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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 st...
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Context 1
... illustrate the differences between classic and population pharmacokinetic analysis methods, data were generated and then analyzed using both classic and population pharmacokinetic techniques as shown in Figure 1. Olanzapine concentrations were simulated using WinNonlin 4.0.1 (Pharsight Corp.) based on pharmacokinetic data adapted from Cal- laghan et al. 19 as well as data from our laboratory. ...
Context 2
... individual sets of pharmacokinetic pa- rameters were generated for 12 individuals based on the reported interindividual variability on the phar- macokinetic parameters in Callaghan et al. The first example uses a classic pharmacokinetic analysis ap-proach, the naı¨venaı¨ve pooled method ( Figure 1A). These data points enter the nonlinear regression and least- squares estimation as a single individual and the least-squares estimator determines the best parame- ters for all of the data points together; thus, unique patterns within individuals are ignored. ...
Citations
... 11 Elderly patients are a special population and commonly show weak compliance, high drug concentrations, with significant and unexplainable variations. 12 A previous report demonstrated that the prevalence of missed medications ranged from 41% to 43%; forgetting to take medications was a key self-reported reason for non-persistence (55%). Other factors related to patients forgetting to take their medications, included age, educational level, employment status, and a lack of attention to medication treatment. ...
Background
Schizophrenia is characterized by a high disease burden. Olanzapine is a common drug used in antipsychotic medication. Little is known about the population pharmacokinetics of olanzapine in elderly patients. Missed doses are a common and unavoidable issue during the treatment of psychiatric diseases, especially in elderly patients. This study aimed to identify what an elderly person should do if doses are inadvertently missed.
Methods
Data were collected from 140 elderly psychiatric patients (aged ≥65 years) who received olanzapine therapy. Olanzapine concentrations were determined by high pressure liquid chromatographic tandem mass spectrometry (HPLC-MS/MS) and a population-based approach was used to quantify the characteristics of elderly patients. A non-linear mixed-effects model was used for data analysis. Simulations based on the final model were applied to predict situations involving a single missed dose or three consecutive missed doses under several remedial regimens.
Results
A total of 474 samples from 140 elderly patients were included in the therapeutic drug monitoring (TDM) data analysis. A one-compartment model, with no significant covariates, was developed to describe the population pharmacokinetics of olanzapine in elderly patients. The population predicted systematic clearance (CL/F) and volumes of distribution (V/F) were 18 L/h and 785 L, respectively. The simulation demonstrated that in a missed dose situation, elderly patients should take the regular dose immediately; the refill dose used at the second remedial time point depends on the length of the time delay.
Conclusion
Here, we used a simulation to provide a remedial regimen for missed doses of olanzapine in the elderly population. Our simulation can provide valuable suggestions for individualized therapy in elderly patients.
... fizyolojik değişikliklerin AD'ların farmakokinetik (FK) ve farmakodinamik (FD) profillerinde oluşturdukları farklılıklar gibi birçok faktöre bağlı olarak YÇD'de AD tedaviye verilen terapötik yanıt azalmaktadır (4). YÇD hastaları komorbid durumlarda oluşan patofizyolojik değişikliklere, komorbid durumlara sekonder gelişen polifarmasiye ve yaşlılıkta oluşan fizyolojik değişikliklere bağlı olarak AD tedavisi ile oluşan yan etkilere de duyarlıdırlar (4). ...
... fizyolojik değişikliklerin AD'ların farmakokinetik (FK) ve farmakodinamik (FD) profillerinde oluşturdukları farklılıklar gibi birçok faktöre bağlı olarak YÇD'de AD tedaviye verilen terapötik yanıt azalmaktadır (4). YÇD hastaları komorbid durumlarda oluşan patofizyolojik değişikliklere, komorbid durumlara sekonder gelişen polifarmasiye ve yaşlılıkta oluşan fizyolojik değişikliklere bağlı olarak AD tedavisi ile oluşan yan etkilere de duyarlıdırlar (4). Yapılan çalışmalarda AD tedavisinin başlangıcından itibaren ilk 30 gün içerisinde hastaların yaklaşık olarak %6'sında yan etki oluştuğu gösterilmiştir (5). ...
... 4 However, the clearance of olanzapine, like other antipsychotics and antidepressants, is impacted more by factors such as smoking and patient's sex, than any one particular genotype. 5 Future studies would benefit from including pharmacometrics (e.g., measurement of drug levels, as recommended by the U.S. Food and Drug Administration), 6 using novel tools to measure symptoms and side effects, including better biomarkers, and expanding outcome measures (e.g., rates of discontinuation and hospitalization) to better characterize the pharmacokinetic-pharmacodynamic relationship in both older and younger adults. ...
... 7,8 In addition to agerelated changes (e.g., weight, fat distribution, and renal function), polypharmacy may contribute to the variability observed in PK parameters. 9 As healthy ageing increasing the presence of vulnerabilities within drug metabolism pathways, such as decreased renal clearance due to declining renal function, 10 pharmacogenetic variation may introduce compounding effects. 11 For example, in the case of decreased renal clearance, older adults who are poor metabolizers may experience a compounded increase in systemic exposure due to the two independent vulnerabilities. ...
Affecting up to 15% of older adults, late-life depression (LLD) is characterized by the occurrence of depressive symptoms after the age of 50-65 years and maybe pathophysiologically distinct from depression in younger adults. Therefore, LLD is challenging to treat, and predictive genetic testing might be essential to improve treatment in this vulnerable population. The current review aims to provide a summary of the literature exploring genetic associations with antidepressant treatment outcomes in late-life. We conducted a systematic search of three integrated electronic databases. We identified 29 articles investigating genetic associations with antidepressant treatment outcomes, pharmacokinetic parameters, and adverse drug reactions in older adults. Given the small number of investigations conducted in older adults, it is difficult to conclude the presence or absence of genetic associations with the outcomes of interest. In sum, the most substantial amount of evidence exists for the CYP2D6 metabolizer status, SLC6A4 5-HTTLPR, and BDNF rs6265. These findings are consistent in the literature when not restricting to older adults, suggesting that similar treatment recommendations may be provided for older adults regarding genetic variation, such as those outlined for CYP2D6 by the Clinical Pharmacogenetics Implementation Consortium. Nonetheless, further studies are required in well-characterized samples, including genome-wide data, to validate if similar treatment adjustments are appropriate in older adults, given that there appear to be significant effects of genetic variation on antidepressant treatment factors.
... However, we have developed a model in which the dopamine D2 receptor occupancy of antipsychotics, including risperidone, olanzapine, and ziprasidone, can be reliably estimated from plasma concentrations ( Uchida et al., 2011b). In addition, recent advances in nonlinear, mixedeffects population pharmacokinetic (PPK) methods have made it possible to estimate individual pharmacokinetic parameters for antipsychotics, including peak and trough plasma concentrations, using two or more sparsely collected blood samples ( Bigos et al., 2006). By combining these models, the dopamine D2 receptor occupancy levels at any given point in time can be reliably estimated using the measurement of antipsychotic plasma concentrations at two separate random time points ( Uchida et al., 2009b). ...
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.
... We have developed a model with which the dopamine D2 receptor occupancy by antipsychotic drugs, including risperidone, olanzapine, and ziprasidone, can be reliably estimated from plasma concentrations of these drugs (Uchida et al., 2011b). In addition, recent advances in nonlinear, mixed-effects population pharmacokinetic methods have made it possible to estimate individual pharmacokinetic parameters for antipsychotic drugs, including peak and trough plasma concentrations, using two or more sparsely collected blood samples (Bigos et al., 2006). By combining these models, the dopamine D2 receptor occupancy levels at any given point in time can be reliably estimated, using the measurement of antipsychotic plasma concentrations at two separate random time points (Uchida et al., 2009a). ...
Background:
Large-scale data are still lacking on the relationship between serum prolactin concentration and dopamine D2 receptor occupancy in patients with schizophrenia treated with antipsychotics.
Methods:
The dataset from 481 subjects (risperidone, N = 172, olanzapine, N = 211, and ziprasidone, N = 98) who participated in Phase 1 of the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) was used in the present analysis. Dopamine D2 receptor occupancy levels on the day of the measurement of serum prolactin level were estimated from plasma antipsychotic concentrations. A multivariate general linear model was used to examine effects of clinical and demographic characteristics, including estimated D2 occupancy levels, on serum prolactin concentrations. Individual subjects were divided into two groups, stratified by the presence of hyperprolactinemia. To evaluate the performance of this binary classification, sensitivity, specificity, and accuracy of consecutive cut-off points in the D2 occupancy were calculated.
Results:
The multivariate general linear model revealed that estimated D2 occupancy levels had significant effects on serum prolactin concentrations while any other variables failed to show significant effects. The cut-off point associated with 0.5 or greater, in both sensitivity and specificity with the greatest accuracy, was 73% (sensitivity, 0.58; specificity, 0.68; accuracy = 0.64) (68-70% for risperidone, 77% for olanzapine, and 55% for ziprasidone.).
Conclusion:
The threshold for hyperprolactinemia in D2 occupancy may lie somewhat on a lower side of the established therapeutic window with antipsychotics (i.e. 65-80%). This finding highlights the need for the use of the lowest possible dose to avoid this hormonal side effect in the treatment of schizophrenia.
... Blood is collected for determination of plasma sertraline and olanzapine concentrations. The analytic strategy will use population pharmacokinetics [59], which uses nonlinear mixed effect modeling to identify intra-and inter-individual sources of variability [60]. Variability from the norm in drug concentrations can be determined using sparse (between two and four) plasma samples per patient [61]. ...
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.
... This said, recent reports suggest that striatal dopamine D2 receptor occupancy of antipsychotic drugs, including risperidone and olanzapine, can be estimated from plasma concentrations of these drugs (Uchida et al., 2011c). In addition, recent advances in nonlinear mixed-effects population pharmacokinetic methods have made it possible to predict individual pharmacokinetic parameters for antipsychotic drugs, including peak and trough plasma concentrations, using two or more sparsely collected samples in real world clinical settings (Bigos et al., 2006;Feng et al., 2008;Jin et al., 2010;Wessels et al., 2011), which has been confirmed by recent data as well (Uchida et al., in press). Alternatively speaking, by combining the D2 prediction model with population pharmacokinetic techniques, dopamine D2 receptor occupancy levels at peak and trough can be estimated with the measurement of antipsychotic plasma concentrations at two separate time points (Uchida et al., 2009a). ...
In treating schizophrenia, it has been established that 65-80% occupancy of dopamine D2 receptors optimizes therapeutic efficacy while minimizing risks of extrapyramidal symptoms. However, it is unclear as to whether it is necessary to keep D2 receptor occupancy within this therapeutic window to maintain response. In this study, daily peak and trough D2 receptor occupancy levels were estimated in clinically stable patients with schizophrenia (DSM-IV) who were receiving risperidone or olanzapine. Using two collected plasma samples, plasma antipsychotic concentrations at peak and trough were estimated with population pharmacokinetic techniques. Corresponding dopamine D2 receptor occupancy levels were then estimated, using a recently developed model. 35 subjects with stable schizophrenia completed the study (mean±SD age, 48.8±13.8years; male [N=14]; Asians [N=23], Caucasians [N=12]; risperidone [N=20] at 3.2±2.3mg/day, and olanzapine [N=15] at 9.2±4.9mg/day) between September and December 2010. 48.6% (N=17) did not achieve a continuous blockade of ≥65%. Moreover, 11.4% (N=4) did not achieve the 65% threshold at estimated peak concentrations. In conclusion, approximately half the subjects with stable schizophrenia did not achieve estimated continuous blockade of D2 receptor occupancy of ≥65%. The results suggest that sustained D2 receptor occupancy levels of ≥65% may not always be necessary for the maintenance treatment of schizophrenia.
... 16 In addition, recent advances in nonlinear mixed-effects population pharmacokinetic methods have made it possible to predict individual pharmacokinetic parameters for antipsychotic drugs, including peak and trough plasma concentrations, using 2 or more sparsely collected blood samples in a real-world setting. 17 By combining these models, the dopamine D 2 receptor occupancy levels at peak and trough can be reliably estimated using the measurement of antipsychotic plasma concentrations at 2 separate time points. 18 For the purpose of elucidating the relationship between neurocognitive function and estimated dopamine D 2 receptor blockade by antipsychotics, the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial provides an ideal dataset in light of its unprecedented large sample size, comprehensive neurocognitive assessments, and assessment of plasma antipsychotic concentrations with which population pharmacokinetic models have already been developed for risperidone, olanzapine, and ziprasidone. ...
Introduction: Antipsychotic drugs exert antipsychotic effects by blocking dopamine D2 receptors in the treatment of schizophrenia. However, effects of D2 receptor blockade on neurocognitive function still remain to be elucidated. The objective of this analysis was to evaluate
impacts of estimated dopamine D2 receptor occupancy with antipsychotic drugs on several domains of neurocognitive function in patients with schizophrenia
in the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial. Methods: The dataset from the CATIE trial was used in the present analysis. Data were extracted from 410 subjects who were treated
with risperidone, olanzapine, or ziprasidone, received assessments for neurocognitive functions (verbal memory, vigilance,
processing speed, reasoning, and working memory) and psychopathology, and provided plasma samples for the measurement of plasma
antipsychotic concentrations. D2 receptor occupancy levels on the day of neurocognitive assessment were estimated from plasma antipsychotic concentrations,
using population pharmacokinetic analysis and our recently developed model. A multivariate general linear model was used to
examine effects of clinical and demographic characteristics, including estimated D2 occupancy levels, on neurocognitive functions. Results: D2 occupancy levels showed significant associations with the vigilance and the summary scores. Neurocognitive functions, including
vigilance, were especially impaired in subjects who showed D2 receptor occupancy level of >77%. Discussion: These findings suggest a nonlinear relationship between prescribed antipsychotic doses and overall neurocognitive function
and vigilance. This study shows that D2 occupancy above approximately 80% not only increases the risk for extrapyramidal side effects as consistently reported in
the literature but also increases the risk for cognitive impairment.
... In order to optimize and individualize drug dosage regimens and achieve the correct target concentration, many dosage prediction techniques are available. These techniques use different PK population models (101-104) and should not exclude populations that contribute to the variability (women, minorities, patients with comorbilities, as well as children and the elderly) to estimate the PK parameters of a drug in a given patient (105). Bayesian techniques have been successfully used and several software programs have been developed for these purposes. ...
Therapeutic drug monitoring (TDM) is a multidisciplinary activity. Because laboratory reports are part of the patient's chart, some clinical information is required. In order to guarantee quality and safety, an increasing number of TDM departments have implemented a quality management system. The aim of the present article is to review the three phases of TDM: the pre-analytical, analytical and post-analytical phases. In the pre-analytical phase, it is necessary to acquire a valid specimen collected at the specific time window. Analytical methods should be validated, assessing possible interfering substances. The objective of the post-analytical phase is the final report, which should include correct interpretation, as well as possible advice. Appropriate pharmacokinetic interpretation avoids unnecessary costs and leads to clinical benefits.
Clin Chem Lab Med 2010;48:437–46.
