Variability and singularity arising from poor compliance in a pharmacokinetic model I: the multi-IV case

Abstract

We consider a simple multi-IV model for drug concentration in the case of poor patient compliance. The model is a stochastic one, and is thus able to take into account an irregular drug intake schedule. Under some assumptions, we study features of the drug concentration relevant for practical purposes such as its variability or the regularity of its cumulative probability distribution. We consider five variants: random instants for drug intake with either deterministic or random doses, both in continuous and discrete-time settings, plus a model with stochastically varying elimination rate. Our computations make it possible to assess in a precise way the effect of various significant parameters such as the mean rate of intake, the elimination rate, and the mean dose. They also quantify how much poor compliance will affect the regimen: in that view, we provide precise comparisons with the variability of concentration in the cases of (a) a fully compliant patient and (b) a population of fully compliant patients with lognormally distributed elimination rates. The time discretized version of our models reveal unexpected links with measures known as infinite Bernoulli convolutions. Our findings help in understanding the consequences of poor compliance, and may have practical outcomes in terms of drug dosing and scheduling.