Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea.
Kidney Research Institute, Seoul National University Medical Research Center, Seoul, Korea.
Clin Transl Sci. 2024 Jul;17(7):e13892. doi: 10.1111/cts.13892.
JBPOS0101 is a new antiepileptic drug and is a substrate of UDP-glucuronosyltransferases (UGTs) in in vitro test. In vitro experiments showed different results regarding whether JBPOS0101 induces (EC 136 μM) or inhibits (IC 95.4-386.5 μM) cytochrome P450 (CYP) 3A4. As co-medication of JBPOS0101 and carbamazepine (CBZ) is expected in clinical settings, drug-drug interactions (DDIs) between them should be determined. This study aimed to investigate pharmacokinetic (PK) interactions of JBPOS0101 influenced by CYP3A4 and UGTs using midazolam (MDZ) and CBZ. A two-cohort, open-label, fixed-sequence study was conducted in healthy Koreans. In cohort A, subjects received MDZ IV alone, and then JBPOS0101 were co-administered with MDZ after oral doses of JBPOS0101 for 7 days. In cohort B, multiple doses of JBPOS0101 and CBZ were administered respectively, and subjects received both together for 7 days. Serial blood samples were collected for PK analysis. When MDZ and JBPOS0101 were co-administered, the systemic exposure of MDZ decreased by 30%. Meanwhile, JBPOS0101 did not significantly changed the PK of CBZ. CBZ decreased the systemic exposure of JBPOS0101 at steady state by 40%, respectively. With IV administration of MDZ, JBPOS0101 acted as a weak inducer of hepatic CYP3A4 and decreased systemic exposure of MDZ. The ability of JBPOS0101 to similarly modulate gut CYP3A4 activity will require further evaluation. Co-administration of multiple doses of JBPOS0101 and CBZ did not significantly alter CBZ pharmacokinetics, but the clinical impact of decreased systemic exposure of JBPOS0101 by CBZ should be further considered.
JBPOS0101 是一种新型抗癫痫药物，在体外试验中是 UDP-葡糖醛酸基转移酶（UGTs）的底物。体外实验结果显示，JBPOS0101 是诱导（EC50 为 136μM）还是抑制（IC95.4-386.5μM）细胞色素 P450（CYP）3A4 存在差异。由于 JBPOS0101 与卡马西平（CBZ）在临床环境中预期联合用药，因此应确定它们之间的药物相互作用（DDI）。本研究旨在使用咪达唑仑（MDZ）和 CBZ 研究 JBPOS0101 对 CYP3A4 和 UGTs 的影响的药代动力学（PK）相互作用。在韩国健康志愿者中进行了一项两队列、开放标签、固定序列研究。在队列 A 中，受试者单独接受 MDZ IV，然后在 JBPOS0101 口服 7 天后给予 MDZ 共同给药。在队列 B 中，分别给予 JBPOS0101 和 CBZ 的多次剂量，然后共同给予两者 7 天。采集连续血样进行 PK 分析。当 MDZ 和 JBPOS0101 共同给药时，MDZ 的全身暴露量减少了 30%。同时，JBPOS0101 对 CBZ 的 PK 没有显著影响。CBZ 使 JBPOS0101 的稳态全身暴露量分别减少了 40%。当给予 MDZ IV 时，JBPOS0101 充当肝 CYP3A4 的弱诱导剂并降低 MDZ 的全身暴露量。JBPOS0101 类似调节肠道 CYP3A4 活性的能力需要进一步评估。多次给予 JBPOS0101 和 CBZ 不会显著改变 CBZ 的药代动力学，但应进一步考虑 CBZ 降低 JBPOS0101 全身暴露量的临床影响。
