Poggesi Italo, Li Lilian Y, Jiao James, Hellemans Peter, Rasschaert Freya, de Zwart Loeckie, Snoeys Jan, De Meulder Marc, Mamidi Rao N V S, Ouellet Daniele
Global Clinical Pharmacology, Quantitative Sciences, Janssen-Cilag SpA, Via Michelangelo Buonarroti 23, 20093, Cologno Monzese, MI, Italy.
Janssen Research & Development, Springhouse, PA, USA.
Eur J Drug Metab Pharmacokinet. 2020 Feb;45(1):101-111. doi: 10.1007/s13318-019-00581-9.
Erdafitinib, an oral selective pan-fibroblast growth factor receptor (FGFR) kinase inhibitor, is primarily metabolized by cytochrome P450 (CYP) 2C9 and 3A4. The aim of this phase 1 study was to assess the pharmacokinetics and safety of erdafitinib in healthy participants when coadministered with fluconazole (moderate CYP2C9 and CYP3A inhibitor), and itraconazole (a strong CYP3A4 and P-glycoprotein inhibitor). The effect of CYP2C9 genotype variants (*1/*1, *1/*2, *1/*3) on the pharmacokinetics of erdafitinib was also investigated.
In this open-label, parallel-group, single-center study, eligible healthy adults were randomized by CYP2C9 genotype to receive Treatment A (single oral dose of erdafitinib 4 mg) on day 1, Treatment B (fluconazole 400 mg/day orally) on days 1-11, or Treatment C (itraconazole 200 mg/day orally) on days 1-11. Healthy adults randomized to Treatment B and C received a single oral 4-mg dose of erdafitinib on day 5. The pharmacokinetic parameters, including mean maximum plasma concentration (C), area under the curve (AUC) from time 0 to 168 h (AUC), AUC from time 0 to the last quantifiable concentration (AUC), and AUC from time 0 to infinity (AUC) were calculated from individual plasma concentration-time data using standard non-compartmental methods.
Coadministration of erdafitinib with fluconazole increased C of erdafitinib by approximately 21%, AUC by 38%, AUC by 49%, and AUC by 48% while coadministration with itraconazole resulted in no change in erdafitinib C and increased AUC by 20%, AUC by 33% and AUC by 34%. Erdafitinib exposure was comparable between participants with CYP2C9 *1/*2 or *1/*3 and with wild-type CYP2C9 genotype. The ratio of total amount of erdafitinib excreted in the urine (inhibited to non-inhibited) was 1.09, the ratio of total amount of excreted metabolite M6 was 1.21, and the ratio of the metabolite to parent ratio in the urine was 1.11, when coadministration of erdafitinib with itraconazole was compared with single-dose erdafitinib. Treatment-emergent adverse events (TEAEs) were generally Grade 1 or 2 in severity; the most commonly reported TEAE was headache. No safety concerns were identified with single-dose erdafitinib when administered alone and in combination with fluconazole or itraconazole in healthy adults.
Coadministration of fluconazole or itraconazole or other moderate/strong CYP2C9 or CYP3A4 inhibitors may increase exposure to erdafitinib in healthy adults and thus may warrant erdafitinib dose reduction or use of alternative concomitant medications with no or minimal CYP2C9 or CYP3A4 inhibition potential.
ClinicalTrials.gov identifier number: NCT03135106.
厄达替尼是一种口服选择性泛成纤维细胞生长因子受体（FGFR）激酶抑制剂，主要通过细胞色素P450（CYP）2C9和3A4代谢。本1期研究的目的是评估厄达替尼与氟康唑（中度CYP2C9和CYP3A抑制剂）及伊曲康唑（强效CYP3A4和P-糖蛋白抑制剂）合用时在健康受试者中的药代动力学及安全性。同时还研究了CYP2C9基因变异型（*1/*1、*1/*2、*1/*3）对厄达替尼药代动力学的影响。
在这项开放标签、平行组、单中心研究中，符合条件的健康成年人根据CYP2C9基因型随机分组，于第1天接受治疗A（单次口服4 mg厄达替尼），于第1 - 11天接受治疗B（口服氟康唑400 mg/天），或于第1 - 11天接受治疗C（口服伊曲康唑200 mg/天）。随机分配至治疗B和C组的健康成年人在第5天接受单次口服4 mg厄达替尼。药代动力学参数包括平均最大血浆浓度（C）、0至168小时的曲线下面积（AUC）、0至最后可定量浓度的AUC以及0至无穷大的AUC，使用标准非房室模型方法根据个体血浆浓度-时间数据计算得出。
厄达替尼与氟康唑合用时，厄达替尼的C增加约21%，AUC增加38%，AUC增加49%，AUC增加48%；而与伊曲康唑合用时，厄达替尼的C无变化，AUC增加20%，AUC增加33%，AUC增加34%。携带CYP2C9 *1/2或1/*3的受试者与野生型CYP2C9基因型受试者的厄达替尼暴露量相当。与单剂量厄达替尼相比，厄达替尼与伊曲康唑合用时，尿液中排泄的厄达替尼总量（受抑制与未受抑制）之比为1.09，代谢物M6排泄总量之比为1.21，尿液中代谢物与母体之比为1.11。治疗期间出现的不良事件（TEAE）严重程度一般为1级或2级；最常报告的TEAE为头痛。在健康成年人中，单剂量厄达替尼单独给药以及与氟康唑或伊曲康唑联合给药时未发现安全性问题。
氟康唑或伊曲康唑或其他中度/强效CYP2C9或CYP3A4抑制剂与厄达替尼合用时，可能会增加健康成年人对厄达替尼的暴露量，因此可能需要减少厄达替尼剂量或使用无或极小CYP2C9或CYP3A4抑制潜力的替代联合用药。
ClinicalTrials.gov标识符编号：NCT03135106。
