Bile acid is important for gastrointestinal absorption of nilotinib.
Bile acid is important for gastrointestinal absorption of nilotinib.
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胆汁酸对于尼洛替尼的胃肠道吸收很重要。
DOI：
10.1007/s00228-012-1282-x
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发表时间：
2012
期刊：
影响因子：
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通讯作者：
Sawada K.
中科院分区：
文献类型：
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作者：
Fujimi A;Takahashi N;Miura M;Kanisawa Y;Ono K;Sawada K.
先生们：最近，Larson等人在该杂志上报道，血液水平检测不太可能在新诊断的Ph+慢性髓性白血病（CML）患者的一般管理中发挥重要作用，这些患者处于尼罗替尼治疗的慢性期。一个原因是他们在12个月时检测到尼洛替尼暴露和分子反应之间没有显著的关系。另一方面，药代动力学分析表明，与伊马替尼超过98%的生物利用度相比，尼洛替尼的生物利用度非常低[2,3]，这可能导致尼洛替尼在个体间和个体内存在广泛的差异。在这里，我们报告我们的经验，治疗药物监测（TDM）的尼洛替尼。2007年3月，一名75岁男子被诊断为慢性粒细胞白血病；患者处于慢慢期，Sokal风险评分中等，最初给予伊马替尼400mg QD。八年前，病人患上了胃癌，并接受了全胃切除术。虽然伊马替尼治疗3个月后血液学完全缓解，但染色体分析显示24个月时细胞遗传学反应最小（Ph+ 95%）。鉴于对伊马替尼的明显耐药性，根据欧洲白血病网的建议，患者改为每日服用达沙替尼100mg。服用达沙替尼（达沙替尼C2； 9.94和7.17 ng/mL） 1个月后，测定2次血药浓度（C2）。结果表明，达沙替尼的生物利用度较低，很可能是由于胃切除术引起的胃酸过低。虽然未检测到ABL点突变，但在改用达沙替尼6个月后，染色体分析仍显示最小的细胞遗传学反应（Ph+ 90%）。因此，我们再次切换，这次是尼罗替尼400mg BID，在6个月内实现了部分细胞遗传学应答。然而，患者发生胆管结石引起的急性胆管炎，经皮经肝胆囊引流术（PTGBD） 1个月。由于PTGBD期间尼洛替尼的生物利用度可能较低，因此在手术期间和手术后监测血浆尼洛替尼水平[5]。在PTGBD期间，摄入尼洛替尼后0 ~ 4 h血浆浓度-时间曲线下面积（AUC0-4）和尼洛替尼C0分别为1194.1 ng·h/mL和298.7 ng/mL。相比之下，PTGBD后的AUC0-4和C0分别为3456.6 ng·h/mL和695.7 ng/mL（图1）。最终，在改用尼罗替尼（Ph+ 0%） 15个月后实现了完全的细胞遗传学应答。我们的研究结果提示，全胃切除术后低酸性或无酸性可能会减少达沙替尼从胃肠道的吸收，导致其血药浓度明显下降，疗效不佳。我们之前报道过，通常的抑酸药治疗剂量对达沙替尼[4]的剂量调整后的AUC0-4有显著的临床影响，本病例与早期的发现一致。这个病例也表明胆汁酸很重要
Sirs: Recently, it was reported in this journal by Larson et al. that blood level testing is unlikely to play an important role in the general management of patients with newly diagnosed Ph+ chronic myeloid leukemia (CML) in the chronic phase treated with nilotinib [1]. One reason is that they detected no significant relationship between nilotinib exposure and the molecular response at 12 months. On the other hand, pharmacokinetic analyses have shown that the bioavailability is very low for nilotinib, as compared to the more than 98% for imatinib [2, 3], which could result in broad interindividual and intraindividual variability with nilotinib. Here, we report our experience with therapeutic drug monitoring (TDM) of nilotinib. In March 2007, a 75-year-old man was diagnosed with CML; he was in the chronic phase with an intermediate Sokal risk score and was initially administrated imatinib 400 mg QD. Eight years earlier, the patient had developed gastric cancer and he underwent total gastrectomy. Although complete hematological remission was achieved after 3 months of imatinib therapy, chromosomal analysis revealed a minimal cytogenetic response (Ph+ 95%) at 24 months. Given the apparent resistance to imatinib, the patient was switched to dasatinib 100 mg QD, as recommended by the European LeukemiaNet. The plasma concentration 2 h after ingestion (C2) was measured twice 1 month after starting dasatinib (dasatinib C2; 9.94 and 7.17 ng/mL)[4]. The results suggested dasatinib bioavailability was low, most likely due to gastric hypoacidity related to the gastrectomy. And although no ABL point mutations were detected, chromosomal analysis still revealed a minimal cytogenetic response (Ph+ 90%) 6 months after switching to dasatinib. We therefore switched again, this time to nilotinib 400 mg BID, and a partial cytogenetic response was achieved within 6 months. However, the patient developed acute cholangitis caused by a bile duct stone, and percutaneous transhepatic gallbladder drainage (PTGBD) was undertaken for 1 month. Because of the potential for low nilotinib bioavailability during PTGBD, plasma nilotinib levels were monitored during and after the procedure [5]. During the period of PTGBD, the area under the plasma concentration-time curve from 0 to 4 h (AUC0–4) after nilotinib ingestion and the nilotinib C0 were 1194.1 ng· h/mL and 298.7 ng/mL, respectively. By comparison, the AUC0–4 and C0 after the PTGBD were 3456.6 ng· h/mL and 695.7 ng/mL, respectively (Fig. 1). Ultimately, a complete cytogenetic response was achieved 15 months after switching to nilotinib (Ph+ 0%). Our findings suggest hypoacidity or anacidity after total gastrectomy may reduce absorption of dasatinib from the gastrointestinal tract, resulting in a significant decrease in its plasma concentration and poor efficacy. We previously reported that the usual therapeutic dose of acid suppressants had a clinically significant effect on the dose-adjusted AUC0–4 for dasatinib [4], and the present case is consistent with that earlier finding. This case also shows that bile acid is important