Pharmacokinetics of immediate and sustained-release formulations of paroxetine: Population pharmacokinetic approach to guide paroxetine personalized therapy in chinese psychotic patients

Abstract

Paroxetine is one of the most potent selective serotonin reuptake inhibitors (SSRIs) approved for treating depression, panic disorder, and obsessive-compulsive disorder. There is evidence linking genetic polymorphisms and nonlinear metabolism to the Paroxetine's pharmacokinetic (PK) variability. The purpose of the present study was to develop a population PK (PPK) model of paroxetine in Chinese patients, which was used to define the paroxetine's PK parameters and quantify the effect of clinical and baseline demographic factors on these PK characteristics. The study included 184 inpatients with psychosis (103 females and 81 males), with a total of 372 serum concentrations of paroxetine for PPK analyses. The total daily dosage ranged from 20 to 75 mg. One compartment model could fit the PKs characterize of paroxetine. Covariate analysis revealed that dose, formulation, and sex had a significant effect on the PK parameters of paroxetine; however, there was no evident genetic influence of CYP2D6 enzymes on paroxetine concentrations in Chinese patients. The study determined that the population's apparent distribution volume (V/F) and apparent clearance (CL/F), respectively, were 8850 and 21.2 L/h. The CL/F decreased 1-2-fold for each 10 mg dose increase, whereas the different formulations caused a decrease in V/F of 66.6%. Sex was found to affect bioavailability (F), which decreased F by 47.5%. Females had higher F values than males. This PPK model described data from patients with psychosis who received paroxetine immediate-release tablets (IR-T) and/or sustained-release tablets (SR-T). Paroxetine trough concentrations and relative bioavailability were different between formulations and sex. The altered serum concentrations of paroxetine resulting from individual variants and additive effects need to be considered, to optimize the dosage regimen for individual patients.

Keywords: Chinese; dose-dependent; formulation; paroxetine; population pharmacokinetics.

FIGURE 1

Goodness-of-fit plots of the final population PK model for paroxetine concentration set. (A) Observed concentration vs. Population predicted concentrations (B) Observed concentration vs. Individual predicted concentrations; (C) Conditional weighted residual errors vs. Population predicted concentrations (D) Conditional weighted residual errors vs. time after last dose.

FIGURE 2

The NPDE plots of the population PK model. (A) The quantile–quantile plot (B) the distribution histogram of NPDE; (C) the NPDE versus time (D) the NPDE versus predictions concentration.

FIGURE 3

Simulated concentration (A) and dose-corrected serum concentrations (B) of different daily doses of immediate-release paroxetine tablet.

FIGURE 4

Simulated concentration about covariates identified. Paroxetine concentration stratified by dose (25 mg, 50 mg), formulation (immediate-release tablet, sustained-release tablet) and sex (male, female). The black dash lines represent the upper and lower limit of the therapeutic window (20–65 ng/ml). The red dash line represents the laboratory alert levels (120 ng/ml).

FIGURE 5

Simulated time courses of paroxetine serum concentration at steady-state under 50 mg daily dose for immediate-release tablet (IR-T, black lines) and sustained-release tablet (SR-T, black dash lines) in males (A) and female (B). Black arrows represent the routine sampling time of TDM (7:00 a.m.).