The plasma and cerebrospinal fluid pharmacokinetics of erlotinib and its active metabolite (OSI-420) after intravenous administration of erlotinib in non-human primates
The plasma and cerebrospinal fluid pharmacokinetics of erlotinib and its active metabolite (OSI-420) after intravenous administration of erlotinib in non-human primates
复制标题
DOI：
10.1007/s00280-007-0616-3
复制
发表时间：
2008-08-01
影响因子：
3
通讯作者：
Balis, Frank M.
中科院分区：
文献类型：
--
作者：
Meany, Holly J.;Fox, Elizabeth;Balis, Frank M.
目的盐酸厄洛替尼是一种表皮生长因子受体（EGFR）小分子抑制剂。EGFR在原发性脑瘤和转移到中枢神经系统的实体瘤中过度表达。我们在非人灵长类动物模型中评估了静脉注射厄洛替尼及其活性代谢物OSI-420后的血浆和脑脊液（CSF）药代动力学。方法4只成年恒河猴静脉滴注厄洛替尼1 h。在48小时内连续抽取血液和脑脊液样本，用高效液相色谱/串联质谱法定量厄洛替尼和osi420。采用非区室法和区室法估计药代动力学参数。通过AUC(CSF):AUC（血浆）计算CSF穿透量。结果短时间静脉输注厄洛替尼后血浆消失呈双指数，平均终末半衰期为5.2 h，平均清除率为128 ml/min /m(2)。血浆中OSI-420暴露量（AUC）为厄洛替尼的30%（范围12-59%），OSI-420清除率比厄洛替尼高5倍以上。脑脊液中检测到厄洛替尼和OSI-420。厄洛替尼和OSI-420的脑脊液穿透(AUC（CSF):AUC（血浆））相对于总血浆浓度< 5%，但脑脊液药物暴露与血浆游离药物暴露的30%相似，这是根据已公布的血浆蛋白结合值计算的。静脉给药厄洛替尼耐受性良好。结论厄洛替尼及其活性代谢物OSI-420在静脉给药后脑脊液中可测量。脑脊液中的药物暴露（AUC）相对于总血浆浓度是有限的，但相对于血浆中的游离药物暴露是可观的。
Purpose Erlotinib hydrochloride is a small molecule inhibitor of epidermal growth factor receptor (EGFR). EGFR is over-expressed in primary brain tumors and solid tumors that metastasize to the central nervous system. We evaluated the plasma and cerebrospinal fluid (CSF) pharmacokinetics of erlotinib and its active metabolite OSI-420 after an intravenous (IV) dose in a non-human primate model.Methods Erlotinib was administered as a 1 h IV infusion to four adult rhesus monkeys. Serial blood and CSF samples were drawn over 48 h and erlotinib and OSI-420 were quantified with an HPLC/tandem mass spectroscopic assay. Pharmacokinetic parameters were estimated using non-compartmental and compartmental methods. CSF penetration was calculated from the AUC(CSF):AUC(plasma).Results Erlotinib disappearance from plasma after a short IV infusion was biexponential with a mean terminal half-life of 5.2 h and a mean clearance of 128 ml/min per m(2). OSI-420 exposure (AUC) in plasma was 30% (range 12-59%) of erlotinib, and OSI-420 clearance was more than 5-fold higher than erlotinib. Erlotinib and OSI-420 were detectable in CSF. The CSF penetration (AUC(CSF):AUC(plasma)) of erlotinib and OSI-420 was < 5% relative to total plasma concentration, but CSF drug exposure was similar to 30% of plasma free drug exposure, which was calculated from published plasma protein binding values. The IV administration of erlotinib was well tolerated.Conclusions Erlotinib and its active metabolite OSI-420 are measurable in CSF after an IV dose. The drug exposure (AUC) in the CSF is limited relative to total plasma concentrations but is substantial relative the free drug exposure in plasma.