“…Using hiPSC-CMs as an in-vitro tool for assessing drug-induced cardiotoxicity, this study has developed a model-based approach for translating in-vitro results to in-vivo predictions, focusing on antineoplastic agents. The in-vitro data were used to develop a mechanistic TD, which was then integrated into the PBPK models for doxorubicin and trastuzumab and into a QSP model describing the systemic response to cardiac injury [ 32 , 36 , 39 ]. Using this in-vitro to in-vivo translational platform, the systolic dysfunction incidence for doxorubicin and trastuzumab alone or in sequential combination has been predicted and validated by comparing our findings to published clinical results.…”
Section: Discussionmentioning
confidence: 99%
“…In the present study, the PBPK models and the parameters used for doxorubicin [ 36 ] and trastuzumab [ 39 ] were taken directly from the literature. Extracellular concentrations of antineoplastic agents in the heart were calculated using these PBPK models.…”
Objective
Antineoplastic agent-induced systolic dysfunction is a major reason for interruption of anticancer treatment. Although targeted anticancer agents infrequently cause systolic dysfunction, their combinations with chemotherapies remarkably increase the incidence. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide a potent in vitro model to assess cardiovascular safety. However, quantitatively predicting the reduction of ejection fraction based on hiPSC-CMs is challenging due to the absence of the body's regulatory response to cardiomyocyte injury.
Methods
Here, we developed and validated an in vitro-in vivo translational platform to assess the reduction of ejection fraction induced by antineoplastic drugs based on hiPSC-CMs. The translational platform integrates drug exposure, drug-cardiomyocyte interaction, and systemic response. The drug-cardiomyocyte interaction was implemented as a mechanism-based toxicodynamic (TD) model, which was then integrated into a quantitative system pharmacology-physiological-based pharmacokinetics (QSP-PBPK) model to form a complete translational platform. The platform was validated by comparing the model-predicted and clinically observed incidence of doxorubicin and trastuzumab-induced systolic dysfunction.
Results
A total of 33,418 virtual patients were incorporated to receive doxorubicin and trastuzumab alone or in combination. For doxorubicin, the QSP-PBPK-TD model successfully captured the overall trend of systolic dysfunction incidences against the cumulative doses. For trastuzumab, the predicted incidence interval was 0.31–2.7% for single-agent treatment and 0.15–10% for trastuzumab-doxorubicin sequential treatment, covering the observations in clinical reports (0.50–1.0% and 1.5–8.3%, respectively).
Conclusions
In conclusion, the in vitro-in vivo translational platform is capable of predicting systolic dysfunction incidence almost merely depend on hiPSC-CMs, which could facilitate optimizing the treatment protocol of antineoplastic agents.
“…Using hiPSC-CMs as an in-vitro tool for assessing drug-induced cardiotoxicity, this study has developed a model-based approach for translating in-vitro results to in-vivo predictions, focusing on antineoplastic agents. The in-vitro data were used to develop a mechanistic TD, which was then integrated into the PBPK models for doxorubicin and trastuzumab and into a QSP model describing the systemic response to cardiac injury [ 32 , 36 , 39 ]. Using this in-vitro to in-vivo translational platform, the systolic dysfunction incidence for doxorubicin and trastuzumab alone or in sequential combination has been predicted and validated by comparing our findings to published clinical results.…”
Section: Discussionmentioning
confidence: 99%
“…In the present study, the PBPK models and the parameters used for doxorubicin [ 36 ] and trastuzumab [ 39 ] were taken directly from the literature. Extracellular concentrations of antineoplastic agents in the heart were calculated using these PBPK models.…”
Objective
Antineoplastic agent-induced systolic dysfunction is a major reason for interruption of anticancer treatment. Although targeted anticancer agents infrequently cause systolic dysfunction, their combinations with chemotherapies remarkably increase the incidence. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide a potent in vitro model to assess cardiovascular safety. However, quantitatively predicting the reduction of ejection fraction based on hiPSC-CMs is challenging due to the absence of the body's regulatory response to cardiomyocyte injury.
Methods
Here, we developed and validated an in vitro-in vivo translational platform to assess the reduction of ejection fraction induced by antineoplastic drugs based on hiPSC-CMs. The translational platform integrates drug exposure, drug-cardiomyocyte interaction, and systemic response. The drug-cardiomyocyte interaction was implemented as a mechanism-based toxicodynamic (TD) model, which was then integrated into a quantitative system pharmacology-physiological-based pharmacokinetics (QSP-PBPK) model to form a complete translational platform. The platform was validated by comparing the model-predicted and clinically observed incidence of doxorubicin and trastuzumab-induced systolic dysfunction.
Results
A total of 33,418 virtual patients were incorporated to receive doxorubicin and trastuzumab alone or in combination. For doxorubicin, the QSP-PBPK-TD model successfully captured the overall trend of systolic dysfunction incidences against the cumulative doses. For trastuzumab, the predicted incidence interval was 0.31–2.7% for single-agent treatment and 0.15–10% for trastuzumab-doxorubicin sequential treatment, covering the observations in clinical reports (0.50–1.0% and 1.5–8.3%, respectively).
Conclusions
In conclusion, the in vitro-in vivo translational platform is capable of predicting systolic dysfunction incidence almost merely depend on hiPSC-CMs, which could facilitate optimizing the treatment protocol of antineoplastic agents.
“… 102 Bae et al developed a whole-body PBPK model using PK and biodistribution data from mice and predicted human PK of trastuzumab with the ratio of simulated versus observed AUC and Cmax being 1.02 and 0.72, respectively. 103 Taken together, these studies have demonstrated that there is a potential to use PBPK models for human PK prediction, which will avoid the use of NHPs when the sole purpose is to predict human PK without TMDD assessment.…”
Section: Efforts To Replace and Minimize The Use Of Nhpmentioning
Monoclonal antibodies (mAbs) deliver great benefits to patients with chronic and/or severe diseases thanks to their strong specificity to the therapeutic target. As a result of this specificity, non-human primates (NHP) are often the only preclinical species in which therapeutic antibodies cross-react with the target. Here, we highlight the value and limitations that NHP studies bring to the design of safe and efficient early clinical trials. Indeed, data generated in NHPs are integrated with in vitro information to predict the concentration/effect relationship in human, and therefore the doses to be tested in first-in-human trials. The similarities and differences in the systems defining the pharmacokinetics and pharmacodynamics (PKPD) of mAbs in NHP and human define the nature and the potential of the preclinical investigations performed in NHPs. Examples have been collated where the use of NHP was either pivotal to the design of the first-in-human trial or, inversely, led to the termination of a project prior to clinical development. The potential impact of immunogenicity on the results generated in NHPs is discussed. Strategies to optimize the use of NHPs for PKPD purposes include the addition of PD endpoints in safety assessment studies and the potential re-use of NHPs after non-terminal studies or cassette dosing several therapeutic agents of interest. Efforts are also made to reduce the use of NHPs in the industry through the use of in vitro systems, alternative in vivo models, and in silico approaches. In the case of prediction of ocular PK, the body of evidence gathered over the last two decades renders the use of NHPs obsolete. Expert perspectives, advantages, and pitfalls with these alternative approaches are shared in this review.
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