PTC Therapeutics, Inc., Warren, NJ, USA.
Clin Pharmacol Drug Dev. 2024 Dec;13(12):1283-1290. doi: 10.1002/cpdd.1461. Epub 2024 Aug 12.
Vatiquinone is a small molecule inhibitor of 15-lipoxygenase in development for patients with Friedreich's ataxia. The objective of this analysis was to determine the effect of a cytochrome P450 isoform 3A4 (CYP3A4) inhibitor and inducer on vatiquinone pharmacokinetics (PKs). The coadministration of 400 mg of vatiquinone with 200 mg of itraconazole (a CYP3A4 inhibitor) resulted in increased maximum observed concentration (C) of vatiquinone and systemic exposure (AUC) by approximately 3.5- and 2.9-fold, respectively. The coadministration of 400 mg of vatiquinone with 600 mg of rifampin (a CYP3A4 inducer) resulted in decreased vatiquinone C and AUC by approximately 0.64- and 0.54-fold, respectively. The terminal half-life of vatiquinone was not affected by itraconazole or rifampin. These clinical study results confirm the in vitro reaction phenotyping data that shows that CYP3A4 plays an important role in vatiquinone metabolism. The result of this analysis together with phase 3 efficacy and safety data, population PK analysis, and the exposure-response relationship will determine if the extent of vatiquinone changes in the presence of CYP3A4 inhibitors and inducers are considered clinically relevant.
瓦替喹酮是一种 15-脂氧合酶的小分子抑制剂，正在开发用于治疗弗里德里希共济失调患者。本分析的目的是确定细胞色素 P450 同工酶 3A4（CYP3A4）抑制剂和诱导剂对瓦替喹酮药代动力学（PKs）的影响。与 200 毫克伊曲康唑（CYP3A4 抑制剂）合用 400 毫克瓦替喹酮，使瓦替喹酮的最大观测浓度（C）和全身暴露（AUC）分别增加约 3.5 倍和 2.9 倍。与 600 毫克利福平（CYP3A4 诱导剂）合用 400 毫克瓦替喹酮，使瓦替喹酮 C 和 AUC 分别降低约 0.64 倍和 0.54 倍。瓦替喹酮的终末半衰期不受伊曲康唑或利福平的影响。这些临床研究结果证实了体外反应表型数据，表明 CYP3A4 在瓦替喹酮代谢中起重要作用。这项分析的结果，以及 3 期疗效和安全性数据、群体 PK 分析和暴露-反应关系，将决定 CYP3A4 抑制剂和诱导剂存在时瓦替喹酮变化的程度是否被认为具有临床相关性。
