Javier Zarzoso-Foj (1,2), Eva M. González-Soler (3), Gloria M. Alfosea-Cuadrado (3), Alfonso A. Valverde-Navarro (3), Albert Adell (4), Arantxa Blasco-Serra, (3), Victor Mangas-Sanjuan (1,2).
(1) Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, Valencia, Spain; (2) Interuniversity Research Institute for Molecular Recognition and Technological Development, Polytechnic University of Valencia – University of Valencia, Valencia, Spain; (3) Department of Human Anatomy and Embryology. University of Valencia, Valencia, Spain; (4) Systems Neurobiology. Institute of Biomedicine and Biotechnology of Cantabria, Santander, Spain. Spanish National Research Council (CSIC)
Introduction: Reserpine administration has been used to generate fibromyalgia (FM) disease in rodents by reproducing both the main symptom (generalized musculoskeletal pain), and main comorbid symptoms, such as depressive symptoms, sleep alteration, and cognitive impairments [1]. This may be due to its action on monoamines, which are involved in the regulation of these affected systems [2]. However, a quantitative framework able to characterize and explore disease dynamics for FM is still lacking. Knowing pharmacokinetic-pharmacodynamic of reserpine in a rat model of FM could help us understand the mechanisms underlying the symptoms.
Objectives: Therefore, the aims of this study are (i) to develop a population pharmacokinetic-pharmacodynamic model able to characterize the time course of reserpine and neurotransmitters (NT) in the prefrontal cortex (PFC), amygdala (Amy), and spinal cord (SC) in rats, and (ii) optimize the reserpine-induced FM disease status using alternative dosing regimens.
Methods: Reserpine was administered QD for three days at three dose levels: 0.1, 0.5, and 1 mg/kg. PK and PD samples were collected from 48 to 96 hours after the first dose was administered. Each animal led to a PD sample of each of the three brain areas. Data analysis was performed by using the non-linear mixed effects (NLME) analysis, in Monolix software (v2023R1). Model selection of the PK/PD model was conducted through a combination of statistical, numerical, and graphical techniques. Model evaluation of the final PK/PD model was performed through the prediction-corrected visual predictive checks (pc-VPC). Reserpine plasma levels and time-course of NT were described through a compartmental approach, evaluating linear and non-linear processes. Deterministic and stochastic simulations were conducted to evaluate disease-related PD outcomes with 0.1, 0.5, and 1 mg/kg dose levels administered QD, BID, and TID for three days.
Results: A total of 120 rats were included for PK model development across evaluated doses with a total number of 120 samples included. Experimental NT observations (n=704) after reserpine administration were obtained from 120 rats, which were divided into different groups according to the NT and the brain area. A one-compartment model with double extravascular absorption (ka1= 19.14 h-1 and Tk02 = 44.69 mg/h) and linear disposition processes were selected as the structural PK model. The final PK/PD framework included a precursor-dependent model [3]. The response (R) is mediated and eliminated through first-order processes (kp =1.6×10-3 h-1 and kout =4.2×10-2 h-1). Parallel to this process, a three-transit compartment chain (M1, M2, M3) was incorporated, governed by a zero-order production rate constant (k0 =1.7×10-1 h-1) and assuming the following initial condition M10=M20=M30=1. The amount of reserpine in the central compartment stimulates the transit from P to R (SLP1 =1.2×10-1 h) and the degradation of R through a linear drug effect model (SLP2 =6.1×10-1 h). The covariate analysis identified the brain regions (PFC, SC, and amygdala) as statistically significant covariates on kin. The simulation-based analysis suggested that 0.5 mg/kg BID regimen would provide a Cmax/baseline ratio of 0.09, 68% of the animals with Cmin after 3rd dose below 1 mg/L and ~50% of the time below 1 mg/L, which is similar to the gold-standard regimen of 1 mg/kg QD: 0.18, 70%, and 53%, respectively. A higher reserpine-induced FM disease status could be achieved with the 0.5 mg/kg TID (0.05, 77%, 64%), 1 mg/kg BID (0.05, 87%, 78%), and 1 mg/kg TID (0.02, 94%, 86%) regimens.
Conclusions: The current population PK/PD model emerges to provide a better understanding of the underlying processes in fibromyalgia, with the potential to improve future research and therapeutic strategies for the disease. The 0.5 mg/kg BID regimen represents an optimal alternative for the reserpine-induced FM disease model, achieving similar levels of response outcomes in the brain area.
References:
[1] Brum, Evelyne Silva, et al. Animal models of fibromyalgia: What is the best choice? Pharmacology & Therapeutics 230 (2022): 107959.
[2] Govindarajulu M, Shankar T, Patel S, Fabbrini M, Manohar A, Ramesh S, et al. Reserpine-Induced Depression and Other Neurotoxicity: A Monoaminergic Hypothesis. Medicinal Herbs and Fungi. 2021.
[3] Sharma A, Ebling WF, Jusko WJ. Precursor-dependent indirect pharmacodynamic response model for tolerance and rebound phenomena. J Pharm Sci. 1998 Dec 1;87(12):1577–84.
Reference: PAGE 32 (2024) Abstr 10916 [www.page-meeting.org/?abstract=10916]
Poster: Drug/Disease Modelling - CNS