Stimulus – Response mechanistic modeling of pharmacodynamic drug-drug interaction: Extension of the operational receptor model of agonism

Abstract

Combination therapy is becoming the cornerstone of pharmacotherapy. The choice of combination therapy is premised on pharmacodynamic drug – drug interactions (PDDIs). There is a disagreement among the existing PDDI reference models which undermines their utility in prediction of combination outcomes. Accounting for properties of the biological system and not just those of the drugs should enable prediction of in vivo efficacy of drug combinations and rational design of effective drug combinations. Attempts to elucidate mechanisms underlying drug PDDIs based on receptor theory are reviewed hereafter and more potential mechanisms are proposed and analysed. The relationship between the input signal (drug –receptor complex) and the final observed response such that signals react with each other biochemically to form a stimulus which then generates the observed response or one signal modulates/facilitates conversion of the other signal into a stimulus that generates the observed response are proposed and analysed using simulations. The signal reaction model demonstrates the capacity to universally describe all drug combinations and is capable of being extended to describe combinations of more than two drugs, with interpretable effects.

Keywords

• Pharmacodynamic drug
• Drug interactions
• Drug –receptor signal
• Signal –stimulus
• Response cascade
• Allosteric