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.

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.

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

Purpose: Proton pump inhibitors (PPIs) are the first-line therapy for gastroesophageal reflux disorder (GERD). Unlike conventional PPIs, non-enteric coated PPIs with antacid salt enable a faster acid suppression through the rapid absorption of the PPI. YPI-011 is a newly developed fixed-dose combination of a rabeprazole with sodium bicarbonate (NaHCO₃). This study compared the pharmacokinetics (PKs) and pharmacodynamics (PDs) of YPI-011 to the conventional enteric-coated rabeprazole (Pariet^®). Materials and Methods: A randomized, open-label, two-treatment, two-sequence crossover study was conducted with two different doses (10 and 20 mg) and 44 subjects in each group. They randomly received either a test or reference treatment for 7 days in the first period and the other treatment in the second period. Blood samples for the PK analysis were taken after the single- and multiple-dose. Intragastric pH monitoring for the PD analysis was implemented for baseline and after the single- and multiple-dose. Results: Gastric acid suppression evaluated by the percentage decrease from baseline in the integrated gastric acidity for a 24-hour interval after the multiple-dose was similar between the treatments in both dose groups. The systemic exposure of rabeprazole at steady state after the multiple-dose was also similar between the treatments in both dose groups. The time to reach the maximum rabeprazole concentration was faster in the test treatment. The PK-PD relationship of PPI is well known, and the faster absorption of rabeprazole resulted in a more rapid mode of action in acid suppression. Conclusion: The fixed dose combination of rabeprazole with NaHCO₃ showed a faster absorption and consequently, a more rapid gastric acid suppression with a similar systemic exposure of rabeprazole at steady state compared to the conventional enteric-coated rabeprazole.

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.

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.