Simulation Analysis to Explore the Optimal Combination of Pregabalin and Duloxetine

Aims: Pregabalin, an anticonvulsant drug and duloxetine, a selective serotonin-norepinephrine reuptake inhibitor (SNRI) are used for pain relief. The purpose of this study was to explore the optimal combination of pregabalin and duloxetine based on reported modeling analyses.

Methods: Visual analogue scale (VAS) for pain over time were simulated as ordered categorical variables for pregabalin and duloxetine, respectively, based on the previously reported pharmacodynamic (PD) models, using NONMEM (version 7.2)(1, 2). In the Monte-Carlo simulation of 1,000 replicates, parameter uncertainties expressed as standard error of the parameter estimates in previous models for pregabalin and duloxetine were taken into account as well as inter-individual variability. The simulated VAS over time for duloxetine were added to those for pregabalin, assuming additive effect of pregabalin and duloxetine on pain control, and the results were visualized in 3-dimensional plots using R (version 3.0.1)(3).

Results: In the 3-dimensional plot for duloxetine and pregabalin dose per day, and VAS, the pain relief effect we could predict the optimal combinations of duloxetine and pregabalin, which will show the maximum pain relief effect. In monotherapy, 200 mg pregabalin and 50 mg duloxetine per day showed maximum effect. Although the time to maximum effect was reduced, the maximum effect increased no more with the increment of pregabalin and duloxetine, respectively.

Conclusion: We predicted the optimal combinations of duloxetine and pregabalin with the smallest amount of duloxetine and pregabalin, each, where pain relief are expected to be maximized.

References:

1. Byon W, Ouellet D, Chew M, Ito K, Burger P, Pauer L, et al. Exposure‐Response Analyses of the Effects of Pregabalin in Patients With Fibromyalgia Using Daily Pain Scores and Patient Global Impression of Change. The Journal of Clinical Pharmacology. 2010;50(7):803-15. 2. Yuen E, Gueorguieva I, Bueno‐Burgos L, Iyengar S, Aarons L. Population pharmacokinetic/pharmacodynamic models for duloxetine in the treatment of diabetic peripheral neuropathic pain. European Journal of Pain. 2013;17(3):382-93. 3. Tesfaye S, Wilhelm S, Lledo A, Schacht A, Tölle T, Bouhassira D, et al. Duloxetine and pregabalin: high-dose monotherapy or their combination? The "COMBO-DN study"–a multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain. PAIN®. 2013;154(12):2616-25.