A-Young Yang

Purpose: Zastaprazan is a novel potassium-competitive acid blocker with CYP3A-mediated metabolism, whereas atorvastatin undergoes CYP3A4- and transporter-mediated disposition. Because these drugs may be co-administered and their net interaction cannot be inferred from shared metabolic pathways alone, this study evaluated their steady-state pharmacokinetic drug–drug interaction. Participants and Methods: This open-label, fixed-sequence, three-period, multiple-dose study included healthy Korean men. Participants received atorvastatin 40 mg once daily, zastaprazan 20 mg once daily, and concomitant atorvastatin and zastaprazan, each for 5 consecutive days, under steady-state conditions. Plasma concentrations of zastaprazan, atorvastatin, and 2-hydroxyatorvastatin were measured, and geometric mean ratios (GMRs) with 90% confidence intervals (CIs) were calculated for C_max,ss and AUC_τ,ss. Results: Twenty-four healthy Korean men received at least one dose of a study drug, and 22 were included in the pharmacokinetic analysis. Atorvastatin decreased zastaprazan C_max,ss by approximately 26% (GMR, 0.740; 90% CI, 0.655– 0.836), whereas AUC_τ,ss was preserved (GMR, 1.054; 90% CI, 0.927– 1.198). Zastaprazan did not meaningfully alter atorvastatin exposure (C_max,ss GMR, 0.982; 90% CI, 0.806– 1.195; AUC_τ,ss GMR, 1.029; 90% CI, 0.944– 1.122). The AUC_τ,ss of 2-hydroxyatorvastatin showed a modest decrease (GMR, 0.940; 90% CI, 0.889– 0.994) that remained within the predefined conventional reference range. Co-administration was generally well tolerated, with no serious adverse events or adverse event-related discontinuations. Conclusion: Zastaprazan did not meaningfully alter atorvastatin C_max,ss or AUC_τ,ss under the studied conditions. Although atorvastatin reduced zastaprazan C_max,ss, total exposure was preserved, a pattern consistent with altered absorption kinetics without establishing a specific mechanism. The pharmacodynamic significance of the lower zastaprazan C_max,ss remains uncertain because intragastric pH was not measured. These pharmacokinetic findings do not suggest a need for atorvastatin dose adjustment under the studied conditions.

Bersiporocin, a potent and selective prolyl‐tRNA synthetase inhibitor, is expected to show a synergistic effect with pirfenidone or nintedanib in patients with idiopathic pulmonary fibrosis. To validate the combination therapy of bersiporocin with pirfenidone or nintedanib, a randomized, open‐label, two‐part, one‐sequence, three‐period, three‐treatment study was designed to evaluate the effect of drug–drug interactions (DDI) regarding their pharmacokinetics, safety, and tolerability in healthy participants. In addition, the pharmacokinetic profiles of the newly formulated, enteric‐coated bersiporocin tablet were evaluated after single and multiple administrations. The potential effects of cytochrome P450 2D6 (CYP2D6) genotyping on bersiporocin pharmacokinetics and DDI were also explored. In Part 1, participants were sequentially administered a single dose of pirfenidone 600 mg, a single dose of bersiporocin 150 mg followed by multiple doses, and bersiporocin in combination with pirfenidone. In Part 2, participants were sequentially administered a single dose of nintedanib 150 mg, multiple doses of bersiporocin 150 mg, and bersiporocin in combination with nintedanib. Forty‐six participants completed the study. There was no significant pharmacokinetic DDI between bersiporocin, and pirfenidone or nintedanib. All adverse events (AEs) were mild to moderate and did not include serious AEs, suggesting bersiporocin alone or in combination therapy were well‐tolerated. The newly formulated bersiporocin 150 mg tablet showed a moderate accumulation index. There was no significant difference in the pharmacokinetic profiles after administration of bersiporocin alone or in combination therapy between CYP2D6 phenotypes. In conclusion, there are no significant DDI regarding the pharmacokinetics, safety, and tolerability of bersiporocin administration with pirfenidone or nintedanib.

Overactive bladder (OAB) is characterized by urinary urgency and increased urinary frequency, substantially affecting quality of life. Tamsulosin and mirabegron combination therapy has been studied as a safe and effective treatment option for patients with OAB. This study evaluated the effects of combining these two drugs on their pharmacokinetics and safety profiles in healthy Korean males. In this open-label, fixed-sequence, three-period, drug–drug interaction phase 1 study, a total of 36 male participants were administered multiple doses of tamsulosin alone (0.2 mg once daily), mirabegron alone (50 mg once daily), or a combination of both drugs. The results showed that the combination of tamsulosin and mirabegron increased tamsulosin exposure in the plasma by approximately 40%. In contrast, the maximum plasma concentration of mirabegron was reduced by approximately 17% when administered with tamsulosin. No clinically significant changes in the safety profiles, vital signs, or clinical laboratory test results were observed in this study. In conclusion, there were no clinically relevant drug–drug interactions between tamsulosin and mirabegron in terms of pharmacokinetics, safety, and tolerability, suggesting that their combination could be a promising treatment option for patients with OAB.

Overactive bladder (OAB) is characterized by urinary urgency and increased urinary frequency, and can impact quality of life significantly. Tamsulosin and mirabegron combination therapy has been studied as a safe and effective treatment option for patients with OAB. This study evaluated the effects of combining these two drugs on their pharmacokinetics and safety profiles in healthy Korean males. In this open-label, fixed-sequence, 3-period, drug-drug interaction phase 1 study, a total of 36 male participants were administered multiple doses of tamsulosin alone (0.2 mg once daily), mirabegron alone (50 mg once daily), and a combination of both drugs. The results showed that the combination of tamsulosin and mirabegron increased tamsulosin exposure in the plasma by approximately 40%. In contrast, the maximum plasma concentration of mirabegron reduced by approximately 17%, when administered along with tamsulosin. No clinically significant changes in safety profiles, vital signs, or clinical laboratory test results were observed in this study. In conclusion, there were no clinically relevant drug-drug interactions between tamsulosin and mirabegron in terms of pharmacokinetics, safety, and tolerability, suggesting that their combination therapy could be a promising treatment option for patients with OAB.

Fexuprazan is a potassium-competitive acid blocker approved for treating gastric-acid-related diseases. Although the effectiveness of the recent formulation fexuprazan 10 mg has been demonstrated in Phase 3 clinical trials, data on the pharmacokinetics (PKs) of administering fexuprazan 10 mg twice daily at a 12 h interval are lacking. Moreover, it is imperative to ensure the bioequivalence of the new formulation with the previously approved 40 mg formulation. This study evaluated the pharmacokinetics (PKs) of the single- and multiple-dose oral administration of fexuprazan 10 mg tablets in healthy participants (Part 1) and investigated their bioequivalence with 40 mg tablets (Part 2). Part 1 comprised a single- and multiple-dose, one-sequence, two-period design and eight participants, while Part 2 comprised a single-dose, 2 × 2 crossover design and 24 participants. In Part 1, in Periods 1 and 2, participants received single and multiple doses (twice daily) of fexuprazan 10 mg, respectively. The maximum plasma concentration (C_max) area under the concentration–time curve from 0 to 12 h (AUC_0–12h) of the multiple-dose participants was approximately double that of the single-dose participants. In Part 2, the geometric mean ratios (90% confidence intervals) for C_max and AUC from zero to the time of the last quantifiable concentration (AUC_last) of the use of four fexuprazan 10 mg tablets to those of one fexuprazan 40 mg tablet were 1.0290 (0.9352–1.1321) and 1.0290 (0.9476–1.1174), respectively, meeting the bioequivalence criteria. Favorable PKs were observed after single and multiple administrations of one fexuprazan 10 mg tablet, and four fexuprazan 10 mg tablets were pharmacokinetically equivalent to one fexuprazan 40 mg tablet.

Fexuprazan is a potassium-competitive acid blocker approved for treating gastric acid-related diseases. Herein, we evaluated the pharmacokinetics (PKs) of single-dose and multiple-dose oral administration of fexuprazan 10 mg tablets in healthy subjects (Part 1) and investigated the bioequivalence between fexuprazan 10 mg and 40 mg tablets (Part 2). Part 1 comprised a single- and multiple-dose, 1-sequence, and 2-period design, and Part 2 comprised a single-dose, 2×2 crossover design. Eight and 23 subjects completed Parts 1 and 2, respectively. In Part 1, multiple doses accumulated twice as much as single doses. In Part 2, the geometric mean ratios [90% confidence intervals] for maximum plasma concentration (Cmax) and area under the concentration–time curve from zero to the time of the last quantifiable concentration (AUClast) of four fexuprazan 10 mg tablets to those of one fexuprazan 40 mg tablet were 1.0290 (0.9352–1.1321) and 1.0290 (0.9476–1.1174), respectively, which met bioequivalence criteria. Overall, favorable PK was observed after single and multiple administrations of one fexuprazan 10 mg tablet, and four fexuprazan 10 mg tablets were pharmacokinetically equivalent to one fexuprazan 40 mg tablet.

Yang AY, et al. Transl Clin Pharmacol. 2023 Mar;31(1):40-48. https://doi.org/10.12793/tcp.2023.31.e3