Physiologically Based Pharmacokinetic Modelling and Simulation to Predict the Plasma Concentration Profile of Doxorubicin

Abstract

Doxorubicin (DOX) is still an important anticancer agent despite its tricky pharmacokinetics (PK) and toxicity potential. The advent of systems pharmacology enables the construction of PK models able to predict the concentration profiles of drugs and shed light on the underlying mechanisms involved in PK and pharmacodynamics (PD). By utilizing existing published data and by analysing two clinical case studies we attempt to create physiologically based pharmacokinetic (PBPK) models for DOX using widely accepted methodologies. Based on two different approaches on three different key points we derived eight plausible models. The validation of the models provides evidence that is all performing as designed and opens the way for further exploitation by integrating metabolites and pharmacogenomic information.

Keywords: PBPK modelling; doxorubicin; pharmacokinetics; physiologically based pharmacokinetic model; simcyp simulator.

Figure 1

Depiction of the three independent but interacting parts of a PBPK model. Adapted from Jamai et al. [21] which is licensed under a Creative Commons Attributions (CC BY 4.0) International License (http://creativecommons.org/licenses/by/4.0/).

Figure 2

(A) Mean, 95th percentile and 5th percentile of the concentration versus time of DOX for model 8 based on the works of Camaggi et al. DOX was given as a single IV bolus injection of 60 mg/m² at 0 h. (B) Comparative mean concentration vs. time for all 8 DOX models.

Figure 3

(A) Mean, 95th percentile and 5th percentile of the concentration versus time of DOX for model 8 based on the works of Speth et al. DOX was given as a 3-day IV bolus injection of 30 mg/m² every 24 h. (B) Comparative mean concentration vs. time for all 8 DOX models for the above-mentioned administration.

Figure 4

(A) Mean, 95th percentile and 5th percentile of the concentration versus time of DOX for model 8 based on the works of Speth et al. DOX was given as a 3-day IV Infusion over 8 h of 30 mg/m² every 24 h. (B) Comparative mean concentration vs. time for all 8 DOX models for the above-mentioned administration.