Population Pharmacokinetics of Tiapride in Children and Adolescents with Tic Disorders: Leveraging Plasma and Saliva...

This study aimed to develop population pharmacokinetic (PopPK) models of tiapride based on plasma and saliva concentration in pediatric patients with tic disorders (TD) and evaluate the feasibility of non-invasive therapeutic drug monitoring (TDM) for precision dosing.

A prospective study was conducted in 38 TD patients aged 5-15 years. PopPK models of tiapride were sequentially developed using nonlinear mixed-effects modeling. Monte Carlo simulation was employed to optimize dosing regimens, and Bayesian maximum a posteriori (MAP) was applied to facilitate model-informed precision dosing (MIPD). The predictive performance of the established model was internally evaluated using saliva concentration.

The PopPK model of tiapride using plasma concentration was best described by a one-compartment structure model. The typical estimates of the absorption rate constant (Ka), plasma clearance (CL/F), and volume of distribution (V/F) were 0.219 h^-1, 15.3 L/h, and 5.77 L, respectively. A plasma-saliva joint model was subsequently established, incorporating Michaelis-Menten nonlinear transport kinetics to characterize the drug distribution from plasma to saliva, with an estimated Michaelis-Menten constant (KM) of 762 ng/mL and a maximum transport rate (Vmax) of 34.7 mg/h. Saliva elimination was modeled as a first-order process. Fat-free mass (FFM) was identified as a significant covariate on both CL/F and saliva clearance (K30), scaled by power exponents of 0.553 and 0.38, respectively, relative to a reference FFM of 30.62 kg. Simulations based on the final model suggested that a dosing regimen of 75 mg administered three times daily (tid) is optimal for achieving target therapeutic concentration. MAP estimation confirmed that saliva concentration can reliably predict the systemic exposure of tiapride.

The PopPK models of tiapride enable MIPD in children and adolescents with TD and support saliva as a non-invasive matrix for TDM. Further prospective validation in independent pediatric cohorts is warranted before routine clinical implementation.