Population Pharmacokinetic Modeling With Enterohepatic Circulation for AZD3241 in Healthy Subjects and Patients With Multiple System Atrophy.

AZD3241 is a potent and selective myeloperoxidase inhibitor potentially for the treatment of a number of neurodegenerative disorders, including multiple system atrophy (MSA). The objectives of this work were to develop a population pharmacokinetic (PopPK) model for AZD3241 and to investigate the correlation between AZD3241 exposure and myeloperoxidase inhibition. The PopPK model was developed using AZD3241 data from one phase 1 study in healthy subjects and one phase 2 study in patients with MSA. A one-compartment model incorporating a gallbladder compartment for enterohepatic circulation, sequential zero-first order absorption, and first-order elimination adequately described the AZD3241 concentration profiles. The apparent clearance and central volume of distribution were 63.1 L/h (interindividual variability: 34.8%) and 121.9 L (interindividual variability: 44.0%), respectively. The enterohepatic circulation model reasonably captured the second peak of AZD3241, and high-fat food increased the absorption rate by 69%. A linear regression model was applied to describe the relationship between AZD3241 exposure and percentage change from baseline in myeloperoxidase-specific activity. The developed PopPK model was consistent with known pharmacokinetic characteristics of AZD3241. This model can be used to estimate AZD3241 exposure in patients with MSA and could be applied to future pharmacokinetic-pharmacodynamic analyses of AZD3241 in clinical development.

A comparison of extrapyramidal symptoms in older outpatients treated with quetiapine or risperidone.

OBJECTIVE: To compare the tolerability of quetiapine with risperidone in older outpatients. RESEARCH DESIGN AND METHODS: Post hoc analysis of a subset of older patients (aged 60-80; n = 92) from a randomized, 4-month, multicenter, open-label trial comparing quetiapine and risperidone in an outpatient setting. Participants had various neuropsychiatric disorders associated with psychosis as defined by criteria from the Diagnostic and Statistical Manual of Mental Disorders (4th edn). MAIN OUTCOME MEASURES: The main outcome measure was an extrapyramidal symptoms (EPS) checklist, used to assess motor symptoms, including parkinsonism, at baseline and after treatment. The Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression scale were used to assess therapeutic efficacy. RESULTS: Substantial EPS (defined as EPS requiring a dosage adjustment or use of medication to reduce EPS) occurred less often with quetiapine (median dosage, 200 mg/day) than with risperidone (median dosage, 3 mg/day); odds ratio, 0.31 (P < 0.03). Quetiapine was also less likely than risperidone to cause akathisia or hypertonia. Both compounds produced comparable reductions in PANSS scores. CONCLUSIONS: Interpretation of findings in this report is limited by the open-label design of the study and the post hoc nature of this analysis. However, the results suggest that quetiapine, when given within the recommended dosage range, has a benign EPS profile, with potentially greater tolerability and comparable efficacy to risperidone in older outpatients with psychotic disorders.

Efficacy of quetiapine and risperidone against depressive symptoms in outpatients with psychosis.

BACKGROUND: The treatment of psychotic symptoms in patients with mood disorders is a complex challenge. Antipsychotic medications in these individuals may be associated with extrapyramidal symptoms (EPS), worsening of depression, and functional impairment. Atypical antipsychotics such as quetiapine and risperidone are associated with a decreased incidence of adverse events such as EPS. The objective of this study was to compare the efficacy and tolerability of quetiapine and risperidone for the treatment of depressive symptoms in outpatients with psychosis. METHOD: In this 4-month, multicenter, open-label trial, patients were randomly assigned in a 3:1 ratio of quetiapine to risperidone, and both drugs were flexibly dosed. Eligible patients had psychoses and demonstrated 1 of several DSM-IV diagnoses, including schizoaffective disorder, bipolar I disorder, major depressive disorder, delusional disorder, Alzheimer's dementia, schizophreniform disorder, vascular dementia, and substance abuse dementia. Patients were classified as mood disordered if they had bipolar disorder, major depressive disorder, or schizoaffective disorder. Efficacy was assessed using the Positive and Negative Syndrome Scale and the Clinical Global Impressions scale. The Hamilton Rating Scale for Depression (HAM-D) was used to assess the level of depressive symptoms. The primary tolerability assessment was presence or absence of substantial EPS, defined as EPS severe enough to require an alteration in treatment. RESULTS: A total of 554 patients were randomly assigned to quetiapine and 175 to risperidone. Mean doses at 16 weeks were 318 mg for quetiapine and 4.4 mg for risperidone. Although both agents produced improvements in mean HAM-D scores, quetiapine produced a greater improvement than risperidone in all patients (p =.0015). Within the mood-diagnosed population, incidences of both substantial EPS (p =.001) and at least moderate EPS (p =.0373) occurred significantly less frequently among patients taking quetiapine. For patients with non-mood diagnoses, incidences of substantial EPS were fewer for patients taking quetiapine than for those taking risperidone (p =.062); however, this was not statistically significant. CONCLUSION: These results suggest that quetiapine may be a useful agent in the management of depressive symptoms in patients with psychosis.