Population Pharmacokinetic-Pharmacodynamic Analysis of a Reserpine-Induced Myalgia Model in Rats.

Abstract

(1) Background: Fibromyalgia syndrome (FMS) is a chronic pain condition with widespread pain and multiple comorbidities, for which conventional therapies offer limited benefits. The reserpine-induced myalgia (RIM) model is an efficient animal model of FMS in rodents. This study aimed to develop a pharmacokinetic-pharmacodynamic (PK-PD) model of reserpine in rats, linking to its impact on monoamines (MAs). (2) Methods: Reserpine was administered daily for three consecutive days at dose levels of 0.1, 0.5, and 1 mg/kg. A total of 120 rats were included, and 120 PK and 828 PD observations were collected from 48 to 96 h after the first dose of reserpine. Non-linear mixed-effect data analysis was applied for structural PK-PD model definition, variability characterization, and covariate analysis. (3) Results: A one-compartment model best described reserpine in rats (V = 1.3 mL/kg and CL = 4.5 × 10^-1 mL/h/kg). A precursor-pool PK-PD model (k_in = 6.1 × 10^-3 mg/h, k_p = 8.6 × 10^-4 h^-1 and k_out = 2.7 × 10^-2 h^-1) with a parallel transit chain (k₀ = 1.9 × 10^-1 h^-1) characterized the longitudinal levels of MA in the prefrontal cortex, spinal cord, and amygdala in rats. Reserpine stimulates the degradation of MA from the pool compartment (Slope₁ = 1.1 × 10^-1 h) and the elimination of MA (Slope₂ = 1.25 h) through the transit chain. Regarding the reference dose (1 mg/kg) of the RIM model, the administration of 4 mg/kg would lead to a mean reduction of 65% (C_max), 80% (C_min), and 70% (AUC) of MA across the brain regions tested. (4) Conclusions: Regional brain variations in neurotransmitter depletion were identified, particularly in the amygdala, offering insights for therapeutic strategies and biomarker identification in FMS research.