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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
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
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2012 (Engelska)Ingår i: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 70, nr 4, s. 591-601Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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.

Ort, förlag, år, upplaga, sidor
2012. Vol. 70, nr 4, s. 591-601
Nyckelord [en]
Trastuzumab emtansine, T-DM1, Thrombocytopenia, Population pharmacokinetic/pharmacodynamic model, Semimechanistic, Cumulative TCP
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-183550DOI: 10.1007/s00280-012-1934-7ISI: 000309201500013OAI: oai:DiVA.org:uu-183550DiVA, id: diva2:575080
Tillgänglig från: 2012-12-07 Skapad: 2012-10-29 Senast uppdaterad: 2017-09-11Bibliografiskt granskad
Ingår i avhandling
1. Pharmacometric Models for Antibody Drug Conjugates and Taxanes in HER2+ and HER2- Breast Cancer
Öppna denna publikation i ny flik eller fönster >>Pharmacometric Models for Antibody Drug Conjugates and Taxanes in HER2+ and HER2- Breast Cancer
2016 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

In oncology, there is a need to optimize drug treatment for efficient eradication of tumors, minimization of adverse effects (AEs), and prolonging patient survival. Pharmacometric models can be developed to streamline information between drug development phases, describe and quantify response to treatment, and determine dose regimens that balance toxicity and efficacy. In this thesis, data from trastuzumab emtansine (T-DM1) and taxane drug treatment were used to develop pharmacometric models of pharmacokinetics (PK), AEs, anti-tumor response, and survival, supporting drug development.

T-DM1 is an antibody-drug conjugate (ADC) for treatment of human epidermal growth factor receptor 2 (HER2)–positive breast cancer. ADCs are a relatively new class of oncologic agents, and contain multiple drug-to-antibody ratio (DAR) moieties in their dose product. The complex distribution of T-DM1 was elucidated through PK models developed using in vitro and in vivo rat and cynomolgus monkey DAR data. Mechanism–based PK/pharmacodynamic (PKPD) models were also developed for T-DM1 that described the AEs thrombocytopenia (TCP) and hepatotoxicity in patients receiving T-DM1. Variable patterns of platelet and transaminase (ALT and AST) response were quantified, including an effect of Asian ethnicity that was related to higher incidences of TCP.  Model simulations, comparing dose intensities (DI) and Grade 3/4 incidences between the approved T-DM1 dose (3.6 mg/kg every three weeks) and weekly regimens, determined that 2.4 mg/kg weekly provided the highest DI.

Docetaxel and paclitaxel are taxane treatment options for HER2–negative breast cancer. Tumor response data from these treatments were used to develop a mechanism–based model of tumor quiescence and drug–resistance. Subsequently, a parametric survival analysis found that tumor baseline and the model–predicted time to tumor growth (TTG) were predictors of overall survival (OS). This tumor and OS modeling approach can be applied to other anticancer treatments with similar patterns of drug–resistance.

Overall, the pharmacometric models developed within this thesis present new modeling approaches and provide understanding on ADC PK and PKPD (TCP and hepatotoxicity), as well as drug–resistance tumor response. These models can inform simulation strategies and clinical study design, and be applied towards dose finding for anticancer drugs in development, especially ADCs.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2016. s. 87
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 217
Nyckelord
pharmacometric, PKPD, model, breast cancer, T-DM1, thrombocytopenia, hepatotoxiticy, HER2
Nationell ämneskategori
Farmaceutiska vetenskaper
Forskningsämne
Farmakokinetik och läkemedelsterapi
Identifikatorer
urn:nbn:se:uu:diva-292617 (URN)978-91-554-9603-6 (ISBN)
Disputation
2016-09-02, B/B42, BMC, Husargatan 3, Uppsala, 13:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2016-06-03 Skapad: 2016-05-04 Senast uppdaterad: 2018-01-10Bibliografiskt granskad

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Bender, Brendan C.Friberg, Lena E.

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