Quartino Angelica L, Hillenbach Carina, Li Jing, Li Hanbin, Wada Russell D, Visich Jennifer, Li Chunze, Heinzmann Dominik, Jin Jin Y, Lum Bert L
Genentech, Inc., California, CA, USA.
Roche, Basel, Switzerland.
Cancer Chemother Pharmacol. 2016 Jan;77(1):77-88. doi: 10.1007/s00280-015-2922-5. Epub 2015 Dec 8.
To characterize the population pharmacokinetics (PKs) of subcutaneous (SC) and intravenous (IV) trastuzumab in early breast cancer (EBC), assess the impact of covariates on trastuzumab PK, and evaluate fixed (nonweight-based) dosing for the SC regimen administrated via handheld syringe.
Serum trastuzumab concentrations from 595 patients with HER2-positive EBC in the HannaH study (fixed 600 mg SC trastuzumab or weight-based IV trastuzumab) were analyzed using nonlinear mixed-effects modeling. Multiple logistic regression was used to assess the exposure-response relationships between PK, efficacy [pathologic complete response (pCR)], and safety [grade ≥3 adverse events (AEs)].
Trastuzumab PK was described by a two-compartment model with parallel linear and nonlinear elimination and first-order SC absorption, with a bioavailability of 77 %. Estimated total clearance (CL) values were 0.18-0.22 L/day for steady-state trough/peak concentrations of 75-148 µg/mL; the estimate for central volume of distribution was 2.9 L. Body weight and alanine transaminase, while showing significant effects on PK, only explained 8% of the variability in CL. Exposure-response analyses showed no relationship between PK, pCR, and grade ≥3 AEs for either regimen.
A fixed 600 mg SC dose of trastuzumab provides the desired exposure, with steady-state trough concentrations (35-123 μg/mL for the 5th-95th percentiles) above the historical target concentration of 20 μg/mL for efficacy. Fixed dosing is further supported by lack of an exposure-response relationship between PK, pCR, and grade ≥3 AEs. No dose adjustment per patient factors is required within the ranges studied.
描述早期乳腺癌（EBC）患者皮下（SC）和静脉注射（IV）曲妥珠单抗的群体药代动力学（PK），评估协变量对曲妥珠单抗PK的影响，并评估通过手持注射器给药的SC方案的固定（非基于体重）剂量。
使用非线性混合效应模型分析了HannaH研究中595例HER2阳性EBC患者的血清曲妥珠单抗浓度（固定600mg SC曲妥珠单抗或基于体重的IV曲妥珠单抗）。采用多元逻辑回归评估PK、疗效[病理完全缓解（pCR）]和安全性[≥3级不良事件（AE）]之间的暴露-反应关系。
曲妥珠单抗PK由具有平行线性和非线性消除以及一级SC吸收的二室模型描述，生物利用度为77%。稳态谷浓度/峰浓度为75-148μg/mL时，估计的总清除率（CL）值为0.18-0.22L/天；中央分布容积估计值为2.9L。体重和丙氨酸转氨酶虽然对PK有显著影响，但仅解释了CL变异性的8%。暴露-反应分析表明，两种方案的PK、pCR和≥3级AE之间均无关系。
固定600mg SC剂量的曲妥珠单抗可提供所需的暴露量，稳态谷浓度（第5-95百分位数为35-123μg/mL）高于疗效所需的历史目标浓度20μg/mL。PK与pCR和≥3级AE之间缺乏暴露-反应关系进一步支持了固定剂量。在所研究的范围内，无需根据患者因素调整剂量。
