Sungyeun Bae

Clinical trials with decentralized elements (DCTs) may improve accessibility and convenience by reducing the need for frequent on‐site visits; however, empirical evidence remains limited. Within a Phase 1 pharmacokinetic drug–drug interaction (DDI) study, we concurrently implemented an additional study arm incorporating decentralized elements to evaluate feasibility, data integrity, and participant perceptions compared to conventional on‐site procedures. In this open‐label, hybrid DCT, 20 healthy adults were randomized in a 1:1 ratio to either the DCT arm or the conventional arm. Between on‐site periods (Periods 1 and 3), 5‐day paroxetine dosing was administered during arm‐differentiated Period 2. During this period, DCT arm participants self‐administered paroxetine with a wearable dosing‐monitoring and remote adverse events (AEs) reporting, whereas conventional‐arm participants underwent on‐site dosing and AE reporting. Participant burden was assessed using a survey conducted at completion of the study. In Period 2, the DCT arm achieved 100% dosing adherence, whereas one participant in the conventional arm missed the on‐site dose. Wearable device records showed 2% missing data with high concordance with paper logs (mean difference, 0.24 min). AE incidence was comparable between the arms, suggesting that remote reporting maintained AE detection sensitivity. Participants rated app/web‐based methods as the least burdensome, followed by paper, wearable devices, and on‐site visits. Burden scores for electronic versus paper AE reporting showed no significant differences between or within arms. This study, one of the earliest reported DCTs in the Republic of Korea, demonstrated the feasibility and reliability of decentralized self‐administration with wearable monitoring and remote AE reporting. These findings support the potential of hybrid DCTs in offering efficient and participant‐friendly alternatives to conventional approaches.

Busulfan's narrow therapeutic index and high pharmacokinetic (PK) variability warrant investigation of its exposure–toxicity relationship. We retrospectively analyzed 334 pediatric and young adult patients who underwent allogeneic hematopoietic stem cell transplantation at Seoul National University Children's Hospital between 2009 and 2020 and received once‐daily intravenous busulfan over four days (3‐hour infusion, n = 122; 6‐hour infusion, n = 212). Factors associated with toxicities were identified using multivariable logistic regression, and overall survival (OS) was evaluated by Kaplan–Meier and Cox regression analyses. Despite comparable exposures, the 3‐hour infusion group showed higher C _max (4,260.2 vs 3,028.6 μg/L, P < 0.0001) and more frequent liver function test elevations (13.1% vs 0.5%, P < 0.0001). Receiver operating characteristic analysis identified a C _max cut‐off of 4269.6 μg/L as a factor for hepatotoxicity. The 4‐year OS was superior in the 6‐hour infusion group (82.3% vs 71.9%, P = 0.02) and in the low C _max group (80.8% vs 66.5%, P = 0.01). Cox regression revealed C _max as an independent predictor of OS. A population PK model was developed using NONMEM. A 1‐compartment model incorporating enzyme turnover auto‐inhibition successfully described the busulfan PK profile. Simulations of published once‐daily dosing regimens showed that extending the infusion to 6 hours successfully maintained C _max below the cut‐off threshold. These results show that maintaining busulfan C _max below 4269.6 μg/L is associated with improved safety and survival. Prolonged infusion should be considered when adopting the busulfan once‐daily regimen.

CYP2D6‐mediated drug–drug–gene interactions (DDGIs) are known to influence the pharmacokinetics of venlafaxine and its metabolism to O‐desmethylvenlafaxine. Solanidine and 3,4‐seco‐solanidine‐3,4‐dioic acid (SSDA) have recently been investigated as candidate endogenous CYP2D6 biomarkers; however, they remain unexplored in East Asian populations, where dietary potato intake is relatively lower than that in Western populations. A prospective clinical study aimed to characterize venlafaxine DDGIs and explore the potential of solanidine as a candidate biomarker of CYP2D6 activity in healthy Korean adults. Twenty participants including 14 CYP2D6 normal metabolizers (NMs) and 6 intermediate metabolizers (IMs)—all confirmed as CYP2C19 NMs—were enrolled. Serial plasma samples for pharmacokinetic assessment were collected before and after coadministration of paroxetine, a potent CYP2D6 inhibitor. Solanidine and SSDA were also measured in plasma and urine. Compared to CYP2D6 NMs, IMs exhibited higher venlafaxine exposure but lower O‐desmethylvenlafaxine exposure. Following CYP2D6 inhibition, phenotype‐dependent differences in venlafaxine and O‐desmethylvenlafaxine pharmacokinetics were attenuated. The metabolic ratio (MR) of plasma solanidine showed a modest positive correlation with both the MR of venlafaxine and CYP2D6 activity score. The MR of plasma solanidine decreased when CYP2D6 activity was reduced by paroxetine coadministration. These findings demonstrate phenotype‐dependent DDGIs of venlafaxine and suggest the exploratory potential of solanidine as an endogenous biomarker of CYP2D6 activity in the Korean population, despite relatively lower dietary exposure to potato‐derived precursors. This study provides preliminary evidence extending endogenous CYP2D6 biomarkers to an East Asian population with distinct dietary backgrounds.

MIT‐001 is a novel ferroptosis inhibitor that is a potent mitochondrial‐targeting antioxidant targeting various inflammatory diseases. Utilizing pharmacokinetic (PK) and safety data from previous clinical trials in healthy individuals with preclinical efficacy data from the animal disease models, we aimed to develop a population PK model for MIT‐001 to provide evidence for selecting optimal dosage in clinical trials with oral mucositis (OM) patients. The PK model was developed using data from three phase 1 clinical trials with NONMEM software. Covariate analysis included demographic characteristics and clinical laboratory tests. Models were validated using objective function value, goodness of fit plots, bootstrap analysis, and prediction‐corrected visual predictive check. PK profiles of MIT‐001 across various doses were simulated using the final population PK model. A three‐compartment model with linear elimination and first‐order absorption without a lag time best described the PK profile of MIT‐001. Weight and ALT were significant covariates for the peripheral compartment and clearance, respectively. The simulated PK profile showed that 97.4% of patients are expected to reach effective exposure after twice weekly 30 mg SC dose in 3 weeks. Furthermore, 93.6% of patients are expected to be within a tolerable range after 13 weeks of 80 mg SC dosing. A 30 to 80 mg twice weekly SC dose is expected to be both effective and tolerable for OM patients.

Background: Lenzilumab is a recombinant monoclonal antibody neutralizing human granulocyte macrophage-colony stimulating factor. By modulating proinflammatory cytokine cascade, lenzilumab is expected to be effective in prevention and treatment of cytokine release syndrome. This study aimed to assess the safety, tolerability and pharmacokinetics (PKs) after a single intravenous (IV) administration of lenzilumab in healthy Korean subjects. Methods: A randomized, double-blind, placebo-controlled, single ascending dose study was conducted. The subjects received a single dose of 1, 3 or 10 mg/kg of lenzilumab or placebo via 1-hour IV infusion. Plasma samples for PK analysis were collected up to 69 days after the administration. PK parameters were estimated using noncompartmental analysis and dose-proportionality of lenzilumab was assessed. Adverse events and other safety variables were monitored throughout the whole study period. Results: Among the 20 subjects who completed the study, three received 1 mg/kg of lenzilumab, while six received 3 mg/kg and another six received 10 mg/kg. The remaining five subjects received the placebo. After 1-hour IV infusion, the maximum concentrations of lenzilumab were observed between 2.0 and 3.0 hours. The time-concentration profile of lenzilumab displayed biphasic decline and the terminal half-life ranged from 25.33 to 31.21 days. Lenzilumab exhibited a dose-proportional increase in its systemic exposure across 1 to 10 mg/kg. Nine cases of treatment-emergent adverse events occurred in six subjects receiving lenzilumab. All were mild and spontaneously recovered. Conclusion: The systemic exposure of lenzilumab was dose-proportional across 1 to 10 mg/kg in healthy Korean subjects. A single IV administration of lenzilumab was safe and well tolerated in the dose range between 1 and 10 mg/kg.

Purpose: MIT-001 is a novel ferroptosis inhibitor with therapeutic potential for oxidative stress-related diseases. This study aimed to evaluate the pharmacokinetic (PK) and safety profiles of MIT-001 after subcutaneous (SC) administration in healthy participants. Methods: A randomized, double-blind, placebo-controlled, dose-escalation study was conducted in two parts: single ascending dose (SAD) and multiple ascending dose (MAD) studies. In the SAD study, participants received a single SC dose of MIT-001 at 10, 20, or 40 mg, with the 40 mg cohort also receiving a single IV dose in a crossover manner. In the MAD study, participants received SC doses of 20 or 40 mg once daily for seven consecutive days. Safety and tolerability were assessed by monitoring adverse events (AEs), physical examinations, vital signs, and clinical laboratory tests. Results: A total of 40 participants completed the study, with 24 in the SAD study and 16 in the MAD study. MIT-001 was rapidly absorbed, reaching the maximum concentration at a median time of 1.5– 2.5 h. Accumulation ratios after multiple SC administrations were 2.75– 2.77. PK profiles were comparable between SC and IV formulations. The most common AEs were mild local reactions at the injection site, with no statistically significant differences in incidence across dose levels. No serious AEs were reported. Conclusion: The systemic exposure of MIT-001 after SC administration increased linearly across the dose levels of 10– 40 mg. 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.

Song J, et al. Transl Clin Pharmacol. 2025 Mar;33(1):40-49. https://doi.org/10.12793/tcp.2025.33.e5

Kim Y, et al. Transl Clin Pharmacol. 2024 Sep;32(3):127-136. https://doi.org/10.12793/tcp.2024.32.e15

Purpose: Empagliflozin is a sodium-glucose cotransporter 2 inhibitor that is commonly used for the treatment of type 2 diabetes mellitus. As cocrystal formulation can improve the chemical properties of drugs, CKD-370 was newly developed as a cocrystal formulation of empagliflozin with solvate L-proline. This study aimed to compare the pharmacokinetics, safety, and tolerability of these two empagliflozin formulations in healthy Korean subjects. Methods: A randomized, open-label, two-sequence, two-period crossover study was conducted on healthy Korean participants. The subjects received a single oral 25 mg dose of either test (CKD-370) or reference treatment (Jardiance^®) tablet at each period. Plasma empagliflozin concentrations were determined using liquid chromatography with tandem mass spectrometry. Pharmacokinetic (PK) parameters were analyzed using non-compartmental methods. The primary PK parameters included the maximum concentration (C_max) and the area under the concentration-time curve from 0 to last (AUC_last). The safety of both formulations was monitored and evaluated. Results: A total of 28 healthy Korean adult subjects were randomized, and 27 subjects were included in the PK analysis. The mean ± standard deviation values of the primary PK parameters, C_max and AUC_last after administration of the test treatment, were 442.02 ± 103.37 μg/L and 3131.08 ± 529.30 μg·h/L, respectively, and those after administration of the reference treatment were 436.29 ± 118.74 μg/L and 3006.88 ± 514.21 μg·h/L, respectively. The geometric mean ratio and its 90% confidence interval of test to reference treatment for C_max and AUC_last were 1.0221 (0.9527– 1.0967) and 1.0411 (1.0153– 1.0677), respectively, which were within the commonly accepted bioequivalence criteria of 0.80 to 1.25. Both treatments were well-tolerated. Conclusion: The two formulations of empagliflozin showed similar PK characteristics and were generally well tolerated in healthy subjects.

Bersiporocin, a novel first‐in‐class prolyl‐tRNA synthetase (PRS) inhibitor currently under clinical development, was shown to exert an antifibrotic effect through the downregulation of collagen synthesis in various pulmonary fibrosis models. The aim of this first‐in‐human, randomized, double‐blind, placebo‐controlled, single‐ and multiple‐dose, dose‐escalation study was to evaluate the safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of bersiporocin in healthy adults. A total of 40 and 32 subjects were included in a single‐ (SAD) and multiple‐ascending dose (MAD) study, respectively. No severe or serious adverse events were observed after a single oral dose up to 600 mg and multiple oral doses up to 200 mg twice daily for 14 days. The most common treatment‐emergent adverse events were gastrointestinal adverse events. To improve the tolerability, initial bersiporocin solution was changed to the enteric‐coated formulation. Afterward, the enteric‐coated tablet was used in the last cohort of SAD and in the MAD study. Bersiporocin showed dose‐proportional PK characteristics after a single dose up to 600 mg and multiple doses up to 200 mg. Upon reviewing the safety and PK data, the final SAD cohort (800 mg enteric‐coated tablet) was canceled by the Safety Review Committee. The levels of pro‐peptide of type 3 procollagen were lower after treatment with bersiporocin than after the placebo in the MAD study, whereas no significant change was observed in other idiopathic pulmonary fibrosis (IPF) biomarkers. In conclusion, the safety, PK, and PD profile of bersiporocin supported its further investigation in patients with IPF.