Assessing pharmacokinetic variability directly induced by drug intake behaviour through development of a feeding behaviour-pharmacokinetic model

Variability in drug intake is increasingly recognized as a major source of variability in drug response. The non-uniform access to medicated feed, influenced by swine individual feeding behaviour, is a determinant of antibiotic exposure, recalling the intrinsic similarity with human compliance to drug regimens. In this paper, we developed a feeding behaviour-pharmacokinetic (FBPK) model of in-feed chlortetracycline (CTC) and established, in a definite way, the effect of feeding behaviour and its induced pharmacokinetic (PK) variability. Based on reported animal behaviour, we mathematically formulated swine feeding behaviour by incorporating its main characteristics: intense feeding periods that repeat on a daily basis and random feeding periods of free access to feed, along with growth stage factors. This behaviour model was then integrated into a PK model of CTC. Moreover, we analysed the effect of each feeding behaviour component and assessed the corresponding PK variability. We have been able to delineate the impact of different feeding behaviour components and characterize the induced PK variability. We have compared different therapeutic assumptions to our model and shown that random features underlying the feeding behaviour have dramatic influence on the PK variability. A practical tool to adopt the dosing regimen in terms of dose and age has been proposed. The method developed here can be generalized to other therapeutic contexts and incorporated into medical practice, particularly to make long-term projections of drug-intake behaviour, to explain possible treatment failure and guide practitioners in adjusting the dosing regimen.