Novartis Pharmaceuticals Corporation, Florham Park, New Jersey, USA.
Clin Drug Investig. 2011;31(3):169-79. doi: 10.2165/11538700-000000000-00000.
Nilotinib (Tasigna®), a highly selective and potent BCR-ABL tyrosine kinase inhibitor, is approved for the treatment of chronic myeloid leukaemia in the chronic phase (CML-CP) and the accelerated phase (CML-AP) in patients resistant or intolerant to prior therapy, including imatinib. Nilotinib has shown competitive inhibition of cytochrome P450 enzyme (CYP) 2C9 in vitro, but its effect on CYP2C9 activity in humans is unknown. This study evaluated the effects of nilotinib on the pharmacokinetics and pharmacodynamics of warfarin, a sensitive CYP2C9 substrate, in healthy subjects.
Twenty-four subjects (six female, 18 male, aged 21-65 years) were enrolled to receive a single oral dose of warfarin 25 mg with either a single oral dose of nilotinib 800 mg or matching placebo (all administered 30 minutes after consumption of a high-fat meal) in a crossover design. Serial blood samples were collected post-dose for determining serum concentrations of nilotinib and plasma concentrations of S- and R-warfarin. Prothrombin time (PT) and international normalized ratio (INR) values were determined as pharmacodynamic measures of warfarin activity. CYP2C9 genotyping was performed in all subjects using TaqMan® assay.
Sixteen subjects were identified as CYP2C9 extensive metabolizers (EMs) and eight as intermediate metabolizers (IMs). There were no CYP2C9 poor metabolizers. Pharmacokinetic parameters of S- and R-warfarin were similar between the two treatments (warfarin + nilotinib vs warfarin alone) in both the EM and the IM groups. The geometric mean ratios (90% CIs) for the maximum concentration in plasma (C(max)) and area under the concentration-time curve from time zero to infinity (AUC(∞)) of S-warfarin in plasma in all subjects were 0.98 (0.95, 1.02) and 1.03 (0.99, 1.07), respectively, and for R-warfarin 1.00 (0.96, 1.04) and 1.02 (0.99, 1.04), respectively. Mean ratios for the maximum observed value and AUC from time zero to the last sampling time for PT were 1.00 (0.96, 1.04) and 1.00 (0.98, 1.02), respectively, and for the maximum observed value for INR and the AUC from time zero to the last sampling time for INR were 1.00 (0.97, 1.03) and 1.00 (0.99, 1.01), respectively. Mean ± SD serum nilotinib C(max) was 1872 ± 560 ng/mL, which is comparable to steady-state C(max) in CML and gastrointestinal stromal tumour patients receiving twice-daily 400 mg doses. Adverse events observed following either treatment were generally consistent with the known safety profiles of both drugs, and no new safety issues were observed.
The study results demonstrate that nilotinib has no effect on single-dose warfarin pharmacokinetics and pharmacodynamics. This implies that nilotinib is unlikely to inhibit CYP2C9 activity in human subjects. These findings suggest that warfarin and nilotinib may be used concurrently as needed.
尼洛替尼（Tasigna®）是一种高度选择性和有效的 BCR-ABL 酪氨酸激酶抑制剂，适用于对先前治疗（包括伊马替尼）耐药或不耐受的慢性髓性白血病慢性期（CML-CP）和加速期（CML-AP）患者的治疗。尼洛替尼在体外对细胞色素 P450 酶（CYP）2C9 具有竞争性抑制作用，但在人类中对 CYP2C9 活性的影响尚不清楚。本研究评估了尼洛替尼对健康受试者中敏感 CYP2C9 底物华法林的药代动力学和药效学的影响。
24 名受试者（6 名女性，18 名男性，年龄 21-65 岁）按交叉设计接受单次口服华法林 25mg 加尼洛替尼 800mg 或匹配安慰剂（均在高脂餐后 30 分钟服用）。给药后采集连续血样，用于测定血清尼洛替尼浓度和血浆 S-和 R-华法林浓度。凝血酶原时间（PT）和国际标准化比值（INR）值作为华法林活性的药效学测量。使用 TaqMan® assay 对所有受试者进行 CYP2C9 基因分型。
16 名受试者被鉴定为 CYP2C9 广泛代谢者（EMs），8 名受试者为中间代谢者（IMs）。没有 CYP2C9 弱代谢者。在 EM 和 IM 组中，两种治疗方案（华法林+尼洛替尼与华法林单独治疗）的 S-和 R-华法林的药代动力学参数相似。所有受试者血浆中 S-华法林最大浓度（C(max)）和从零时到无穷大的浓度-时间曲线下面积（AUC(∞)）的几何均数比值（90%置信区间）分别为 0.98（0.95，1.02）和 1.03（0.99，1.07），R-华法林分别为 1.00（0.96，1.04）和 1.02（0.99，1.04）。PT 最大观察值和从零时到最后采样时间的 AUC 的平均比值为 1.00（0.96，1.04）和 1.00（0.98，1.02），INR 最大观察值和从零时到最后采样时间的 INR 的 AUC 的平均比值为 1.00（0.97，1.03）和 1.00（0.99，1.01）。平均±SD 血清尼洛替尼 C(max)为 1872±560ng/ml，与 CML 和胃肠道间质瘤患者接受每日两次 400mg 剂量时的稳态 C(max)相当。两种治疗方案后观察到的不良事件通常与两种药物已知的安全性特征一致，未观察到新的安全性问题。
研究结果表明，尼洛替尼对华法林的单次剂量药代动力学和药效学没有影响。这意味着尼洛替尼不太可能抑制人类受试者的 CYP2C9 活性。这些发现表明，华法林和尼洛替尼可能需要时同时使用。
