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.

长期服用药物会导致补偿机制的激活，这种机制可能会抑制其某些活性并引起不良的毒性。这些机制是维持许多慢性药物可持续作用的障碍。适应慢性药物引起的负担的途径，无论是否与潜在疾病有关，都可能导致部分或完全失去作用。变异性是许多生物系统的特征，并表现为对药物反应的巨大的个体内和个体间差异。基于昼夜节律的计时疗法还与患者中注意到的反应差异相关。本文回顾了有关慢性药物疗效丧失以及在反应和反应丧失中描述的变异范围的最新知识。建立了克服这些禁止机制的个性化平台，作为确保长期持续用药效果的模型。这个新颖的平台实现了个性化的变异性特征和个性化的昼夜节律，可以预防和对抗由慢性药物管理引起的代偿机制的抑制作用。