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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.

SUBMITTER: Alfosea-Cuadrado GM

PROVIDER: S-EPMC11359992 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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

Alfosea-Cuadrado Gloria M GM Zarzoso-Foj Javier J Adell Albert A Valverde-Navarro Alfonso A AA González-Soler Eva M EM Mangas-Sanjuán Víctor V Blasco-Serra Arantxa A

Pharmaceutics 20240821 8

(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 ...[more]

PMID: 39204446

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Project description:Cyclophosphamide (CPA) containing chemotherapy regimen is the standard of care for breast cancer treatment in sub-Saharan Africa. Wide inter-individual variations in pharmacokinetics (PK) of cyclophosphamide (CPA) influence the efficacy and toxicity of CPA containing chemotherapy. Data on the pharmacokinetics (PK) profile of CPA and its covariates among black African patients is lacking. We investigated population pharmacokinetic/pharmacogenetic/pharmacodynamic (PK-PG-PD) of CPA in Ethiopian breast cancer patients. During the first cycle of CPA-based chemotherapy, the population PK parameters for CPA were determined in 267 breast cancer patients. Absolute neutrophil count was recorded at baseline and day 20 post-CPA administration. A population PK and covariate model analysis was performed using non-linear mixed effects modeling. Semi-mechanistic and empiric drug response models were explored to describe the relationship between the area under concentration-time curve (AUC), and neutrophil toxicity. One compartment model better described CPA PK with population clearance and apparent volume of distribution (VD) of 5.41 L/h and 46.5 L, respectively. Inter-patient variability in CPA clearance was 54.5%. Patients carrying CYP3A5*3 or *6 alleles had lower elimination rate constant and longer half-life compared to wild type carriers. CYP2C9 *2 or *3 carriers were associated with increased clearance of CPA. Patients who received 500 mg/m2 based CPA regimen were associated with a 32.3% lower than average clearance and 37.1% lower than average VD compared to patients who received 600 mg/m2. A 0.1 m2 unit increase in body surface area (BSA) was associated with a 5.6% increment in VD. The mean VD (33.5 L) in underweight group (BMI < 18.5 kg/m2) was significantly lower compared to those of overweight (48.1 L) or obese patients (51.9 L) (p < 0.001). AUC of CPA was positively correlated with neutropenic toxicity. In conclusion, we report large between-patient variability in clearance of CPA. CYP3A5 and CYP2C9 genotypes, BSA, BMI, and CPA dosage regimen influence PK of CPA. Plasma CPA exposure positively predicts chemotherapy-associated neutropenic toxicity.

Dataset Information

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

Publications

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

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