Dataset Information

Can Population Modelling Principles be Used to Identify Key PBPK Parameters for Paediatric Clearance Predictions? An Innovative Application of Optimal Design Theory.

ABSTRACT:

Purpose

Physiologically-based pharmacokinetic (PBPK) models are essential in drug development, but require parameters that are not always obtainable. We developed a methodology to investigate the feasibility and requirements for precise and accurate estimation of PBPK parameters using population modelling of clinical data and illustrate this for two key PBPK parameters for hepatic metabolic clearance, namely whole liver unbound intrinsic clearance (CLint_,u,WL) and hepatic blood flow (Qh) in children.

Methods

First, structural identifiability was enabled through re-parametrization and the definition of essential trial design components. Subsequently, requirements for the trial components to yield precise estimation of the PBPK parameters and their inter-individual variability were established using a novel application of population optimal design theory. Finally, the performance of the proposed trial design was assessed using stochastic simulation and estimation.

Results

Precise estimation of CLint_,u,WL and Qh and their inter-individual variability was found to require a trial with two drugs, of which one has an extraction ratio (ER)???0.27 and the other has an ER???0.93. The proposed clinical trial design was found to lead to precise and accurate parameter estimates and was robust to parameter uncertainty.

Conclusion

The proposed framework can be applied to other PBPK parameters and facilitate the development of PBPK models.

SUBMITTER: Calvier EAM

PROVIDER: S-EPMC6156772 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Publications

Can Population Modelling Principles be Used to Identify Key PBPK Parameters for Paediatric Clearance Predictions? An Innovative Application of Optimal Design Theory.

Calvier Elisa A M EAM Nguyen Thu Thuy TT Johnson Trevor N TN Rostami-Hodjegan Amin A Tibboel Dick D Krekels Elke H J EHJ Knibbe Catherijne A J CAJ

Pharmaceutical research 20180914 11

<h4>Purpose</h4>Physiologically-based pharmacokinetic (PBPK) models are essential in drug development, but require parameters that are not always obtainable. We developed a methodology to investigate the feasibility and requirements for precise and accurate estimation of PBPK parameters using population modelling of clinical data and illustrate this for two key PBPK parameters for hepatic metabolic clearance, namely whole liver unbound intrinsic clearance (CLint<sub>,u,WL</sub>) and hepatic bloo ...[more]

PMID: 30218393

Similar Datasets

Project description:The interest in using physiologically-based pharmacokinetic (PBPK) models as a support to the drug development decision making process has rapidly increased in the last years. These kind of models are examples of the "bottom up" modelling strategy, which progressively integrates into a mechanistic framework different information as soon as they become available along the drug development. For this reason PBPK models can be used with different aims, from the early stages of drug development up to the clinical phases. Different software tools are nowadays available. They can be categorized in "designed software" and "open software". The first ones typically include commercial platforms expressly designed to implement PBPK models, in which the model structure is pre-defined, assumptions are generally not explicitly declared and equations are hidden to the user. Even if the software is validated and routinely used in the pharmaceutical industry, sometimes they do not allow working with the flexibility needed to cope with specific applications/tasks. For this reason, some scientists prefer to define and implement their own PBPK tool in "open" software. This paper shows how to build an in-house PBPK tool from species-related physiological information available in the literature and a limited number of drug specific parameters generally made available by the drug development process. It also reports the results of an evaluation exercise that compares simulated plasma concentration-time profiles and related pharmacokinetic (PK) parameters (i.e., AUC, Cmax and Tmax) with literature and in-house data. This evaluation involved 25 drugs with different physico-chemical properties, intravenously or orally administrated in three different species (i.e., rat, dog and man). The comparison shows that model predictions have a good degree of accuracy, since the average fold error for all the considered PK parameters is close to 1 and only in few cases the fold error is greater than 2. In summary, the paper demonstrates that addressing specific aims when needed is possible by creation of in-house PBPK tools with satisfactory performances and it provides some suggestions how to do that.

Dataset Information

Can Population Modelling Principles be Used to Identify Key PBPK Parameters for Paediatric Clearance Predictions? An Innovative Application of Optimal Design Theory.

Purpose

Methods

Results

Conclusion

Publications

Can Population Modelling Principles be Used to Identify Key PBPK Parameters for Paediatric Clearance Predictions? An Innovative Application of Optimal Design Theory.

Similar Datasets

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