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A population pharma...
A population pharmacokinetic/pharmacodynamic model of thrombocytopenia characterizing the effect of trastuzumab emtansine (T-DM1) on platelet counts in patients with HER2-positive metastatic breast cancer
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- Bender, Brendan C., 1967- (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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Schaedeli-Stark, Franziska (författare)
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Koch, Reinhold (författare)
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Joshi, Amita (författare)
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Chu, Yu-Waye (författare)
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Rugo, Hope (författare)
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Krop, Ian E. (författare)
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Girish, Sandhya (författare)
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- Friberg, Lena E. (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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Gupta, Manish (författare)
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(creator_code:org_t)
- 2012-08-12
- 2012
- Engelska.
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Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 70:4, s. 591-601
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate in the development for the treatment of human epidermal growth factor receptor 2-positive cancers. Thrombocytopenia (TCP) is the dose-limiting toxicity of T-DM1. A semimechanistic population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to characterize the effect of T-DM1 on patient platelet counts. A PK/PD model with transit compartments that mimic platelet development and circulation was fit to concentration-platelet-time course data from two T-DM1 single-agent studies (TDM3569g; N = 52 and TDM4258g; N = 112). NONMEMA (R) 7 software was used for model development. Data from a separate phase II study (TDM4374g; N = 110) were used for model evaluation. Patient baseline characteristics were evaluated as covariates of model PD parameters. The model described the platelet data well and predicted the incidence of grade a parts per thousand yen3 TCP. The model predicted that with T-DM1 3.6 mg/kg given every 3 weeks (q3w), the lowest platelet nadir would occur after the first dose. Also predicted was a patient subgroup (46 %) having variable degrees of downward drifting platelet-time profiles, which were predicted to stabilize by the eighth treatment cycle to platelet counts above grade 3 TCP. Baseline characteristics were not significant covariates of PD parameters in the model. This semimechanistic PK/PD model accurately captures the cycle 1 platelet nadir, the downward drift noted in some patient platelet-time profiles, and the similar to 8 % incidence of grade a parts per thousand yen3 TCP with T-DM1 3.6 mg/kg q3w. This model supports T-DM1 3.6 mg/kg q3w as a well-tolerated dose with minimal dose delays or reductions for TCP.
Nyckelord
- Trastuzumab emtansine
- T-DM1
- Thrombocytopenia
- Population pharmacokinetic/pharmacodynamic model
- Semimechanistic
- Cumulative TCP
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Bender, Brendan ...
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Schaedeli-Stark, ...
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Koch, Reinhold
-
Joshi, Amita
-
Chu, Yu-Waye
-
Rugo, Hope
-
visa fler...
-
Krop, Ian E.
-
Girish, Sandhya
-
Friberg, Lena E.
-
Gupta, Manish
-
visa färre...
- Artiklar i publikationen
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Cancer Chemother ...
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Uppsala universitet