PK/PD analysis of trazodone and gabapentin in neuropathic pain rodent models: Translational PK‐PD modeling from nonclinical to clinical development

Abstract

A pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the time course of writhings after intraperitoneal injection of acetic acid in mice. The model was applied to investigate the antinociceptive effect of trazodone and gabapentin alone and in combination. Writhings time course was described by a transit compartment model with the delay due to the transit of the acetic acid being represented by a chain of intermediate compartments. In the drug‐treated animals, the number of writhings decreases according to a k2 factor linking drug concentration and antinociceptive effect. Compounds' potency parameters were 10.9 and 0.0459 L/μmoles/min for trazodone and gabapentin, respectively, indicating a much higher in vivo potency of trazodone in the PD writhing test. The PK/PD parameters were used to simulate the expected writhing counts in mice at combined doses without efficacy alone, assuming pharmacological additivity. Simulation results indicated that, at low dose combinations, experimental data were mostly below the simulated writhings median, suggesting possible synergic effect. Such hypothesis was tested by adding the γ parameter in the PK/PD model to represent the deviation from the assumption of no‐interaction, leading to a reduction of the objective function compared to the additive model. On this basis, several simulations were performed to identify possible starting dose combinations of trazodone and gabapentin in humans, by selecting doses yielding systemic exposures close to those being synergic in the mouse. Simulations indicated that doses of 50–100 mg trazodone could enhance gabapentin antinociceptive effect in humans, supporting the development of a low dose combination for optimal analgesia treatment.

Efficacy and Safety of Trazodone and Gabapentin Fixed-Dose Combination in Patients Affected by Painful Diabetic Neuropathy: Randomized, Controlled, Dose-Finding Study

“…Overall, although the primary efficacy endpoint was not reached in the present RCT, statistically significant results alongside various and consistent trends encourage further investigation of the Trazo/Gaba FDC for NP. Eventually, the results of this RCT are backed up by previous experimental findings, suggesting that synergy between trazodone and gabapentin is likely to occur at the least doses while higher dosages do not bring about additional benefit [16,17,30]. Moreover, we argue that the positive trend toward a mood and sleep quality improvement effect (as indicated by specific validated tools utilized in the present RCT) suggests that the Trazo/Gaba FDC may help improve multidimensional aspects of diabetes such as pain, insomnia, and depressive-like disturbances.…”

“…This was a randomized, double-blind, placebo and reference controlled, double-dummy, dosefinding, parallel-group, multicenter, international, prospective study that was performed in 30 was obtained from all individual participants included in the study prior starting any studyrelated procedure. The study consisted of three main study periods: the screening and wash-out, the 8-week double-blind investigational treatment period, and the 8-day tapering period, for a maximum of ten visits (Fig.…”