Publications by authors named "Robert R Bies"

89 Publications

Impact of once- versus twice-daily perphenazine dosing on clinical outcomes: an analysis of the CATIE data.

J Clin Psychiatry 2014 May;75(5):506-11

Schizophrenia Division, Complex Mental Illness Program, Centre for Addiction and Mental Health, 250 College St, Toronto, Ontario, M5T 1R8, Canada

Objective: The objective of this study was to evaluate the impact of once- versus twice-daily dosing of perphenazine, which has a plasma half-life of 8-12 hours, on clinical outcomes in patients with schizophrenia.

Method: Data from phase 1 of the Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) conducted between January 2001 and December 2004 were used in this post hoc analysis. Patients with schizophrenia (DSM-IV) randomly allocated to treatment with perphenazine were also randomly assigned to once-daily (N = 133) or twice-daily (N = 124) dosing and followed over 18 months. Discontinuation rate and time to discontinuation were used as primary outcomes to compare the 2 groups. The following clinical outcomes were analyzed as secondary measures: efficacy-Positive and Negative Syndrome Scale, Clinical Global Impressions-Severity scale, Calgary Depression Scale for Schizophrenia, and Drug Attitude Inventory and safety/tolerability-Abnormal Involuntary Movement Scale, Barnes Akathisia Rating Scale, Simpson-Angus Scale, and body weight. Data on treatment-emergent adverse events, concomitant psychotropic medications, and medication adherence (pill count and clinician rating scale) were also analyzed for each group.

Results: No significant differences were found in any outcome measures between the once-daily and twice-daily dosing groups, which remained the same when using the mean dose of perphenazine as a covariate.

Conclusions: Perphenazine is routinely administered in a divided dosage regimen because of its relatively short plasma half-life. However, the present findings challenge such a strategy, suggesting that once-daily represents a viable treatment option. Results are discussed in the context of more recent evidence that challenges the need for high and continuous dopamine D2 receptor blockade to sustain antipsychotic response.

Trial Registration: ClinicalTrials.gov identifier: NCT00014001.
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http://dx.doi.org/10.4088/JCP.13m08695DOI Listing
May 2014

Tardive dyskinesia in relation to estimated dopamine D2 receptor occupancy in patients with schizophrenia: analysis of the CATIE data.

Schizophr Res 2014 Mar 1;153(1-3):184-8. Epub 2014 Feb 1.

Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan; Geriatric Mental Health Program, Centre for Addiction and Mental Health, Toronto, ON, Canada. Electronic address:

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 ≥6months, 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.
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http://dx.doi.org/10.1016/j.schres.2014.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3960457PMC
March 2014

Modelling the sitagliptin effect on dipeptidyl peptidase-4 activity in adults with haematological malignancies after umbilical cord blood haematopoietic cell transplantation.

Clin Pharmacokinet 2014 Mar;53(3):247-259

Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, 1001 W. 10th Street W7138, Indianapolis, IN, 46202, USA.

Background And Objectives: Dipeptidyl peptidase-4 (DPP4) inhibition is a potential strategy to increase the engraftment rate of haematopoietic stem/progenitor cells. A recent clinical trial using sitagliptin, a DPP4 inhibitor approved for type 2 diabetes mellitus, has been shown to be a promising approach in adults with haematological malignancies after umbilical cord blood (UCB) haematopoietic cell transplantation (HCT). On the basis of data from this clinical trial, a semi-mechanistic model was developed to simultaneously describe DPP4 activity after multiple doses of sitagliptin in subjects with haematological malignancies after a single-unit UCB HCT.

Methods: The clinical study included 24 patients who received myeloablative conditioning followed by oral sitagliptin with single-unit UCB HCT. Using a nonlinear mixed-effects approach, a semi-mechanistic pharmacokinetic-pharmacodynamic model was developed to describe DPP4 activity from these trial data, using NONMEM version 7.2 software. The model was used to drive Monte Carlo simulations to probe the various dosage schedules and the attendant DPP4 response.

Results: The disposition of sitagliptin in plasma was best described by a two-compartment model. The relationship between sitagliptin concentrations and DPP4 activity was best described by an indirect response model with a negative feedback loop. Simulations showed that twice daily or three times daily dosage schedules were superior to a once daily schedule for maximal DPP4 inhibition at the lowest sitagliptin exposure.

Conclusion: This study provides the first pharmacokinetic-pharmacodynamic model of sitagliptin in the context of HCT, and provides a valuable tool for exploration of optimal dosing regimens, which are critical for improving the time to engraftment in patients after UCB HCT.
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http://dx.doi.org/10.1007/s40262-013-0109-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4133124PMC
March 2014

Predicting relapsing-remitting dynamics in multiple sclerosis using discrete distribution models: a population approach.

PLoS One 2013 5;8(9):e73361. Epub 2013 Sep 5.

Indiana University School of Medicine; Indianapolis, Indiana, United States of America ; Indiana Clinical and Translational Sciences Institute (CTSI), Indianapolis, Indiana, United States of America.

Background: Relapsing-remitting dynamics are a hallmark of autoimmune diseases such as Multiple Sclerosis (MS). A clinical relapse in MS reflects an acute focal inflammatory event in the central nervous system that affects signal conduction by damaging myelinated axons. Those events are evident in T1-weighted post-contrast magnetic resonance imaging (MRI) as contrast enhancing lesions (CEL). CEL dynamics are considered unpredictable and are characterized by high intra- and inter-patient variability. Here, a population approach (nonlinear mixed-effects models) was applied to analyse of CEL progression, aiming to propose a model that adequately captures CEL dynamics.

Methods And Findings: We explored several discrete distribution models to CEL counts observed in nine MS patients undergoing a monthly MRI for 48 months. All patients were enrolled in the study free of immunosuppressive drugs, except for intravenous methylprednisolone or oral prednisone taper for a clinical relapse. Analyses were performed with the nonlinear mixed-effect modelling software NONMEM 7.2. Although several models were able to adequately characterize the observed CEL dynamics, the negative binomial distribution model had the best predictive ability. Significant improvements in fitting were observed when the CEL counts from previous months were incorporated to predict the current month's CEL count. The predictive capacity of the model was validated using a second cohort of fourteen patients who underwent monthly MRIs during 6-months. This analysis also identified and quantified the effect of steroids for the relapse treatment.

Conclusions: The model was able to characterize the observed relapsing-remitting CEL dynamic and to quantify the inter-patient variability. Moreover, the nature of the effect of steroid treatment suggested that this therapy helps resolve older CELs yet does not affect newly appearing active lesions in that month. This model could be used for design of future longitudinal studies and clinical trials, as well as for the evaluation of new therapies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0073361PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3764125PMC
June 2014

Estimated dopamine D2 receptor occupancy from plasma concentrations of atypical antipsychotics and subjective experience/drug attitude in schizophrenia: an analysis of the CATIE data.

Schizophr Res 2013 Nov 9;150(2-3):373-9. Epub 2013 Sep 9.

Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan; Schizophrenia Division, Complex Mental Illness Program, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, ON, Canada. Electronic address:

Objective: The objective of this analysis was to evaluate both cross-sectional and longitudinal relationships between estimated dopamine D2 receptor occupancy from plasma concentrations of atypical antipsychotics and subjective experience/drug attitude in patients with schizophrenia.

Method: The data from the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) were used in this analysis. The cross-sectional data included 371 patients receiving risperidone, olanzapine, or ziprasidone, who had completed the Drug Attitude Inventory (DAI-10) at six months and provided plasma antipsychotic concentrations. Samples were analyzed to examine the relationship between DAI-10 total scores and estimated D2 occupancy using Spearman's rank correlations, followed by multiple regression analysis. In addition, to elucidate the relationship between changes in DAI-10 scores and estimated D2 occupancy, the longitudinal data from 45 patients who experienced an increase in antipsychotic dosage between six and 12months were analyzed. Mean peak and trough D2 occupancy levels were estimated from plasma antipsychotic concentrations using a population pharmacokinetic approach.

Results: A positive association was found between estimated D2 occupancy and DAI-10 total scores in patients receiving ziprasidone in the cross-sectional dataset (rs=0.395, P=0.001). In contrast, a negative association was found in changes in estimated D2 occupancy and DAI-10 scores among patients receiving olanzapine in the longitudinal dataset (rs=-0.534, P=0.010). No significant associations were found in patients receiving risperidone, or in the whole sample regarding both cross-sectional and longitudinal datasets.

Conclusion: Dopamine D2 receptor occupancy may mediate subjective experience/drug attitude in patients with schizophrenia. The directionality may however differ between antipsychotics, which warrants further investigation.
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http://dx.doi.org/10.1016/j.schres.2013.08.033DOI Listing
November 2013

Estimated dopamine D₂ receptor occupancy and remission in schizophrenia: analysis of the CATIE data.

J Clin Psychopharmacol 2013 Oct;33(5):682-5

Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan.

In treating schizophrenia, 65% to 80% occupancy of dopamine D₂ receptors optimizes therapeutic efficacy while minimizing risks of extrapyramidal symptoms and cognitive impairments. However, it is unclear as to whether it is necessary to keep D₂ receptor occupancy within this therapeutic window to maintain clinical response. The data set from phase 1 of the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial was reappraised. Thirty patients receiving risperidone (12 patients), olanzapine (12 patients), or ziprasidone (6 patients) fulfilled the following definition of remission and were included: a score of 3 or less on the 8 specific items in the Positive and Negative Syndrome Scale (ie, P1, P2, P3, N1, N4, N6, G5, and G9; adopted from Andreasen et al, 2005) at the initial assessment and months 1, 2, and 6. Peak and trough D₂ receptor occupancy levels at month 6 were estimated from plasma antipsychotic concentrations using population pharmacokinetic analysis and our D₂ prediction model. Estimated mean ± SD peak and trough D₂ receptor occupancy levels at month 6 were 70.3% ± 9.8% and 60.5% ± 20.2%, respectively; among these individuals, 46.7% (14 patients) did not achieve continuous blockade of 65% or greater (ie, trough D₂ occupancy of <65%). In conclusion, approximately half of patients with remission did not achieve continuous blockade of estimated D₂ receptor occupancy 5% or greater. These results extend our previous findings and suggest that sustained D₂ receptor occupancy greater than 65% may not always be necessary for the maintenance treatment of schizophrenia.
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http://dx.doi.org/10.1097/JCP.0b013e3182979a0aDOI Listing
October 2013

Therapeutic hypothermia decreases phenytoin elimination in children with traumatic brain injury.

Crit Care Med 2013 Oct;41(10):2379-87

1Department of Pharmacy and Therapeutics, Center for Clinical Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA. 2Division of Clinical Pharmacology, School of Medicine and Indiana Clinical and Translational Sciences Institute, Indiana University, Indianapolis, IN. 3Department of Critical Care Medicine, School of Medicine, and the Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA. 4Department of Neurological Surgery, School of Medicine, and the Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA. 5Department of Pharmaceutical Sciences, Center for Clinical Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA. 6Division of Neurosurgery/Children's Neuroscience, Department of Child Health, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ.

Objective: Preclinical and clinical studies have suggested that therapeutic hypothermia, while decreasing neurologic injury, may also lead to drug toxicity that may limit its benefit. Cooling decreases cytochrome P450 (CYP)-mediated drug metabolism, and limited clinical data suggest that drug levels are elevated. Fosphenytoin is metabolized by cytochrome P450 2C, has a narrow therapeutic range, and is a commonly used antiepileptic medication. The objective of this study was to evaluate the impact of therapeutic hypothermia on phenytoin levels and pharmacokinetics in children with severe traumatic brain injury.

Design: Pharmacokinetic analysis of subjects participating in a multicenter randomized phase III study of therapeutic hypothermia for severe traumatic brain injury.

Setting: ICU at the Children's Hospital of Pittsburgh.

Patients: Nineteen children with severe traumatic brain injury.

Interventions: None.

Measurements And Main Results: A sum of 121 total and 114 free phenytoin levels were evaluated retrospectively in 10 hypothermia-treated and nine normothermia-treated children who were randomized to 48 hours of cooling to 32-33°C followed by slow rewarming or controlled normothermia. Drug dosing, body temperatures, and demographics were collected during cooling, rewarming, and posttreatment periods (8 d). A trend toward elevated free phenytoin levels in the hypothermia group (p=0.051) to a median of 2.2 mg/L during rewarming was observed and was not explained by dosing differences. Nonlinear mixed-effects modeling incorporating both free and total levels demonstrated that therapeutic hypothermia specifically decreased the time-variant component of the maximum velocity of phenytoin metabolism (Vmax) 4.6-fold (11.6-2.53 mg/hr) and reduced the overall Vmax by ~50%. Simulations showed that the increased risk for drug toxicity extends many days beyond the end of the cooling period.

Conclusions: Therapeutic hypothermia significantly reduces phenytoin elimination in children with severe traumatic brain injury leading to increased drug levels for an extended period of time after cooling. Pharmacokinetic interactions between hypothermia and medications should be considered when caring for children receiving this therapy.
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http://dx.doi.org/10.1097/CCM.0b013e318292316cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3783553PMC
October 2013

Effects of risperidone and olanzapine dose reduction on cognitive function in stable patients with schizophrenia: an open-label, randomized, controlled, pilot study.

Schizophr Bull 2013 Sep 1;39(5):993-8. Epub 2013 Jul 1.

Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

Impact of dose reduction of atypical antipsychotics on cognitive function has not been investigated in stable patients with schizophrenia. In this open-label, 28-week, randomized controlled trial, stable patients with schizophrenia treated with risperidone or olanzapine were randomly assigned to the reduction group (dose reduced by 50% in 4 weeks and then maintained) or maintenance group (dose kept constant). Assessments at baseline and week 28 included the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Positive and Negative Syndrome Scale (PANSS), and Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). Sixty-one patients were enrolled; 2 of 31 (6.5%) and 5 of 30 (16.7%) patients prematurely withdrew from the study in the reduction and maintenance groups, respectively. While no significant differences in change in the PANSS total score were observed between the 2 groups, the reduction group showed significantly greater improvements in the RBANS and DIEPSS total scores compared with the maintenance group (mean ± SD, +7.0±7.1 vs -0.1±8.0, P < .001; -0.9±1.7 vs +0.1±1.2, P = .010, respectively). This 6-month pilot study suggests that risperidone or olanzapine dose reduction of 50% can improve cognitive function for stable patients with schizophrenia. Due to the open-label design, small sample size, and short study duration, however, there is a need to confirm the finding through double-blind, larger scale trials with longer follow-up periods. Moreover, potential risks of relapse following antipsychotic dose reduction should be thoroughly investigated in longer term studies.
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http://dx.doi.org/10.1093/schbul/sbt090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756793PMC
September 2013

Hyperprolactinemia and estimated dopamine D2 receptor occupancy in patients with schizophrenia: analysis of the CATIE data.

Prog Neuropsychopharmacol Biol Psychiatry 2013 Aug 29;45:178-82. Epub 2013 May 29.

Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan.

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.
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http://dx.doi.org/10.1016/j.pnpbp.2013.05.010DOI Listing
August 2013

Population pharmacokinetic modeling of sertraline treatment in patients with Alzheimer disease: the DIADS-2 study.

J Clin Pharmacol 2013 Feb 24;53(2):234-9. Epub 2013 Jan 24.

Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

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http://dx.doi.org/10.1177/0091270012445793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3604147PMC
February 2013

The relationship of polymorphisms in ABCC2 and SLCO1B3 with docetaxel pharmacokinetics and neutropenia: CALGB 60805 (Alliance).

Pharmacogenet Genomics 2013 Jan;23(1):29-33

Sections of Clinical Pharmacology and Hematology/Oncology, Department of Medicine, The Geisel School of Medicine at Dartmouth, The Norris Cotton Cancer Center, Lebanon, NH 03756, USA.

Docetaxel-related neutropenia was associated with polymorphisms in the drug transporters ABCC2 and SLCO1B3 in Japanese cancer patients. We hypothesized that this association is because of reduced docetaxel clearance, associated with polymorphisms in those genes. We studied 64 US cancer patients who received a single cycle of 75 mg/m of docetaxel monotherapy. We found that the ABCC2 polymorphism at rs-12762549 trended to show a relationship with reduced docetaxel clearance (P=0.048), but not with neutropenia. There was no significant association of the SLCO1B3 polymorphisms with docetaxel clearance or neutropenia. We conclude that the relationship between docetaxel-associated neutropenia and polymorphisms in drug transporters identified in Japanese patients was not confirmed in this cohort of US cancer patients.
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http://dx.doi.org/10.1097/FPC.0b013e32835b16d8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3647228PMC
January 2013

Adherence to escitalopram treatment in depression: a study of electronically compiled dosing histories in the 'Depression: the search for phenotypes' study.

Int Clin Psychopharmacol 2012 Nov;27(6):291-7

Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.

Poor adherence to depression treatment is common. Understanding determinants of poor adherence to therapy is crucial to ensure optimal clinical outcomes. The aim of this study was to describe characteristics of dosing history in participants with depression receiving once daily escitalopram. Participants were randomly assigned to interpersonal psychotherapy (IPT) or pharmacotherapy. Participants assigned to IPT who did not evidence a response or remission had escitalopram added to their treatment. Adherence to pharmacotherapy was assessed using an electronically monitored pill cap (MEMS). Fifty-four participants on escitalopram alone and 32 on escitalopram+IPT were monitored. After 200 days, 71.7% of the participants in the escitalopram group and 54.8% of those in the escitalopram+IPT group were still engaged with the dosing regimen. Of those engaged in the dosing regimen, 17.9% (average over 210 days) of the participants did not take their medication (nonexecution). In 69% of the days participants took the correct dosage required. On average, participants had three drug holidays and the mean length of a holiday was 7 days per patient. No difference in adherence patterns was observed between patients receiving escitalopram alone vs. IPT+escitalopram. Early discontinuation of treatment and suboptimal daily execution of the prescribed regimen are the most common facets of poor adherence in this study population.
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http://dx.doi.org/10.1097/YIC.0b013e3283597678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3502044PMC
November 2012

Population pharmacokinetic modeling of risperidone and 9-hydroxyrisperidone to estimate CYP2D6 subpopulations in children and adolescents.

Ther Drug Monit 2012 Oct;34(5):535-44

Division of Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, MLC 6018, Cincinnati, OH 45229-3039, USA.

Aim: The study aims were to characterize risperidone and (±)-9-hydroxyrisperidone pharmacokinetic (PK) variability in children and adolescents and to evaluate covariate effects on PK parameters.

Methods: Steady-state samples were drawn at predose, 1, 2, 4, and 7 hours postdose; cytochrome P450 2D6 (CYP2D6) genotypes were available for 28 subjects. A nonlinear mixed-effects model (NONMEM) modeled the PKs of risperidone and (±)-9-hydroxyrisperidone; covariates included age, weight, sex, and CYP2D6 phenotype. The model included 497 observations [risperidone (n = 163), (+) and (-)-9-hydroxyrisperidone (n = 334)] from 45 subjects aged 3-18.3 (mean 9.6 ± 3.7) years, weighing 16.8-110 (43 ± 20.2) kg.

Results: A 1-compartment mixture model described risperidone and (±)-9-hydroxyrisperidone clearances for 3 CYP2D6 metabolizer subpopulations: extensive, intermediate, and poor. Weight significantly affected (±)-9-hydroxyrisperidone clearance. Clearance estimates in the mixture model were poor metabolizer 9.38 L/h, intermediate metabolizer 29.2 L/h, and extensive metabolizer 37.4 L/h.

Conclusion: Active moiety [risperidone plus (±)-9-hydroxyrisperidone] PK variability and the covariate effects were better explained with the addition of metabolite PK parameters. This model may aid the development of individualized risperidone dosing regimens in children and adolescents.
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http://dx.doi.org/10.1097/FTD.0b013e318261c240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3442132PMC
October 2012

Bayesian model of Hamilton Depression Rating Score (HDRS) with memantine augmentation in bipolar depression.

Br J Clin Pharmacol 2013 Mar;75(3):791-8

Department of Medicine and Medical Genetics, Division of Clinical Pharmacology, School of Medicine, Indiana University, Indianapolis, IN 46202, USA.

Aim: Presynaptic and post-synaptic glutamatergic modulation is associated with antidepressant activity that takes several weeks to reach a maximal full effect. Limiting mood elevating effects after single drug administration may be the result of compensatory synaptic processes. Therefore, using augmentation treatment with agents having presynaptic and post-synaptic effects on the glutamatergic system, this study aims to evaluate the effect of augmentation therapy on the rate of change in mood elevation in patients with bipolar depression.

Methods: In a pilot study, 29 outpatients with bipolar depression on a stable lamotrigine dose regimen received placebo or memantine pills daily (titrated up by 5 mg week⁻¹ to 20 mg) in a randomized, double-blind, parallel group, 8 week study. Patients were evaluated weekly using the 17-item Hamilton Depression Rating Score (HDRS) and all data were analyzed simultaneously. Linear, exponential, maximal effect, Gompertz and inverse Bateman functions were evaluated using a Bayesian approach population pharmacodynamic model framework. In these models, differences in parameters were examined across the memantine and placebo augmentation groups.

Results: A Gompertz function with a treatment switch on the parameter describing the speed of HDRS decline (γ, 95% confidence interval [CI]) best described the data (γ(memantine) = 1.8, 95% CI 0.9, 3.6), γ(placebo) = 1.2, 95% CI 0.5, 3.5)). Between subject variability was identified on baseline HDRS (2.9, 95% CI 1.5, 4.4) and amplitude of score improvement (4.3, 95% CI 2.7, 6.5).

Conclusions: This pharmacodynamic approach identified an increased speed of response after memantine augmentation, compared with placebo augmentation in bipolar depression patients.
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http://dx.doi.org/10.1111/j.1365-2125.2012.04398.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3575945PMC
March 2013

Application of a single-objective, hybrid genetic algorithm approach to pharmacokinetic model building.

J Pharmacokinet Pharmacodyn 2012 Aug 6;39(4):393-414. Epub 2012 Jul 6.

Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.

A limitation in traditional stepwise population pharmacokinetic model building is the difficulty in handling interactions between model components. To address this issue, a method was previously introduced which couples NONMEM parameter estimation and model fitness evaluation to a single-objective, hybrid genetic algorithm for global optimization of the model structure. In this study, the generalizability of this approach for pharmacokinetic model building is evaluated by comparing (1) correct and spurious covariate relationships in a simulated dataset resulting from automated stepwise covariate modeling, Lasso methods, and single-objective hybrid genetic algorithm approaches to covariate identification and (2) information criteria values, model structures, convergence, and model parameter values resulting from manual stepwise versus single-objective, hybrid genetic algorithm approaches to model building for seven compounds. Both manual stepwise and single-objective, hybrid genetic algorithm approaches to model building were applied, blinded to the results of the other approach, for selection of the compartment structure as well as inclusion and model form of inter-individual and inter-occasion variability, residual error, and covariates from a common set of model options. For the simulated dataset, stepwise covariate modeling identified three of four true covariates and two spurious covariates; Lasso identified two of four true and 0 spurious covariates; and the single-objective, hybrid genetic algorithm identified three of four true covariates and one spurious covariate. For the clinical datasets, the Akaike information criterion was a median of 22.3 points lower (range of 470.5 point decrease to 0.1 point decrease) for the best single-objective hybrid genetic-algorithm candidate model versus the final manual stepwise model: the Akaike information criterion was lower by greater than 10 points for four compounds and differed by less than 10 points for three compounds. The root mean squared error and absolute mean prediction error of the best single-objective hybrid genetic algorithm candidates were a median of 0.2 points higher (range of 38.9 point decrease to 27.3 point increase) and 0.02 points lower (range of 0.98 point decrease to 0.74 point increase), respectively, than that of the final stepwise models. In addition, the best single-objective, hybrid genetic algorithm candidate models had successful convergence and covariance steps for each compound, used the same compartment structure as the manual stepwise approach for 6 of 7 (86 %) compounds, and identified 54 % (7 of 13) of covariates included by the manual stepwise approach and 16 covariate relationships not included by manual stepwise models. The model parameter values between the final manual stepwise and best single-objective, hybrid genetic algorithm models differed by a median of 26.7 % (q₁ = 4.9 % and q₃ = 57.1 %). Finally, the single-objective, hybrid genetic algorithm approach was able to identify models capable of estimating absorption rate parameters for four compounds that the manual stepwise approach did not identify. The single-objective, hybrid genetic algorithm represents a general pharmacokinetic model building methodology whose ability to rapidly search the feasible solution space leads to nearly equivalent or superior model fits to pharmacokinetic data.
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http://dx.doi.org/10.1007/s10928-012-9258-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3400037PMC
August 2012

Population pharmacokinetic analysis of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) in adult patients with solid tumors.

Cancer Chemother Pharmacol 2012 Jul 27;70(1):201-5. Epub 2012 Mar 27.

Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, 1001 W. 10th Street, WD W7123, Indianapolis, IN 46202, USA.

Purpose: To identify sources of exposure variability for the tumor growth inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) using a population pharmacokinetic analysis.

Methods: A total 67 solid tumor patients at 2 centers were given 1 h infusions of 17-DMAG either as a single dose, daily for 3 days, or daily for 5 days. Blood samples were extensively collected and 17-DMAG plasma concentrations were measured by liquid chromatography/mass spectrometry. Population pharmacokinetic analysis of the 17-DMAG plasma concentration with time was performed using nonlinear mixed effect modeling to evaluate the effects of covariates, inter-individual variability, and between-occasion variability on model parameters using a stepwise forward addition then backward elimination modeling approach. The inter-individual exposure variability and the effects of between-occasion variability on exposure were assessed by simulating the 95 % prediction interval of the AUC per dose, AUC(0-24 h), using the final model and a model with no between-occasion variability, respectively, subject to the five day 17-DMAG infusion protocol with administrations of the median observed dose.

Results: A 3-compartment model with first order elimination (ADVAN11, TRANS4) and a proportional residual error, exponentiated inter-individual variability and between occasion variability on Q2 and V1 best described the 17-DMAG concentration data. No covariates were statistically significant. The simulated 95% prediction interval of the AUC(0-24 h) for the median dose of 36 mg/m(2) was 1,059-9,007 mg/L h and the simulated 95 % prediction interval of the AUC(0-24 h) considering the impact of between-occasion variability alone was 2,910-4,077 mg/L h.

Conclusions: Population pharmacokinetic analysis of 17-DMAG found no significant covariate effects and considerable inter-individual variability; this implies a wide range of exposures in the population and which may affect treatment outcome. Patients treated with 17-DMAG may require therapeutic drug monitoring which could help achieve more uniform exposure leading to safer and more effective therapy.
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http://dx.doi.org/10.1007/s00280-012-1859-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383947PMC
July 2012

Predicting plasma concentration of risperidone associated with dosage change: a population pharmacokinetic study.

Ther Drug Monit 2012 Apr;34(2):182-7

Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan.

Background: Due to high interindividual variability in peripheral pharmacokinetic parameters, dosing of antipsychotics relies on clinical trial and error. This blind process of upward or downward clinical dose titration carries a risk of relapse and adverse effects in the treatment of schizophrenia. Using population pharmacokinetic methods, the authors therefore sought to predict plasma concentrations of risperidone (RIS) plus 9-hydroxyrisperidone (9-OH-RIS) before a dosage change.

Methods: Two plasma samples were collected at 2 separate given time points for the measurement of RIS and 9-OH-RIS concentrations from 50 patients with schizophrenia or schizoaffective disorder maintained on risperidone (mean ± SD age = 56 ± 15 years; 39 men). After an oral risperidone dose adjustment, a third sample was collected. The plasma concentration of the third sample was individually predicted in a blinded fashion with the 2 baseline plasma concentrations before dose adjustment and clinical and demographic information, using the mixed-effects model with NONMEM that was derived from the data of the Clinical Antipsychotic Trials in Intervention Effectiveness study.

Results: The mean (95% confidence interval) prediction errors (in ng/mL) were as low as 0.0 (-1.3 to 1.4) for RIS and 1.0 (-1.1 to 3.0) for 9-OH-RIS. The observed and predicted concentrations of RIS and 9-OH-RIS were highly correlated (r = 0.96, P < 0.0001 and r = 0.92, P < 0.0001, respectively).

Conclusions: Antipsychotic plasma concentrations can be predicted before risperidone dose adjustment. In light of the known relationship between plasma drug concentration, dopamine D2 receptor occupancy, and clinical effects, our results confirm that individualized dosing with the measurement of antipsychotic plasma concentrations has the potential for bedside clinical application.
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http://dx.doi.org/10.1097/FTD.0b013e3182489a6fDOI Listing
April 2012

Dopamine D2 receptor occupancy and cognition in schizophrenia: analysis of the CATIE data.

Schizophr Bull 2013 May 30;39(3):564-74. Epub 2012 Jan 30.

Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

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.
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http://dx.doi.org/10.1093/schbul/sbr189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3627781PMC
May 2013

Resampling phase III data to assess phase II trial designs and endpoints.

Clin Cancer Res 2012 Apr 27;18(8):2309-15. Epub 2012 Jan 27.

Departments of Medicine and Health Studies, University of Chicago, Chicago, Illinois, USA.

Purpose: The best phase II design and endpoint for growth inhibitory agents is controversial. We simulated phase II trials by resampling patients from a positive (sorafenib vs. placebo; TARGET) and a negative (AE941 vs. placebo) phase III trial in metastatic renal cancer to compare the ability of various designs and endpoints to predict the known results.

Experimental Design: A total of 770 and 259 patients from TARGET and the AE 941 trial, respectively, were resampled (5,000 replicates) to simulate phase II trials with α = 0.10 (one-sided). Designs/endpoints: single arm, two-stage with response rate (RR) by Response Evaluation Criteria in Solid Tumors (RECIST; 37 patients); and randomized, two arm (20-35 patients per arm) with RR by RECIST, mean log ratio of tumor sizes (log ratio), progression-free survival (PFS) rate at 90 days (PFS-90), and overall PFS.

Results: Single-arm trials were positive with RR by RECIST in 55% and 1% of replications for sorafenib and AE 941, respectively. Randomized trials versus placebo with 20 patients per arm were positive with RR by RECIST in 55% and 7%, log ratio in 88% and 25%, PFS-90 in 64% and 15%, and overall PFS in 69% and 9% of replications for sorafenib and AE 941, respectively.

Conclusions: Compared with the single-arm design and the randomized design comparing PFS, the randomized phase II design with the log ratio endpoint has greater power to predict the positive phase III result of sorafenib in renal cancer, but a higher false positive rate for the negative phase III result of AE 941.
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http://dx.doi.org/10.1158/1078-0432.CCR-11-1815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3328614PMC
April 2012

Dopamine D2 receptor occupancy with risperidone or olanzapine during maintenance treatment of schizophrenia: a cross-sectional study.

Prog Neuropsychopharmacol Biol Psychiatry 2012 Apr 30;37(1):182-7. Epub 2011 Dec 30.

Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

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.
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http://dx.doi.org/10.1016/j.pnpbp.2011.12.013DOI Listing
April 2012

Cardiac arrest and therapeutic hypothermia decrease isoform-specific cytochrome P450 drug metabolism.

Drug Metab Dispos 2011 Dec 25;39(12):2209-18. Epub 2011 Aug 25.

Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA 15261, USA.

Mild therapeutic hypothermia is emerging clinically as a neuroprotection therapy for individuals experiencing cardiac arrest (CA); however, its effects combined with disease pathogenesis on drug disposition and response have not been fully elucidated. We determined the activities of four major hepatic-metabolizing enzymes (CYP3A, CYP2C, CYP2D, and CYP2E) during hypothermia after experimental CA in rats by evaluating the pharmacokinetics of their probe drugs as a function of altered body temperature. Animals were randomized into sham normothermia (37.5-38°C), CA normothermia, sham hypothermia (32.5-33°C), and CA hypothermia groups. Probe drugs (midazolam, diclofenac, dextromethorphan, and chlorzoxazone) were given simultaneously by intravenous bolus after temperature stabilization. Multiple blood samples were collected between 0 and 8 h after drug administration. Pharmacokinetic (PK) analysis was conducted using a noncompartmental approach and population PK modeling. Noncompartmental analysis showed that the clearance of midazolam (CYP3A) in CA hypothermia was reduced from sham normothermia rats (681.6 ± 190.0 versus 1268.8 ± 348.9 ml · h(-1) · kg(-1), p < 0.05). The clearance of chlorzoxazone (CYP2E) in CA hypothermia was also reduced from sham normothermia rats (229.6 ± 75.6 versus 561.89 ± 215.9 ml · h(-1) · kg(-1), p < 0.05). Population PK analysis further demonstrated the decreased clearance of midazolam (CYP3A) was associated with CA injury (p < 0.05). The decreased clearance of chlorzoxazone (CYP2E1) was also associated with CA injury (p < 0.01). Hypothermia was found to be associated with the decreased volume of distribution of midazolam (V(1)), dextromethorphan (V(1)), and peripheral compartment for chlorzoxazone (V(2)) (p < 0.05, p < 0.05, and p < 0.01, respectively). Our data indicate that hypothermia, CA, and their interaction alter cytochrome P450-isoform specific activities in an isoform-specific manner.
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http://dx.doi.org/10.1124/dmd.111.040642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3226379PMC
December 2011

Performance of Cpred/Cobs concentration ratios as a metric reflecting adherence to antidepressant drug therapy.

Neuropsychiatr Dis Treat 2011 17;7:117-25. Epub 2011 Mar 17.

Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb, Lawrenceville, NJ, USA;

Background: Nonadherence is very common among subjects undergoing pharmacotherapy for schizophrenia and depression. This study aimed to evaluate the performance of the ratio of the nonlinear mixed effects pharmacokinetic model predicted concentration to observed drug concentration (ratio of population predicted to observed concentration (Cpred/Cobs) and ratio of individual predicted to observed concentration (Cipred/Cobs) as a measure of erratic drug exposure, driven primarily by variable execution of the dosage regimen and unknown true dosage history.

Methods: Modeling and simulation approaches in conjunction with dosage history information from the Medication Event Monitoring System (MEMS, provided by the "Depression: The search for treatment relevant phenotypes" study), was applied to evaluate the consistency of exposure via simulation studies with scenarios representing a long half-life drug (escitalopram). Adherence rates were calculated based on the percentage of the prescribed doses actually taken correctly during the treatment window of interest. The association between Cpred/Cobs, Cipred/Cobs ratio, and adherence rate was evaluated under various assumptions of known dosing history.

Results: Simulations for those scenarios representing a known dosing history were generated from historical MEMS data. Simulations of a long half-life drug exhibited a trend for overprediction of concentrations in patients with a low percentage of doses taken and underprediction of concentrations in patients taking more than their prescribed number of doses. Overall, the ratios did not predict adherence well, except when the true adherence rates were extremely high (greater than 100% of prescribed doses) or extremely low (complete nonadherence). In general, the Cipred/Cobs ratio was a better predictor of adherence rate than the Cpred/Cobs ratio. Correct predictions of extreme (high, low) 7-day adherence rates using Cipred/Cobs were 73.8% and 64.0%.

Conclusion: This simulation study demonstrated the limitations of the Cpred/obs and Cipred/obs ratios as metrics for actual dosage intake history, and identified that use of MEMS dosing history monitoring combined with sparse pharmacokinetic sampling is a more reliable approach.
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http://dx.doi.org/10.2147/NDT.S15921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3083985PMC
July 2011

Core competencies for research training in the clinical pharmaceutical sciences.

Am J Pharm Educ 2011 Mar;75(2):27

University of Pittsburgh, School of Pharmacy, Pittsburgh, PA 15261, USA.

Objective: To identify and apply core competencies for training students enrolled in the clinical pharmaceutical scientist PhD training program at the University of Pittsburgh School of Pharmacy.

Design: Faculty members reached consensus on the required core competencies for the program and mapped them to curricular and experiential requirements.

Assessment: A rubric was created based on core competencies spanning 8 major categories of proficiency, and competencies of clinical versus traditional PhD training were delineated. A retrospective evaluation of the written comprehensive examinations of 12 former students was conducted using the rubric. Students scored above satisfactory in 11 out of 14 comprehensive examination metrics, with a mean score greater than 3.8 on a 5-point scale.

Conclusions: The core competencies identified will provide an essential foundation for informed decision-making and assessment of PhD training in the clinical pharmaceutical sciences.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3073101PMC
http://dx.doi.org/10.5688/ajpe75227DOI Listing
March 2011

Age and sex impact clozapine plasma concentrations in inpatients and outpatients with schizophrenia.

Am J Geriatr Psychiatry 2012 Jan;20(1):53-60

Centre for Addiction and Mental Health, Geriatric Mental Health Program, Toronto, Ontario, Canada.

Background: Although clozapine is primarily used in a younger to mid-life population of patients with psychosis, there are limited data on the clinical pharmacology of clozapine later in life. The objective of this study was to assess the magnitude and variability of plasma concentrations of clozapine and norclozapine across the lifespan in a real-world clinical setting.

Design: A population pharmacokinetic study using nonlinear mixed effect modeling (NONMEM). Age, sex, height, weight, and dosage formulation were covariates.

Setting: Inpatients and outpatients at the Centre for Addiction and Mental Health, Toronto, from 2001 to 2007.

Participants: Patients ranging in ages from 11 to 79 with schizophrenia spectrum disorders and prescribed clozapine (Clozaril).

Measurements: A total of 1142 plasma clozapine and norclozapine concentrations (2,284 concentration measurements) from 391 patients with schizophrenia spectrum disorder.

Results: A one-compartment model with first-order absorption and elimination best described the data. The population predicted clearance of clozapine for females was 27.1 L/h (SE 11.1%) and 36.7 L/h (SE 9.7%) for males. For norclozapine, clearance in females was 48.6 L/h (SE 10.8%) and 63.1 L/h (SE 9.3%) in males. The only covariates with a significant effect on clearance were age and sex: clearance for both parent and metabolite decreased exponentially with age at least 39 years.

Conclusions: Decreased clearance of clozapine and norclozapine with age results in increased blood concentrations and, hence, the potential for adverse drug reactions. These findings have particular clinical relevance for the dosing and safety monitoring of clozapine in older adults, highlighting a need for increased vigilance.
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http://dx.doi.org/10.1097/JGP.0b013e3182118318DOI Listing
January 2012

Population pharmacokinetic modeling of ziprasidone in patients with schizophrenia from the CATIE study.

J Clin Pharmacol 2011 Nov 5;51(11):1587-91. Epub 2011 Jan 5.

Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, USA.

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http://dx.doi.org/10.1177/0091270010387604DOI Listing
November 2011

Association of 9-hydroxy risperidone concentrations with risk of switching or discontinuation in the clinical antipsychotic trial of intervention effectiveness-Alzheimer's disease trial.

J Clin Psychopharmacol 2010 Dec;30(6):683-7

Division of Clinical Pharmacology, Wishard Memorial Hospital, 1001 West 10th St, WD Meyers Building, W7123, Indianapolis, IN 46202, USA.

Risperidone has been used to treat behavioral symptoms, such as delusions and agitation, in people with Alzheimer's disease. The relationship between magnitude and variability of risperidone and 9-hydroxy risperidone exposure and the relationship with time to discontinuation of the medication were explored. Sixty-five subjects from the Clinical Antipsychotic Trial of Intervention Effectiveness-Alzheimer's Disease Trial that received risperidone were included in this study. Eighteen subjects completed the study without switching medication (completers on risperidone), whereas 47 discontinued the medication. Those who discontinued were divided into 2 groups according to responsiveness to therapy. Using Cox proportional survival regression analysis, we estimated time to discontinuation and factors associated with treatment discontinuation including age, dose, body mass index, neuropsychiatric inventory baseline score, and average exposure (area under the curve [AUC]) to risperidone and 9-hydroxy risperidone. Twenty-four and 17 subjects discontinued therapy because of inadequate therapeutic effect and side effects, respectively (6 subjects were excluded because of missing information about reason for switching or discontinuation). Discontinuation hazards for those with a higher than median AUC of the metabolite were 2.54 (P = 0.029; inadequate and side effect group combined) and 3.48 (P = 0.025; inadequate effect group) times that of those in the lower than median AUC group. None of the other covariates contributed significantly to the switching hazard. Risperidone metabolite, 9-hydroxy risperidone concentrations, correlated with the risk of switching or discontinuing the medication, suggesting that 9-hydroxy risperidone contributes to adverse events and intolerability in dementia patients.
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http://dx.doi.org/10.1097/jcp.0b013e3181fa05bbDOI Listing
December 2010

Relation of serotonin transporter genetic variation to efficacy of escitalopram for generalized anxiety disorder in older adults.

J Clin Psychopharmacol 2010 Dec;30(6):672-7

Department of Psychiatry, Washington University School of Medicine, 660 S Euclid, Box 8134, St Louis, MO 63110, USA.

Objective: Generalized anxiety disorder (GAD) is common in older adults and can be treated with selective serotonin reuptake inhibitors (SSRIs). Genetic variation in the serotonin transporter gene promoter region is posited to be associated with SSRI efficacy: 2 polymorphisms (5-HTTLPR S/L and rs25531 g/a) form a haplotype with the La combination having higher transcription activity than other haplotypes. We hypothesized that GAD patients with no La haplotypes (La⁻) have lower SSRI treatment efficacy than those with 1 to 2 La haplotypes (La+).

Method: The study enrolled subjects aged 60 years or older with a principal diagnosis of GAD into a 12-week, randomized trial of escitalopram versus placebo. One hundred fifty subjects were genotyped for the serotonin transporter promoter region haplotype and were divided into La⁻ and La+ genotype groups; the primary analyses were done in European Americans only (n = 125; n = 59 with escitalopram and n = 66 with placebo).

Results: Escitalopram had no efficacy in the La⁻ group versus moderate efficacy in the La+ group. This genetic moderation of SSRI efficacy was due to a higher placebo response in La⁻ subjects, compared with La+ subjects. Drug concentration did not affect the genetic results. Exploratory analyses suggest that La⁻ subjects had greater variability of anxiety symptoms unrelated to treatment.

Conclusions: The serotonin transporter promoter haplotype is associated with variability in SSRI efficacy for late-life GAD. The variability may result from a genetic effect on anxiety symptom variability unrelated to treatment, rather than a pharmacodynamic effect that has been previously assumed. Further research is needed to understand the pharmacogenetic mechanism of this haplotype.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3059101PMC
http://dx.doi.org/10.1097/jcp.0b013e3181fc2befDOI Listing
December 2010

Pharmacokinetic-pharmacodynamic analysis of the static allodynia response to pregabalin and sildenafil in a rat model of neuropathic pain.

J Pharmacol Exp Ther 2010 Aug 5;334(2):599-608. Epub 2010 May 5.

Leiden-Amsterdam Center for Drug Research, Division of Pharmacology, Leiden University, Leiden, The Netherlands.

The objective of this study was to develop a pharmacokinetic-pharmacodynamic (PK-PD) model of the static allodynia response to pregabalin with and without sildenafil in a chronic constriction injury model of neuropathic pain. Six treatment groups were evaluated every 30 min for 6 h. Rats were treated with either 1) a saline infusion; 2) a 2-h pregabalin infusion at 4 mgxkg(-1)xh(-1); 3) a 2-h pregabalin infusion at 10 mgxkg(-1)xh(-1); 4) a 2.2-mg loading dose + 12 mgxkg(-1)xmin(-1) infusion of sildenafil; 5) a 2-h pregabalin infusion at 1.6 mgxkg(-1)xh(-1) with sildenafil; and 6) a 2-h infusion of pregabalin at 4 mgxkg(-1)xh with sildenafil. The static allodynia endpoint was modeled by using three population PD approaches: 1) the behavior of the injured paw using a three-category ordinal logistic regression model; 2) paw withdrawal threshold (PWT) (g) between the injured and uninjured paw using the Hill equation with a baseline function; and 3) the baseline normalized difference in PWT between the injured and uninjured paw. The categorical model showed a significant shift in the concentration-response relationship of pregabalin to lower concentrations with concomitant sildenafil. Likewise, the continuous PK-PD models demonstrated a reduction in the EC(50) of pregabalin necessary for PD response in the presence of sildenafil. The difference-transformed PD model resulted in a 54.4% (42.3-66.9%) decrease in EC(50), whereas the percentage-transformed PD model demonstrated a 53.5% (42.7-64.3%) shift. It is concluded from these studies that there is a synergistic PD interaction between pregabalin and sildenafil.
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http://dx.doi.org/10.1124/jpet.110.166074DOI Listing
August 2010

An exploratory study of body composition as a determinant of epirubicin pharmacokinetics and toxicity.

Cancer Chemother Pharmacol 2011 Jan 5;67(1):93-101. Epub 2010 Mar 5.

Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada.

Purpose: Although body composition has emerged as an important predictor of drug efficacy and toxicity, explanations for this association are unclear. Our goal was to investigate relationships between lean body mass (LBM), liver size/function and epirubicin pharmacokinetics (PK) and toxicity.

Methods: Data from a clinical study (n = 24) of patients with breast cancer receiving adjuvant intravenous FE(100)C chemotherapy were used to examine relationships between LBM, liver size, and epirubicin clearance. Muscle tissue and liver mass were measured by analysis of computerized tomography cross-sectional images, and an extrapolation of muscle mass to total LBM compartment was employed. Population PK analysis of epirubicin was undertaken to test effects of body composition on epirubicin clearance and area under the curve (AUC).

Results: Estimated LBM was extremely variable in this cohort ranging from 32.9 to 67.3 kg. LBM was associated with neutrophil nadir (r = 0.5, P = 0.023), and mean LBM was lower for patients presenting with toxicity compared to those where toxicity was absent (41.6 vs. 56.2 kg, P = 0.002); 33% of variance in clearance was explained by LBM and aspartate aminotransferase (AST). Liver mass was not related to epirubicin clearance likely due to larger livers presenting with larger fat content, but liver attenuation (degree of fat infiltration) and AST were associated with AUC.

Conclusion: To our knowledge, this is the first study to examine relationships between LBM, liver mass/function and epirubicin PK and toxicity. This exploratory work investigates the notion of organs and tissues having distinctive contributions to the distribution and metabolism of antineoplastic drugs.
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http://dx.doi.org/10.1007/s00280-010-1288-yDOI Listing
January 2011
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