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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.

SUBMITTER: Pilla Reddy V

PROVIDER: S-EPMC3603470 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Pharmacokinetic-pharmacodynamic modeling of severity levels of extrapyramidal side effects with markov elements.

Pilla Reddy V V Petersson K J KJ Suleiman A A AA Vermeulen A A Proost J H JH Friberg L E LE

CPT: pharmacometrics & systems pharmacology 20120926

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 o ...[more]

PMID: 23835881

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Project description:BackgroundAntipsychotic agents are the basis for the pharmacological management of acute and chronic schizophrenia, bipolar disorders, mood disorders with psychotic feature, and other psychotic disorders. Antipsychotic medication use is frequently associated with unfavorable adverse effects such as extrapyramidal side effects (EPSEs). Hence, this systematic review and meta-analysis was aimed to determine the magnitude of antipsychotic-induced EPSEs.MethodA literature search was conducted using legitimate databases, indexing services, and directories including PubMed/MEDLINE (Ovid®), EMBASE (Ovid®), google scholar and WorldCat to retrieve studies. Following screening and eligibility, the relevant data were extracted from the included studies using an Excel sheet and exported to STATA 15.0 software for analyses. The Random effects pooling model was used to analyze outcome measures at a 95% confidence interval. Besides, publication bias analysis was conducted. The protocol has been registered on PROSPERO with ID: CRD42020175168.ResultIn total, 15 original articles were included for the systematic review and meta-analysis. The pooled prevalence of antipsychotic-induced EPSEs among patient taking antipsychotic medications was 37% (95% CI: 18-55%, before sensitivity) and 31% (95% CI: 19-44%, after sensitivity). The prevalence of antipsychotic-induced parkinsonism, akathisia, and tardive dyskinesia was 20% (95% CI: 11-28%), 11% (95% CI: 6-17%), and 7% (95% CI: 4-9%), respectively. To confirm a small-study effect, Egger's regression test accompanied by funnel plot asymmetry demonstrated that there was a sort of publication bias in studies reporting akathisia and tardive dyskinesia.ConclusionThe prevalence of antipsychotic-induced EPSEs was considerably high. One in five and more than one in ten patients experienced parkinsonism and akathisia, respectively. Appropriate prevention and early management of these effects can enhance the net benefits of antipsychotics.

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Pharmacokinetic-pharmacodynamic modeling of severity levels of extrapyramidal side effects with markov elements.

Publications

Pharmacokinetic-pharmacodynamic modeling of severity levels of extrapyramidal side effects with markov elements.

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