Martin Paul, Gillen Michael, Millson David, Oliver Stuart, Brealey Clive, Grossbard Elliott B, Baluom Muhammad, Lau David, Sweeny David, Mant Tim, Craven Kelli
AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, SK10 4TF, UK.
AstraZeneca, Gaithersburg, MD, USA.
Drugs R D. 2016 Mar;16(1):81-92. doi: 10.1007/s40268-015-0118-4.
Fostamatinib (R788) is a spleen tyrosine kinase (SYK) inhibitor. The active metabolite of fostamatinib, R406, is primarily metabolized by CYP3A4.
The aim of this study was to characterize hepatic microsomal metabolism of R406 and confirm the role of CYP3A4 in R406 metabolism, determining whether co-administration of CYP3A4 inhibitors (ketoconazole, verapamil) or inducers (rifampicin) affects R406 pharmacokinetics.
R406 stability was determined using human hepatic microsomes. The CYP450 isoforms responsible for R406 metabolism in humans were identified using expressed CYP450 isoforms and specific chemical inhibitors. The ketoconazole interaction study (double-blind, randomized, placebo-controlled, two-period crossover) involved fostamatinib administration (single 80-mg dose), alone and with ketoconazole (200 mg twice daily). The verapamil and rifampicin interaction studies (open-label, two-period, fixed-sequence) involved fostamatinib administration (single 150-mg dose), alone and with immediate-release verapamil (80 mg three times daily) or rifampicin (600 mg once daily). Standard pharmacokinetic parameters were calculated in all studies.
RESULTS/DISCUSSION: Hepatic microsomes showed time-dependent loss of R406 and formation of para-O-demethylated R406. Microsomal metabolism of R406 was markedly inhibited by CYP3A4 inhibitors and, in the expressed CYP450 studies, the rate of R406 disappearance was greatest with CYP3A4. In the clinical studies, co-administration of ketoconazole caused a 2-fold (CI 1.77-2.30) increase in R406 exposure. Verapamil increased R406 exposure (39% increase, CI 8-80), whereas rifampicin co-administration decreased exposure by 75% (CI 68-81). Fostamatinib was well tolerated.
The oxidative metabolism of R406 is predominantly catalyzed by CYP3A4. In clinical studies, exposure to R406 is affected by concomitant administration of CYP3A4 inducers/inhibitors. These findings should be taken into account when considering co-prescription of fostamatinib with such agents.
福他替尼（R788）是一种脾酪氨酸激酶（SYK）抑制剂。福他替尼的活性代谢产物R406主要由CYP3A4代谢。
本研究旨在表征R406的肝微粒体代谢，确认CYP3A4在R406代谢中的作用，确定CYP3A4抑制剂（酮康唑、维拉帕米）或诱导剂（利福平）的联合使用是否会影响R406的药代动力学。
使用人肝微粒体测定R406的稳定性。使用表达的CYP450同工酶和特异性化学抑制剂鉴定负责R406在人体内代谢的CYP450同工酶。酮康唑相互作用研究（双盲、随机、安慰剂对照、两期交叉）包括单独给予福他替尼（单次80mg剂量）以及与酮康唑联合给药（200mg，每日两次）。维拉帕米和利福平相互作用研究（开放标签、两期、固定顺序）包括单独给予福他替尼（单次150mg剂量）以及与速释维拉帕米（80mg，每日三次）或利福平（600mg，每日一次）联合给药。在所有研究中计算标准药代动力学参数。
结果/讨论：肝微粒体显示R406随时间减少以及对羟基去甲基化R406的形成。CYP3A4抑制剂显著抑制R406的微粒体代谢，并且在表达的CYP450研究中，R406消失速率在CYP3A4作用下最快。在临床研究中，联合给予酮康唑导致R406暴露增加2倍（可信区间1.77 - 2.30）。维拉帕米增加R406暴露（增加39%，可信区间8 - 80），而联合给予利福平使暴露减少75%（可信区间68 - 81）。福他替尼耐受性良好。
R406的氧化代谢主要由CYP3A4催化。在临床研究中，R406的暴露受CYP3A4诱导剂/抑制剂联合使用的影响。在考虑福他替尼与此类药物联合处方时应考虑这些发现。
