Abstract
Chronic administration of drugs leads to the activation of compensatory mechanisms that may inhibit some of their activity and induce unwanted toxicity. These mechanisms are an obstacle for maintaining a sustainable effect for many chronic medications. Pathways that adapt to the burden induced by chronic drugs, whether or not related to the underlying disease, can lead to a partial or complete loss of effect. Variability characterizes many biological systems and manifests itself as large intra- and inter-individual differences in the response to drugs. Circadian rhythm-based chronotherapy is further associated with variability in responses noted among patients. This paper reviews current knowledge regarding the loss of effect of chronic medications and the range of variabilities that have been described in responses and loss of responses. Establishment of a personalized platform for overcoming these prohibitive mechanisms is presented as a model for ensuring long-term sustained medication effects. This novel platform implements personalized variability signatures and individualized circadian rhythms for preventing and opposing the prohibitive effect of the compensatory mechanisms induced by chronic drug administration.