Population pharmacokinetics in geriatric psychiatry.
ABSTRACT 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.
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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.Methods/design: 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. DISCUSSION: 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.Trial registration and URL: Clinicaltrials.govRegistry ID: NCT01427608.BMC Psychiatry 01/2013; 13(1):38. DOI:10.1186/1471-244X-13-38 · 2.24 Impact Factor
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ABSTRACT: Objective The objective of this study was to evaluate the relationship between antipsychotic-induced tardive dyskinesia (TD) and estimated dopamine D2 receptor occupancy levels in patients with schizophrenia, using the dataset from the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE). Methods The dataset from 218 subjects (risperidone, N = 78; olanzapine, N = 100; ziprasidone, N = 40) who presented with a score of zero on the Abnormal Involuntary Movement Scale (AIMS) at baseline in Phase 1 of the CATIE study, and remained for ≥ 6 months, was used. Peak and trough dopamine D2 receptor occupancy levels on the day of the AIMS assessment at the endpoint were estimated from plasma antipsychotic concentrations, using population pharmacokinetic analysis and our D2 prediction model. The estimated dopamine D2 receptor occupancy levels were compared between patients who presented an AIMS score of ≥ 2 at endpoint and those with a score of zero, using the Mann–Whitney U test. Results Estimated dopamine D2 receptor occupancy levels at trough were significantly higher in subjects who developed involuntary movements (N = 23) than those who did not (N = 195) (71.7 ± 14.4% vs. 64.3 ± 19.3%, p < 0.05) while no significant difference was found in the estimated peak D2 receptor occupancy between them (75.4 ± 8.7% vs. 72.1 ± 9.9%, p = 0.07). When the analyses were separately conducted for the three drugs, there were no significant differences in estimated peak or trough D2 occupancy although the values were consistently numerically higher among those developing involuntary movements. Conclusion Greater dopamine D2 receptor blockade with antipsychotics at trough might increase the risk of tardive involuntary movements although this finding needs to be replicated in larger trials.Schizophrenia Research 04/2014; 153(1-3). DOI:10.1016/j.schres.2014.01.017 · 4.43 Impact Factor
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ABSTRACT: More than 50 % of individuals affected by adverse drug events (ADEs) are older adults. Establishing a drug dosing regimen that balances benefit and risk, and minimizes ADEs in older populations can be challenging. The aim of this study is to evaluate the use of modeling, simulation, and risk-benefit acceptability methods to establish a drug dosing regimen that balances benefit and risk. The study population comprised nondiabetic patients with schizophrenia from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) ≥50 years old, who had been on oral olanzapine for ≥2 weeks. We used mixed-effects modeling based on a preexisting pharmacokinetic model to derive clearance estimates, which were then used to determine the olanzapine area under the concentration-time curve (AUC). Subsequently, with multivariate regression and Monte Carlo simulation, we estimated the olanzapine dose corresponding to the benefit-risk AUC breakpoint. The study population (n = 34) was predominantly male (82.3%) and white (67.6%), with a mean age of 54.4 years and treatment duration of 361.8 days. The mean AUC was 747.6 ng h/mL (95% CI = 524.5, 970.7) for the benefit group (n = 16) and 754.1 (95% CI = 505.9, 1002.4) for the risk group (n = 15). The benefit-risk AUC breakpoint was 524.5 ng h/mL and the corresponding oral olanzapine dose that optimizes benefit-risk balance was 17.8 mg/d. Our study introduces a real-world approach for finding the safe drug dosing regimen without extensive exposure of a vulnerable and older population to drugs. Further studies into the use of modeling, simulation, and risk-benefit acceptability methods to enhance geriatric drug safety are needed.Annals of Pharmacotherapy 01/2014; 48(3). DOI:10.1177/1060028013514376 · 2.92 Impact Factor