Population pharmacokinetics of the selective serotonin 5-HT1A receptor partial agonist piclozotan

Serotonin (5-HT) and its receptors are known to play important roles in various physiological and pathophysiological processes. The 5-HT1A receptor subtype is thought to be involved in psychiatric disorders, immunomodulation, and in cerebral ischemic conditions. Piclozotan, a selective and potent partial agonist of 5-HT1A, has been shown to be neuroprotective against ischemic neuronal damage in animal models. Its pharmacokinetics (PK), tolerability, and safety have been evaluated in patients with acute ischemic stroke. The aim of the study was to describe piclozotan PK, using population PK modeling.

A total of 1308 plasma piclozotan concentration measurements from 84 healthy subjects and 412 plasma piclozotan measurements from 74 stroke patients were included in the analysis. Covariates considered during the model building process included disease status, age, weight, sex, smoking status, and alcohol consumption. Data were analyzed using nonlinear mixed-effects modeling with the NONMEM software system. The final model was qualified via predictive check and nonparametric bootstrap procedures.

Piclozotan PK was well described using a 3-compartment model with first-order elimination. Parameter estimates (intersubject variability) were V1, central volume: 64.0 L (66.5%) and CL, systemic clearance: 18.0 L/h (31.4%). Peripheral volumes (V2, V3) were related to total body weight, whereas CL was related to ideal body weight. Clearance decreased with advancing age, yielding a decrease of 35%-65% in patients aged 70-90. There was no discernable difference in PK between healthy subjects and stroke patients.

Piclozotan disposition was well described by the population model, and the intersubject variability around the estimated parameters was moderate in magnitude (<60%). The population PK analysis of piclozotan allows for characterization of piclozotan exposure in individual subjects based on their age and body weight. The availability of a population PK model will facilitate dose optimization and further clinical development of piclozotan.