Effects of ketoconazole and carbamazepine on lapatinib pharmacokinetics in healthy subjects.
Effects of ketoconazole and carbamazepine on lapatinib pharmacokinetics in healthy subjects.
复制标题
酮康唑和卡马西平对健康受试者拉帕替尼药代动力学的影响。
DOI：
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发表时间：
2009
影响因子：
3.4
通讯作者：
A. Beelen
中科院分区：
文献类型：
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作者：
Deborah A. Smith;K. Koch;Nikita Arya;C. Bowen;J. Herendeen;A. Beelen
旨在
描述强效CYP3A4抑制和诱导对拉帕替尼药代动力学的影响。
方法
在健康受试者中进行了两项研究。一项研究检查了酮康唑200 mg b.i.d. 22名健康受试者接受拉帕替尼100 mg单次给药7天。另一项研究检查了卡马西平滴定至200 mg b.i.d.的效果。24名健康受试者接受250 mg拉帕替尼单次给药超过20天。
结果
酮康唑改变了拉帕替尼的AUC、C（max）和半衰期，几何平均值[95%置信区间（CI）]分别增加了3.57倍（3.07，4.15）、2.14倍（1.74，2.64）和1.66倍（1.50，1.84），但对吸收率没有影响。卡马西平改变了拉帕替尼的AUC、C（max）和吸收率，几何平均值（95% CI）分别降低72%（68，77）、59%（49，66）和28%（4，46），但对半衰期无影响。
结论
通过强效抑制和诱导CYP3A4显著改变拉帕替尼的全身暴露量。当拉帕替尼与可能改变该酶活性的口服药物联合给药时，可能需要调整剂量。
AIMS
To characterize the impact of potent CYP3A4 inhibition and induction on lapatinib pharmacokinetics.
METHODS
Two studies were conducted in healthy subjects. One study examined the effect of ketoconazole 200 mg b.i.d. for 7 days on a single 100-mg dose of lapatinib in 22 healthy subjects. The other study examined the effect of carbamazepine titrated up to 200 mg b.i.d. over 20 days on a single 250-mg dose of lapatinib in 24 healthy subjects.
RESULTS
Ketoconazole altered lapatinib AUC, C(max) and half-life, with geometric mean [95% confidence interval (CI)] increases of 3.57-fold (3.07, 4.15), 2.14-fold (1.74, 2.64) and 1.66-fold (1.50, 1.84), respectively, but had no effect on absorption rate. Carbamazepine altered lapatinib AUC, C(max) and absorption rate, with geometric mean (95% CI) decreases of 72% (68, 77), 59% (49, 66) and 28% (4, 46), respectively, but had no effect on half-life.
CONCLUSIONS
Systemic exposure to lapatinib was significantly altered by potent inhibition and induction of CYP3A4. Dose adjustments may be required when lapatinib is administered with orally administered drugs that potently alter the activity of this enzyme.