Although geriatric patients are the major recipients of drugs, most research during drug development is conducted in healthy younger adults. Safe and effective drug therapy in the elderly requires an understanding of both drug disposition and response in older individuals. One of the major issues in studying the elderly relates to the ability to study a large number of people in a minimally invasive way. Population pharmacokinetics can be used to model drug concentrations from a large population of sparsely sampled individuals. Population pharmacokinetics characterizes both the interindividual (between-subject) and intraindividual (within-subject) variability, and can identify factors that contribute to pharmacokinetic and pharmacodynamic variability. Population pharmacokinetics can be used to aid in designing large clinical trials by simulating virtual data based on the study design. It can also be used to assess consistency of drug exposure and evaluate its effect on clinical outcome. This article reviews the methods used in pharmacokinetic modeling, as well as providing examples of population pharmacokinetic modeling, highlighting its application to geriatric psychiatry.
"Blood is collected for determination of plasma sertraline and olanzapine concentrations. The analytic strategy will use population pharmacokinetics
, which uses nonlinear mixed effect modeling to identify intra- and inter-individual sources of variability
. Variability from the norm in drug concentrations can be determined using sparse (between two and four) plasma samples per patient
[Show abstract][Hide abstract] ABSTRACT: Background:
Psychotic depression (PD) is a severe disabling disorder with considerable morbidity and mortality. Electroconvulsive therapy and pharmacotherapy are each efficacious in the treatment of PD. Expert guidelines recommend the combination of antidepressant and antipsychotic medications in the acute pharmacologic treatment of PD. However, little is known about the continuation treatment of PD. Of particular concern, it is not known whether antipsychotic medication needs to be continued once an episode of PD responds to pharmacotherapy. This issue has profound clinical importance. On the one hand, the unnecessary continuation of antipsychotic medication exposes a patient to adverse effects, such as weight gain and metabolic disturbance. On the other hand, premature discontinuation of antipsychotic medication has the potential risk of early relapse of a severe disorder.
The primary goal of this multicenter randomized placebo-controlled trial is to assess the risks and benefits of continuing antipsychotic medication in persons with PD once the episode of depression has responded to treatment with an antidepressant and an antipsychotic. Secondary goals are to examine age and genetic polymorphisms as predictors or moderators of treatment variability, potentially leading to more personalized treatment of PD. Individuals aged 18-85 years with unipolar psychotic depression receive up to 12 weeks of open-label treatment with sertraline and olanzapine. Participants who achieve remission of psychosis and remission/near-remission of depressive symptoms continue with 8 weeks of open-label treatment to ensure stability of remission. Participants with stability of remission are then randomized to 36 weeks of double-blind treatment with either sertraline and olanzapine or sertraline and placebo. Relapse is the primary outcome. Metabolic changes are a secondary outcome.
This trial will provide clinicians with much-needed evidence to guide the continuation and maintenance treatment of one of the most disabling and lethal of psychiatric disorders.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to examine the prevalence of potentially inappropriate medication use (PIMs) among community-dwelling older adults and the association between PIMs and health care outcomes. Participants were 17,971 individuals age 65 years and older. PIM use was defined by the Beers criteria. Drug-related problems (DRPs) were defined using ICD-9 codes. Forty percent of the 17,971 individuals filled at least 1 PIM prescription, and 13% filled 2 or more PIM prescriptions. Overall DRP prevalence among those with at least 1 PIM prescription was 14.3% compared to 4.7% in the non-PIM group (p < .001). In conclusion, preventing PIM use may be important for decreasing medication-related problems, which are increasingly being recognized as requiring an integrated interdisciplinary approach.
Research in Nursing & Health 02/2008; 31(1):42-51. DOI:10.1002/nur.20232 · 1.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Response to antipsychotics is highly variable, which may be due in part to differences in drug exposure. The goal of this study was to evaluate the magnitude and variability of concentration exposure of olanzapine. Patients with Alzheimer's disease (n = 117) and schizophrenia (n = 406) were treated with olanzapine as part of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Combined, these patients (n = 523) provided 1527 plasma samples for determination of olanzapine concentrations. Nonlinear mixed-effects modeling was used to determine the population pharmacokinetics of olanzapine, and patient-specific covariates were evaluated as potential contributors to variability in drug exposure. The population mean olanzapine clearance and volume of distribution were 16.1 L/h and 2150 L, respectively. Elimination of olanzapine varied nearly 10-fold (range, 6.66-67.96 L/h). Smoking status, sex, and race accounted for 26%, 12%, and 7% of the variability, respectively (P < .0001). Smokers cleared olanzapine 55% faster than non/past smokers (P < .0001). Men cleared olanzapine 38% faster than women (P < .0001). Patients who identified themselves as black or African American cleared olanzapine 26% faster than other races (P < .0001). Differences in olanzapine exposure due to sex, race, and smoking may account for some of the variability in response to olanzapine.
The Journal of Clinical Pharmacology 02/2008; 48(2):157-65. DOI:10.1177/0091270007310385 · 2.48 Impact Factor
Clara Conde Ruiz, Andrea P Del Carro, Emilie Rosset, Emilie Guyot, Laura Maroiller, Samuel Buff, Karine Portier
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