preventing and treating OM. These trials target patients with locally advanced head and neck squamous cell carcinoma undergoing concurrent chemoradiotherapy and patients with lymphoma or multiple myeloma receiving conditioning chemotherapy followed by autologous hematopoietic stem cell transplantation. In addition to its potential in treating OM, MIT-001 is anticipated to benefit other inflammatory conditions, such as graft-versus-host disease.⁹

MIT-001 was originally developed as an intravenous (IV) formulation. In previous studies, the IV formulation of MIT-001 was well tolerated, with no dose-limiting toxicities, and systemic exposure increased proportionally across a single-dose range of 0.3–200 mg and a multiple-dose range of 3–30 mg.^16,17 The IV formulation showed a multi-compartmental disposition, with a mean terminal elimination half-life (t_1/2) of 27.3 to 45.4 h. With less than 5% of unchanged MIT-001 excreted in the urine, hepatic metabolism is presumed to be its primary elimination route (Supplementary Table 1). ^16,17 During multiple dosing, a mean accumulation ratio (R_ac) of 2.58 to 2.79 was reported.¹⁷

To enhance the ease of self-administration for patients and improve convenience for long-term management, a novel subcutaneous (SC) formulation of MIT-001 is currently under development. Compared to IV administration, SC delivery is expected to result in slower absorption, potentially leading to a more stable systemic exposure profile. While the IV formulation demonstrated a favorable systemic safety profile, SC administration presents new considerations, such as local injection site reactions and altered bioavailability, which have not been characterized. Therefore, understanding the pharmacokinetic (PK) and safety profiles of the SC formulation is essential to support appropriate dose selection and inform further formulation development for long-term and outpatient use.

This study aimed to evaluate the PK and safety profiles of MIT-001 after SC administration in healthy participants.

Materials and Methods

The study protocol was approved by the Ministry of Food and Drug Safety and the Institutional Review Board (IRB) of Seoul National University Hospital (ClinicalTrials.gov identifier: NCT05389696) in Korea. The study was conducted in compliance with the Declaration of Helsinki and the Korean Good Clinical Practice guidelines. Written informed consent forms were obtained from all participants prior to screening.

Study Population

Healthy Korean participants aged 19–45 years with a body mass index (BMI) between 18.0 and 27.0 kg/m² were recruited. Participants were screened based on their medical history, physical examination, 12-lead electrocardiograms (ECGs), vital signs (blood pressure, pulse rate, and body temperature), and clinical laboratory tests (hematology, blood chemistry, coagulation, urinalysis, and serology). Exclusion criteria included any medical history or condition likely to affect PKs, including clinically significant hepatic or renal disease. Participants were also excluded if they had a history of drug abuse, positive urine drug screening result, smoking, or regular alcohol consumption, or recent use of prescription drugs within 2 weeks or herbal medicines within 2 weeks, or over-the-counter drugs or vitamin supplements within 1 week prior to the first administration of the investigational product (IP).

Study Design

A randomized, double-blind, placebo-controlled, dose-escalation study was conducted in two parts: single ascending dose (SAD) and multiple ascending dose (MAD) studies (Figure 2). In the SAD study, participants received a single SC dose of MIT-001 at 10 mg, 20 mg, or 40 mg. Participants in the 40 mg cohort also received a single IV dose of MIT-001 40 mg in a crossover manner after a 14-day washout period. In the MAD study, participants received SC doses of MIT-001 at 20 mg or 40 mg once daily for seven consecutive days. Each cohort included eight participants randomized in a 3:1 ratio to receive either MIT-001 or placebo. Dose escalation decisions were based on safety and tolerability data from the previous dose levels.

Figure 2 Study design. Abbreviation: SC, subcutaneous; IV, intravenous; HOS, hospitalization; DIS, discharge; OPV, outpatient visit; PSV, post-study visit.

In the SAD study, blood samples for PK analysis were collected at pre-dose and 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48, 96, and 144 h post-dose for the 10 mg and 20 mg cohorts. For the 40 mg cohort, blood samples were collected at the same time points after SC administration, and at pre-dose and 0.17 (10 min), 0.33 (20 min), 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 96, and 144 h after IV administration (0.5h infusion duration). In the MAD study, blood samples were collected at pre-dose and 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 h after the first administration (Day 1), at pre-dose from Day 5 to Day 7, and at 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48, 96, 144, and 216 h after the last (7^th) administration (Day 7). At each blood sampling point, approximately 4 mL of blood was collected into a sodium heparin tube, centrifuged at 3,000 rpm for 10 min at 4°C. The plasma aliquots were mixed with acetonitrile containing 0.005% ascorbic acid in a 10:1 ratio for matrix matching and stored at −70°C until analysis.

Bioanalytic Methods

Plasma concentrations of MIT-001 were quantified using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Analyses were conducted using a Shimadzu LC system (Shimadzu, Kyoto, Japan) coupled with an AB SCIEX API 5000 mass spectrometer (Applied Biosystems/MDS Sciex, Foster City, CA, USA) in positive ion electrospray ionization mode. Separation was performed using a C18 column (2.1 × 30 mm, 3 μm particle size; ACE 3 C18; Aberdeen, Scotland) maintained at 40°C. The mobile phase consisted of water containing 0.1% formic acid and acetonitrile containing 0.1% formic acid, delivered at a flow rate of 0.5 mL/min. Mass transitions for multiple reaction monitoring were 440.0 → 305.4 m/z for MIT-001 and 445.1 → 310.2 m/z for the internal standard, MIT-001-d₅. Calibration curves demonstrated correlation coefficients exceeding 0.9963 for all plasma sample batches, within a validated concentration range of 2–2000 μg/L (Supplementary Table 2). Quality-control sample accuracies ranged from 100.5% to 104.0%, with imprecision below 5.0%. Full details of the validation results for plasma MIT-001 are provided in the Supplementary Material.

Pharmacokinetic Analysis

PK parameters were calculated using non-compartmental analysis with Phoenix WinNonlin^® (version 8.4; Pharsight, Sunnyvale, CA, USA). Analysis was performed based on actual times of blood sample collection. Maximum observed plasma concentration (C_max) and time to maximum plasma concentration (T_max) were directly determined from the observed plasma concentration-time profiles. The area under the concentration-time curve (AUC) was calculated using the linear-up/log-down method. The R_ac was defined as the ratio of the AUC during the dosing interval at steady state (AUC_τ,ss) to the AUC during the dosing interval after the first dose (AUC_τ,ss/AUC_τ). Bioavailability (F) was estimated as the ratio of AUC_inf for SC to IV administration.

Safety and Tolerability Assessments

Safety and tolerability were assessed by monitoring adverse events (AEs), physical examinations, 12- lead ECGs, vital signs (blood pressure, pulse rate, and body temperature), and clinical laboratory tests (hematology, blood chemistry, coagulation, and urinalysis). AEs were summarized by severity (mild, moderate, severe, life threatening consequences, or death) and their relationship with the IP. Local reactions at the injection site were evaluated throughout the study using a predefined scoring system that assessed symptoms such as pain, erythema, induration, and swelling.¹⁸

Statistical Analysis

Statistical analysis was performed using SAS software (version 9.4; SAS Institute Inc., Cary, NC, USA). Descriptive statistics were presented as mean ± standard deviation (SD) for continuous variables and as frequencies and percentages for categorical variables. Dose proportionality was assessed by analyzing dose-normalized C_max and AUC of MIT-001 using the Kruskal–Wallis test or the Mann–Whitney test. A linear mixed-effects model was used to compare the PKs of the SC and IV formulations, with the formulation as a fixed effect and participants as a random effect. The Fisher exact test was used to compare the proportions of participants with AEs across dose levels.

Results

Study Population

A total of 40 participants were enrolled and completed the study as planned, with 24 participants in the SAD study and 16 participants in the MAD study. All participants were included in the PK analysis and safety assessments. The mean ± SD values for age, weight, height, and BMI of participants in the SAD study were 32.96 ± 6.84 years, 69.13 ± 6.79 kg, 172.33 ± 6.84 cm, and 23.96 ± 2.26 kg/m², respectively. For participants in the MAD study, these values were 28.69 ± 7.45 years for age, 71.38 ± 9.08 kg for weight, 173.56 ± 5.80 cm for height, and 23.66 ± 2.42 kg/m² for BMI. Demographic characteristics, including age, weight, height, and BMI, were similar across dose levels.

Pharmacokinetic Analysis

In the SAD study, MIT-001 showed a mono-exponential decrease pattern (Figure 3). It was rapidly absorbed, reaching C_max at a median time of 1.5–2.0 h. The mean t_1/2 ranged from 26.97 to 40.30 h (Table 1). C_max and AUCs (AUC_last and AUC_inf) increased with the dose level of MIT-001. While dose linearity was observed within the SC dose range of 10–40 mg, dose proportionality was not confirmed. The difference in dose-normalized C_max across dose levels was not statistically significant (P =0.1492), but significant differences were observed in dose-normalized AUC_last and AUC_inf (both P =0.0115).

Table 1 Pharmacokinetic Parameters of MIT-001 After a Single Subcutaneous (SC) and Intravenous (IV) Administration

Figure 3 Mean plasma concentration–time profiles of MIT-001 after a single subcutaneous (SC) dose of 10, 20, or 40 mg, and a single intravenous (IV) dose of 40 mg, presented on (A) linear and (B) semi-logarithmic scales. Error bars represent standard deviations.

In the MAD study, the overall concentration-time profiles of MIT-001 after multiple SC administrations were similar to those observed after a single SC administration, with a median time to C_max at steady state (C_max,ss) of 1.5–2.25 h (Figure 4). The mean t_1/2 at steady state (t_1/2,ss) ranged from 32.89 to 36.10 h (Table 2). C_max,ss and AUC_τ,ss at SC doses of 40 mg were more than doubled those observed at SC doses of 20 mg. No statistically significant differences were observed in dose-normalized C_max,ss and AUC_τ,ss between the 20 mg and 40 mg dose levels (both P =0.1564). The mean R_ac values were 2.75 and 2.77 after multiple SC doses of MIT-001 at 20 mg and 40 mg, respectively.

Table 2 Pharmacokinetic Parameters of MIT-001 After Single and Multiple Subcutaneous (SC) Administrations

Figure 4 Mean plasma concentration–time profiles of MIT-001 after single and multiple subcutaneous (SC) doses of 20 or 40 mg, presented on (A) linear and (B) semi-logarithmic scales. Error bars represent standard deviations.

The mean plasma concentration-time profiles of MIT-001 were comparable between SC and IV administration during the terminal elimination phase, with a t_1/2 of approximately 40 h (Figure 3, Table 1). Consistent with previous studies, MIT-001 showed a multi-compartmental disposition after IV administration, with a rapid initial distribution phase followed by a slower elimination phase.¹⁶ The mean F of MIT-001 after SC administration was 0.94.

Safety and Tolerability Assessments

In the SAD study, 26 treatment-emergent adverse events (TEAEs) were reported in 14 participants (58.3%), with 20 events in 13 participants (54.2%) classified as adverse drug reactions (ADRs) (Table 3). No ADRs were reported after a single MIT-001 IV administration. The most common ADRs were local reactions at the injection site, observed in 7 MIT-001-treated participants (38.9%) with 11 cases (4 cases of erythema, 3 cases of bruising, 3 cases of pain, and 1 case of induration) and in 4 placebo-treated participants (66.7%) with 6 cases (4 cases of erythema, 1 cases of bruising, and 1 case of discomfort).

Table 3 Summary of Adverse Drug Reactions (ADRs) After a Single Subcutaneous (SC) and Intravenous (IV) Administration of MIT-001 or Placebo

In the MAD study, 34 TEAEs were reported in 15 participants (93.8%), all of which were classified as ADRs (Table 4). The most common ADRs were also local reactions at the injection site, observed in 10 MIT-001-treated participants (83.3%) with 26 cases (8 cases of bruising, 7 cases of induration, 6 cases of erythema, 3 cases of pain, 1 case of dysaesthesia, and 1 case of oedema) and in 4 placebo-treated participants (100.0%) with 4 cases (2 cases of erythema, 1 case of induration, and 1 case of pain).

Table 4 Summary of Adverse Drug Reactions (ADRs) After Multiple Subcutaneous (SC) Administrations of MIT-001 or Placebo

In clinical laboratory tests, one ADR (eosinophilia) was reported in the SAD study, and three ADRs (blood phosphokinase increased, blood uric acid increased, and white blood cell count decreased) were reported in the MAD study. Except for one placebo-treated participant who reported nausea and headache, no clinically significant changes or abnormalities in physical examinations, vital signs, or 12- lead ECGs were observed in any participants.

In both the SAD and MAD studies, no statistically significant differences were observed in the proportions of participants with ADRs, including local reactions, across dose levels. All ADRs were mild, except for one moderate case of white blood cell count decreased, which resolved without medication or therapy and was not associated with observable symptoms, such as fever. All ADRs resolved without intervention, except for one mild case of injection site induration, which was classified as resolving. No serious AEs were reported during the study.

Discussion

This study aimed to evaluate the PK and safety profiles of MIT-001 after SC administration in healthy participants. Previous studies on the IV formulation demonstrated that MIT-001 was well tolerated at a maximum single dose of 200 mg and a maximum multiple dose of 30 mg once daily for seven consecutive days.^16,17 Based on these findings, an initial SC dose of 10 mg for the SAD study and 20 mg for the MAD study were selected, as these doses were anticipated to be both safe and pharmacologically effective.

In consideration of the ease of self-administration for patients performing SC injections independently, injection site of this study was determined as the abdominal region. Given that SC injection volumes exceeding 2 mL can cause issues such as injection site pain, doses were administered at intra-abdominal sites divided into eight zones.¹⁹ This ensured that injections were given without overlap and that the volume per each injection site did not exceed 2mL.

The most common ADRs were mild local reactions at the injection site, with no statistically significant differences in incidence across dose levels. These local reactions resolved without sequelae, except for one mild case of injection site induration, which was classified as resolving. This suggests that local reactions are unlikely to constitute dose-limiting toxicities in future studies involving patient populations.

In clinical laboratory tests, all ADRs were mild, except for one moderate case of white blood cell count decreased reported after multiple doses of MIT-001 20 mg. The causality with the IP was classified as possible, considering the timing of the AE onset and the possible anti-inflammatory mechanism of MIT-001. However, the AE resolved without intervention, was not associated with observable symptoms, and was not observed at the higher 40 mg dose, indicating it was not clinically significant. Apart from clinical laboratory test abnormalities, no systemic ADRs were observed in MIT-001-treated participants after SC and IV administration. These findings suggest that the SC formulation is not expected to cause systemic issues, consistent with results from previous studies on the IV formulation.^16,17

In the SAD study, the mean t_1/2 increased with dose, ranging from 26.97 to 40.30 h. However, this trend was not considered significant, as it aligns with previous studies where the mean t₁_/2 ranged from 27.3 to 45.4 h after a single IV administration.¹⁶ While dose linearity was observed within the SC dose of 10–40 mg, dose proportionality was not confirmed. In the MAD study, the AUC_τ,ss at SC doses of 40 mg was more than doubled that observed at SC doses of 20 mg, indicating a greater-than-dose-proportional increase in systemic exposure and suggesting a nonlinear PK profile. This nonlinearity may be due to saturation of pre-systemic elimination mechanisms at the injection site.²⁰ SC tissue contains metabolizing enzymes that can contribute to local drug degradation prior to systemic absorption.²¹ At lower doses, a substantial portion of the drug may be metabolized locally, reducing bioavailability. However, at higher concentrations, these enzymatic pathways may become saturated, resulting in a greater proportion of the dose reaching systemic circulation. This would explain the supraproportional increase in systemic exposure observed in SC administration, in contrast to the proportional exposure increases reported with IV administration.^16,17

The F of MIT-001 after SC administration was high, with a mean value of 0.94. Additionally, the GMRs and 90% CIs for AUCs (AUC_last and AUC_inf) of the SC formulation relative to the IV formulation were within the bioequivalence limit of 0.80 to 1.25, indicating comparable systemic exposure between the two formulations. These findings suggest that the SC formulation of MIT-001 can serve as a switchable alternative to the IV formulation.

In an in vitro study, MIT-001 demonstrated a ROS scavenging capacity, with an IC₅₀ of 14.3 µM.²² Another in vitro study using IEC-6 cells, normal small intestinal epithelial cells irradiated at 10 and 20 Gy, showed significant restoration of cell viability at MIT-001 concentrations of 20 and 40 µg/L.²³ In an OM hamster model, the minimal effective dose of MIT-001 was 0.3 mg/kg, equivalent to 2.34 mg in adult humans.^24,25 Based on these findings, SC doses of MIT-001 at 10 mg or more are expected to achieve sufficient exposure to exert pharmacological effects in patients with OM. Accordingly, the Phase 2 clinical trials (ClinicalTrials.gov identifier: NCT04651634, NCT05493800) were appropriately designed to evaluate IV dose levels of 5–20 mg and 20–60 mg, encompassing the expected effective dose while enabling both dose–response characterization and safety profiling.

This study was conducted in healthy participants, which may not fully represent the PK and safety profiles in patient populations. Additionally, the relatively small sample size (N=40) may also limit the generalizability of these findings. Therefore, further investigations in patients are warranted to confirm these results under pathological conditions.

Conclusion

The systemic exposure of MIT-001 after SC administration increased linearly across the dose levels of 10–40 mg after SC administration. The PK profiles of MIT-001 were comparable between SC and IV formulations, with an F value of 0.94. MIT-001 was well tolerated after a single SC dose of 10–40 mg and multiple SC doses of 20–40 mg in healthy participants. The SC formulation of MIT-001 is anticipated to provide benefits to patients by improving patient adherence and convenience for long-term management.

Data Sharing Statement

De-identified individual participant data that support the finding of this study are available from the corresponding author ([email protected]) upon reasonable request and with appropriate approvals, at any time after publication.

Acknowledgments

This study was sponsored by MitoImmune Therapeutics Inc., Seoul, Korea. The investigation was conducted at the Clinical Trials Center, Seoul National University Hospital.

Disclosure

The authors report no conflicts of interest in this work.

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