title: Pharmacokinetic-pharmacodynamic modeling of severity levels of extrapyramidal side effects with markov elements.
abstract: A major problem in the treatment of schizophrenic patients with current antipsychotic drugs, mainly acting as dopamine-2 receptor antagonists, is the occurrence of side effects such as extrapyramidal symptoms (EPS). Meta-analyses of summary data of EPS occurrence, and receptor occupancies inferred from mean plasma concentrations, have shown the incidence of EPS to rise when receptor occupancy is above ~80%. In this analysis, individual longitudinal EPS data from 2,630 patients participating in one of seven different trials and treated with haloperidol, paliperidone, ziprasidone, olanzapine, JNJ-37822681, or placebo were analyzed using a continuous time probability model with Markov elements. The developed pharmacokinetic-pharmacodynamic model describes the longitudinal changes of spontaneously reported EPS-related adverse events and their severity levels rated by clinicians. Individual steady-state concentrations and occupancy levels were found to be predictors for EPS. The results confirm 80% occupancy as a level of increased EPS occurrence rates, also at the individual level.CPT: Pharmacometrics & Systems Pharmacology (2012) 1, e1; doi:10.1038/psp.2012.9; advance online publication 26 September 2012.
authors.affiliation: Division of Pharmacokinetics, Toxicology and Targeting, University Centre for Pharmacy, University of Groningen, Groningen, The Netherlands.
authors.forename: V
authors.initials: V
authors.lastname: Pilla Reddy
authors.forename: K J
authors.initials: KJ
authors.lastname: Petersson
authors.forename: A A
authors.initials: AA
authors.lastname: Suleiman
authors.forename: A
authors.initials: A
authors.lastname: Vermeulen
authors.forename: J H
authors.initials: JH
authors.lastname: Proost
authors.forename: L E
authors.initials: LE
authors.lastname: Friberg