Phase I Study of the Effect of Gastric Acid pH Modulators on the Bioavailability of Oral Dasatinib in Healthy Subjects
Phase I Study of the Effect of Gastric Acid pH Modulators on the Bioavailability of Oral Dasatinib in Healthy Subjects
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DOI：
10.1177/0091270009333854
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发表时间：
2009-06-01
影响因子：
2.9
通讯作者：
Bertz, Richard
中科院分区：
文献类型：
--
作者：
Eley, Timothy;Luo, Feng R.;Bertz, Richard
达沙替尼是一种酪氨酸激酶抑制剂（包括BCR-ABL和SRC家族），对慢性髓性白血病患者有效。达沙替尼具有ph依赖性溶解度，作为口服制剂具有生物可利用性。在一项开放标签、随机、3期、3治疗的交叉研究中，评估胃pH调节剂对达沙替尼药代动力学的影响。24名健康受试者接受治疗A（2剂达沙替尼50mg，间隔12小时）、治疗B（法莫替丁40mg，在达沙替尼50mg后2小时给予，在另一剂达沙替尼50mg前10小时给予）和治疗C（在达沙替尼50mg前2小时给予含有铝/镁的抗酸剂30ml，在前一次达沙替尼剂量后12小时与达沙替尼50mg同时给予）；每个治疗期间隔7天的洗脱期。当法莫替丁在达沙替尼后2小时给药时，达沙替尼暴露与单独给药达沙替尼相似。然而，当法莫替丁在达沙替尼给药前10小时给药时，达沙替尼暴露减少了60%。相比之下，当抗酸剂（Maalox）在使用达沙替尼前2小时使用达沙替尼时，达沙替尼暴露量不变；但当抗酸剂与达沙替尼同时使用时，达沙替尼暴露量减少了55%至58%。这表明H(2)受体拮抗剂不应与达沙替尼共给药。达沙替尼可以与酸中和抗酸剂一起给药，如果剂量暂时间隔至少2小时。
Dasatinib is a tyrosine kinase inhibitor (including BCR-ABL and the SRC family) that is effective in patients with chronic myeloid leukemia. Dasatinib has pH-dependent solubility and is bioavailable as an oral formulation. The effect of gastric pH modifiers on dasatinib pharmacokinetics is evaluated in an open-label, randomized, 3-period, 3-treatment crossover study. Twenty-four healthy subjects receive treatment A (2 doses of dasatinib 50 mg separated by 12 hours), treatment B (famotidine 40 mg given 2 hours after dasatinib 50 mg and 10 hours before another dose of dasatinib 50 mg), and treatment C (30 mL of an antacid containing aluminum/magnesium hydroxides given 2 hours before dasatinib 50 mg and concomitantly with dasatinib 50 mg 12 hours after the previous dasatinib dose); a 7-day washout separates each treatment period. When famotidine is administered 2 hours after dasatinib, dasatinib exposure is similar to dasatinib administered alone. However, dasatinib exposure is reduced by similar to 60% when famotidine is administered 10 hours before dasatinib dosing. In contrast, dasatinib exposure is unchanged when antacid ( Maalox) is administered 2 hours before dasatinib; but when the antacid is coadministered with dasatinib, dasatinib exposure is reduced by similar to 55% to 58%. This indicates that H(2)-receptor antagonists should not be coadministered with dasatinib. Dasatinib may be administered with acid-neutralizing antacids if the doses are temporally separated by at least 2 hours.