Systems pharmacology models can be used to understand complex pharmacokinetic-pharmacodynamic behavior: an example using 5-lipoxygenase inhibitors

Abstract

Zileuton, a 5-lipoxygenase (5LO) inhibitor, displays complex pharmaokinetic (PK)-pharmacodynamic (PD) behavior. Available clinical data indicate a lack of dose-bronchodilatory response during initial treatment, with a dose response developing after ~1-2 weeks. We developed a quantitative systems pharmacology (QSP) model to understand the mechanism behind this phenomenon. The model described the release, maturation, and trafficking of eosinophils into the airways, leukotriene synthesis by the 5LO enzyme, leukotriene signaling and bronchodilation, and the PK of zileuton. The model provided a plausible explanation for the two-phase bronchodilatory effect of zileuton-the short-term bronchodilation was due to leukotriene inhibition and the long-term bronchodilation was due to inflammatory cell infiltration blockade. The model also indicated that the theoretical maximum bronchodilation of both 5LO inhibition and leukotriene receptor blockade is likely similar. QSP modeling provided interesting insights into the effects of leukotriene modulation.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e74; doi:10.1038/psp.2013.49; advance online publication 11 September 2013.

Figure 1

Schematic representation of processes considered in the model. Broken arrows signify transport across tissues. Solid arrows signify production/synthesis/stimulation process. Lines (red) identify points of therapeutic intervention. CysLT, cysteinyl leukotrienes; EO, non-activated eosinophils; EOa, activated eosinophils; FEV₁, forced expiratory volume in 1 s; Hn, histamine; IL-5, interleukin-5; ML, montelukast; ZL, zileuton.

Figure 2

Simulated and clinically measured response to administration of labeled dosages of zileuton (ZL) and montelukast (ML) presented in longer and shorter time scales. Solid lines represent simulations, symbols (squares, triangles, and diamonds) represent clinical observations. Dependence of (a) forced expiratory volume in 1 s (FEV₁), (b) airways LTD4 concentration, and (c) airways eosinophils (EOs) number on time under condition of ZL and ML administration. Four hundred milligrams (blue curve, closed squares) and 600 mg (red curve, closed triangles) of ZL is administered four times a day (q.i.d.); 10 mg (green curve, open diamonds) and 50 mg (violet curve) of ML is administered q.d. All simulated characteristics are expressed as percentage from baseline. Clinically measured data on FEV₁ response to ZL were taken from Liu et al. Vertical blue and green arrows indicate time of administration of ZL during the first day of therapy and ML during two initial days of therapy. q.d., once daily.

Figure 3

Simulated response to administration of high dosages of zileuton (ZL) and montelukast (ML) presented over chronic and acute time scales. Dependence of FEV₁ (% from baseline) on time under condition of (a) ZL q.i.d. and (b) ML q.d. administration: blue, red, green, and violet curves correspond to 400, 600, 800, 1,000 mg of ZL and 10, 50, 250, 1,250 mg of ML, respectively. Vertical blue and green arrows indicate time of administration of ZL during the first day of therapy and ML during two initial days of therapy, respectively. FEV₁, forced expiratory volume in 1 s; q.d., once daily; q.i.d., four times a day.