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P.3.c.067 Effect of meal size and fat content on oral ziprasidone absorption
P.3.c Psychotic disorders and antipsychotics – Antipsychotics (clinical) all cognitive measures. Significant improvements were noted in 4 of the 6 domains evaluated, with improvements of many domains occurring at time of first re-assessment (week 12). These improved domains (baseline to endpoint) included attention [(P < 0.05)], processing speed [(P < 0.001)], working memory [P < 0.05] executive function [(P < 0.05)]. Differences in symptomatology, global functioning and attitudes toward medication were also found. Finally, the improvement in attitudes toward medication showed a signitficant correlation with improvements in psychomotor speed (P < 0.001) and working memory (P < 0.05). Discussion: Improvements in cognitive functioning were observed in stable patients switched to maintenance treatment with long acting risperidone over the course of one year. More positive attitude toward medication was related to neurocognitive improvement after switching. Further analyses will look to explore the relationship between cognitive functioning and attitudes toward medication and putative relationship with a more favorable subjective experience of long-acting injectable in schizophrenics. References [1] Harvey PD, Patterson TL, Patterson LS, Potter LS, Zhong K, Brecher M, 2006, Improvement in social competence with shortterm atypical antipsychotic treatment: a randomized, double-blind comparison of quetiapine versus risperidone for social competence, social cognition, and neuropsychological functioning. Am J Psychiatry 136(11), 1918−25. [2] Fleischnacker WW, Rabinowitz J, Kemmler G, Eerdekens M, Mehnert A, 2005, Perceived functioning, well-being and psychiatric symptomps in patients with satble schizophrenia treated with long-acting risperidone for 1 year. Br J Psychiatry 187, 131–136. [3] Harrison TS, Goa KL, 2004, Long-acting risperidone: a review of its use in schizophrenia. CNS Drugs 18(2), 113−32.
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40 mg, +87%; 80 mg, +101%). Increases in AUC and peak plasma concentration (Cmax) with dose were less than proportional to dose in the fasting state but dose proportional in the fed state. Lack of dose proportionality was attributed to dose-limiting absorption at the higher doses in the fasting condition. In the second study, AUC increased 104% for the high-fat meal and 79% for the lower fat meal compared with the fasting state. There was no significant difference observed on decreasing the fat content from 60% to 30% in test meals (using the 40-mg dose). Less variability of AUC and Cmax values was observed in the fed state, suggesting more consistent absorption of ziprasidone when taken with food, which is attributed to enhanced ziprasidone solubilization (Lebel et al., 1993). In the third study, meals with varied fat and calorie compositions increased ziprasidone absorption above the fasting condition. Substantial increases in AUC and Cmax were observed following both 500 kcal and 1000 kcal meals, with only a modest increase following a 250 kcal meal. The fat composition of the meal did not appear to impact absorption. Collectively, these results show that administration of ziprasidone with food is crucial to ensure linear pharmacokinetics and optimal absorption and for achieving consistent systemic exposure to ziprasidone. Moreover, food also reduced pharmacokinetic variability in drug absorption, indicating that coadministration of ziprasidone with food will also provide greater consistency in daily systemic exposure to ziprasidone and, thereby, symptom control and tolerability. A minimum meal size of 500 kcal is needed for optimal absorption. References
P.3.c.067 Effect of meal size and fat content on oral ziprasidone absorption
[1] Geodon® (ziprasidone) prescribing information Physician’s Desk Reference 60th edn, 2006. Montvale, NJ: Thompson PDR, pp. 2514–2520. [2] Lebel M, Proulx MJ, Allard S, et al, 1993, Influence of a high fat breakfast on the absorption and the pharmacodynamics of CP-88,059, a new antipsychotic. Clin Invest Med 16, B18.
S. Preskorn1 ° , I. Lombardo2 , J. Alderman2 , P. Glue2 , M. Versavel3 , K. Gandelman2 . 1 CRI Research, Psychiatry, Wichita, USA; 2 Pfizer Inc, Medical, New York, USA; 3 Pfizer Inc, Global R&D, Groton, USA
P.3.c.068 Systematic screening for CYP2D6 polymorphisms in the patients with neuroleptic malignant syndrome
Oral ziprasidone has been shown to have increased bioavailability in the presence of food, and therefore administration with food is recommended (Geodon Prescribing Information, 2006). This report describes 3 pharmacokinetic studies conducted to quantify the impact of different components of food on ziprasidone absorption. The first study, an open-label, non-randomized, 6-way crossover trial, investigated ziprasidone absorption in 8 healthy male subjects. The subjects received 20 mg, 40 mg and 80 mg single doses of oral ziprasidone after an 8-hour fast or immediately following consumption of an FDA standard meal (60% fat content). In the second study, an open-label, randomized, 3-way crossover study, the impact of dietary fat content on ziprasidone absorption was investigated in 14 healthy subjects. The subjects received ziprasidone 40 mg using a steady-state regimen under 3 conditions: fasting, with an FDA standard meal (60% fat content), and with a lower fat meal (30% fat content). The third study was an open-label, randomized, 6-way crossover study of the effects of total calories (fasting, 250 kcal, 500 kcal, and 1000 kcal) and fat content (15% or 50% of calories) on steady-state serum concentrations of ziprasidone following an 80-mg oral dose in male or female patients with schizophrenia. In the first study, area under the curve (AUC) was greater in fed than fasting states at each dose tested (20 mg, +48%;
D. Kato1 ° , C. Kawanishi1 , I. Kishida1 , T. Furuno1 , K. Suzuki1 , H. Onishi2 , Y. Hirayasu1 . 1 Yokohama City University, Department of Psychiatry, Yokohama, Japan; 2 Saitama Medical University, Department of Psycho-oncology, Saitama, Japan Purpose: Neuroleptic malignant syndrome (NMS) is a potentially lethal adverse reaction to antipsychotic administration. In addition to neuroleptic drugs, NMS also can be caused by antidepressants, lithium carbonate, and other psychotropic agents. NMS is characterized by hyperthermia, extrapyramidal signs, altered consciousness, fluctuating blood pressure, incontinence, and dyspnea as well as other features. The frequency of its occurrence with conventional antipsychotic agents has been reported to vary from 0.02−2.44% while atypical antipsychotic agents can also cause NMS, even severe enough to cause mortality in some instances. Minimizing risk factors and increased awareness of NMS can decrease its incidence, and detection of prodromal symptoms can decrease morbidity from NMS, but prediction and prevention are still difficult because there are individual differences in response to drugs. CYP2D6, an isozyme among the CYP monooxygenases, is responsible for the hepatic metabolism of various psychotropic agents. Recent findings in pharmacogenetics indicate that the polymorphisms of CYP2D6 gene are associated with the interindividual differences in drug responses. NMS is considered
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40 mg, +87%; 80 mg, +101%). Increases in AUC and peak plasma concentration (Cmax) with dose were less than proportional to dose in the fasting state but dose proportional in the fed state. Lack of dose proportionality was attributed to dose-limiting absorption at the higher doses in the fasting condition. In the second study, AUC increased 104% for the high-fat meal and 79% for the lower fat meal compared with the fasting state. There was no significant difference observed on decreasing the fat content from 60% to 30% in test meals (using the 40-mg dose). Less variability of AUC and Cmax values was observed in the fed state, suggesting more consistent absorption of ziprasidone when taken with food, which is attributed to enhanced ziprasidone solubilization (Lebel et al., 1993). In the third study, meals with varied fat and calorie compositions increased ziprasidone absorption above the fasting condition. Substantial increases in AUC and Cmax were observed following both 500 kcal and 1000 kcal meals, with only a modest increase following a 250 kcal meal. The fat composition of the meal did not appear to impact absorption. Collectively, these results show that administration of ziprasidone with food is crucial to ensure linear pharmacokinetics and optimal absorption and for achieving consistent systemic exposure to ziprasidone. Moreover, food also reduced pharmacokinetic variability in drug absorption, indicating that coadministration of ziprasidone with food will also provide greater consistency in daily systemic exposure to ziprasidone and, thereby, symptom control and tolerability. A minimum meal size of 500 kcal is needed for optimal absorption. References
P.3.c.067 Effect of meal size and fat content on oral ziprasidone absorption
[1] Geodon® (ziprasidone) prescribing information Physician’s Desk Reference 60th edn, 2006. Montvale, NJ: Thompson PDR, pp. 2514–2520. [2] Lebel M, Proulx MJ, Allard S, et al, 1993, Influence of a high fat breakfast on the absorption and the pharmacodynamics of CP-88,059, a new antipsychotic. Clin Invest Med 16, B18.
S. Preskorn1 ° , I. Lombardo2 , J. Alderman2 , P. Glue2 , M. Versavel3 , K. Gandelman2 . 1 CRI Research, Psychiatry, Wichita, USA; 2 Pfizer Inc, Medical, New York, USA; 3 Pfizer Inc, Global R&D, Groton, USA
P.3.c.068 Systematic screening for CYP2D6 polymorphisms in the patients with neuroleptic malignant syndrome
Oral ziprasidone has been shown to have increased bioavailability in the presence of food, and therefore administration with food is recommended (Geodon Prescribing Information, 2006). This report describes 3 pharmacokinetic studies conducted to quantify the impact of different components of food on ziprasidone absorption. The first study, an open-label, non-randomized, 6-way crossover trial, investigated ziprasidone absorption in 8 healthy male subjects. The subjects received 20 mg, 40 mg and 80 mg single doses of oral ziprasidone after an 8-hour fast or immediately following consumption of an FDA standard meal (60% fat content). In the second study, an open-label, randomized, 3-way crossover study, the impact of dietary fat content on ziprasidone absorption was investigated in 14 healthy subjects. The subjects received ziprasidone 40 mg using a steady-state regimen under 3 conditions: fasting, with an FDA standard meal (60% fat content), and with a lower fat meal (30% fat content). The third study was an open-label, randomized, 6-way crossover study of the effects of total calories (fasting, 250 kcal, 500 kcal, and 1000 kcal) and fat content (15% or 50% of calories) on steady-state serum concentrations of ziprasidone following an 80-mg oral dose in male or female patients with schizophrenia. In the first study, area under the curve (AUC) was greater in fed than fasting states at each dose tested (20 mg, +48%;
D. Kato1 ° , C. Kawanishi1 , I. Kishida1 , T. Furuno1 , K. Suzuki1 , H. Onishi2 , Y. Hirayasu1 . 1 Yokohama City University, Department of Psychiatry, Yokohama, Japan; 2 Saitama Medical University, Department of Psycho-oncology, Saitama, Japan Purpose: Neuroleptic malignant syndrome (NMS) is a potentially lethal adverse reaction to antipsychotic administration. In addition to neuroleptic drugs, NMS also can be caused by antidepressants, lithium carbonate, and other psychotropic agents. NMS is characterized by hyperthermia, extrapyramidal signs, altered consciousness, fluctuating blood pressure, incontinence, and dyspnea as well as other features. The frequency of its occurrence with conventional antipsychotic agents has been reported to vary from 0.02−2.44% while atypical antipsychotic agents can also cause NMS, even severe enough to cause mortality in some instances. Minimizing risk factors and increased awareness of NMS can decrease its incidence, and detection of prodromal symptoms can decrease morbidity from NMS, but prediction and prevention are still difficult because there are individual differences in response to drugs. CYP2D6, an isozyme among the CYP monooxygenases, is responsible for the hepatic metabolism of various psychotropic agents. Recent findings in pharmacogenetics indicate that the polymorphisms of CYP2D6 gene are associated with the interindividual differences in drug responses. NMS is considered