Abstract
A quantitative analysis of dose–response relationships is essential in preclinical and clinical drug development in order to optimize drug efficacy and safety, respectively. However, there is a lack of quantitative understanding about the dynamics of pharmacological drug–target interactions in biological systems. In this study, a quantitative systems pharmacology (QSP) approach is applied to quantify the drug efficacy of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) inhibitors by coupling physiologically based pharmacokinetic models, at the whole-body level, with affected biological networks, at the cellular scale. Both COX-2 and 5-LOX are key enzymes in the production of inflammatory mediators and are known targets in the design of anti-inflammatory drugs. Drug efficacy is here evaluated for single and appropriate co-treatment of diclofenac, celecoxib, zileuton, and licofelone by quantitatively studying the reduction of prostaglandins and leukotrienes. The impact of rifampicin pre-treatment on prostaglandin formation is also investigated by considering pharmacokinetic drug interactions with diclofenac and celecoxib, finally suggesting optimized dose levels to compensate for the reduced drug action. Furthermore, a strong correlation was found between pain relief observed in patients as well as celecoxib- and diclofenac-induced decrease in prostaglandins after 6 h. The findings presented reveal insights about drug-induced modulation of cellular networks in a whole-body context, thereby describing complex pharmacokinetic/pharmacodynamic behavior of COX-2 and 5-LOX inhibitors in therapeutic situations. The results demonstrate the clinical benefit of using QSP to predict drug efficacy and, hence, encourage its use in future drug discovery and development programs.
Highlights
Novel drugs need to be efficacious and safe and the validation of both properties is mandatory for market authorization
As these enzymes are involved in the clearance of celecoxib and diclofenac from the human body (Fig. 2),[51] their altered pharmacological activities caused by a PK drug interaction with rifampicin are here investigated for two clinical studies, in which 200 mg celecoxib and 100 mg diclofenac are orally applied with a pre-treatment with 600 mg and 450 mg rifampicin q.d. over 5 and 6 days, respectively.[21,22]
A physiologically based pharmacokinetic (PBPK)/PD quantitative systems pharmacology (QSP) approach is applied to quantify drug efficacy over time for a set of COX-2 and 5-LOX inhibitors in humans (Fig. 1, Table 1)
Summary
Novel drugs need to be efficacious and safe and the validation of both properties is mandatory for market authorization. Simulated drug concentrations are linked via reversible binding to the respective biological targets (COX-2, 5-LOX, or PXR) present in the cellular models of arachidonic acid metabolism[23] and rifampicin-induced CYP activation.[24] The pharmacological activity of diclofenac, celecoxib, zileuton, and licofelone is quantified by the decrease in prostaglandin and leukotriene synthesis. The impact Validation of therapeutic drug concentrations simulated using of pre-treatment with rifampicin on the drug clearances of COX-2 PBPK modeling and 5-LOX inhibitors and, on their pharmacological It has been argued that a quantitative understanding of on-target action is investigated. Therapeutic drug concentrations are simulated and used as input to quantify the pharmacological activity of the considered COX-2 and 5-LOX inhibitors
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