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      Population pharmacokinetics of trastuzumab emtansine (T-DM1), a HER2-targeted antibody-drug conjugate, in patients with HER2-positive metastatic breast cancer: clinical implications of the effect of covariates.
      作者:Lu D, Girish S, Gao Y, Wang B, Yi JH, Guardino E, Samant M, Cobleigh M, Rimawi M, Conte P, Jin JY. | 發布:yangyuting | 發布時間: 2018-08-01 | 1794 次瀏覽 | 分享到:
      Trastuzumab emtansine (TDM1) is an antibody drug conjugate comprising the humanized monoclonal antibody trastuzumab linked to DM1, a highly potent cytotoxic agent. A population pharmacokinetic (PK) analysis was performed to estimate typical values and interindividual variability of TDM1 PK parameters and the effects of clinically relevant covariates.

      Serum samples were collected from 671 patients with human epidermal growth factor receptor 2 positive locally advanced or metastatic breast cancer (MBC) who received single-agent TDM1 in five phase I to phase III studies. Nonlinear mixed effects modeling with the first-order conditional estimation method was used.

      A linear two compartment model with first-order elimination from the central compartment described TDM1 PKs in the clinical dose range. TDM1 elimination clearance was 0.676 L/day, volume of distribution in the central compartment (V c) was 3.127 L, and terminal elimination half-life was 3.94 days. Age, race, region, and renal function did not influence TDM1 PK. Given the low-to-moderate effect of all statistically significant covariates on TDM1 exposure, none of these covariates is expected to result in a clinically meaningful change in TDM1 exposure.

      TDM1 PK properties are consistent and predictable in patients. A further refinement of dose based on baseline covariates other than body weight for the current 3.6 mg/kg regimen would not yield clinically meaningful reductions in interindividual PK variability in patients with MBC.
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