Strategies for Predicting Plasma Concentrations of Antipsychotics

• Main Authors: Hsien-Yuan Lane, 藍先元
• Other Authors: Muh-Hwan Su
• Format: Others
• Language: en_US
• Published: 2000
• Online Access: http://ndltd.ncl.edu.tw/handle/48990563409118174293

博士 === 國防醫學院 === 生命科學研究所 === 88 === The efficacy and side effects of antipsychotic agents are usually related with plasma drug levels in schizophrenic patients. However, the metabolism and blood levels of antipsychotics vary markedly among the patients. This thesis aimed to develop strategies for predicting plasma levels of commonly used antipsychotics via 3 dimensions of data: (1) phenotyping activities of drug-metabolizing enzymes, (2) patients’demographic characteristics, and (3) adverse drug reactions. For exploring the first dimension, we attempted to correlate plasma levels of haloperidol (a commonly used traditional antipsychotic drug) and reduced haloperidol with metabolic ratios of dextromethorphan (a probe for phenotyping cytochrome P450 2D6) in schizophrenic patients. Actually, no previous studies have investigated the relationships between plasma concentrations of antipsychotics and phenotyping activities of drug-metabolizing enzymes. For the second dimension, we evaluated how patient-related variables would affect plasma levels of clozapine (an atypical antipsychotic agent for treatment-resistant patients) using rigorous statistics. Since the frequency distribution of plasma clozapine levels is skewed to the right, the statistical methods (such as regression analyses) used in earlier studies are actually inappropriate. For the third dimension, we hypothesized that, even under a medium dose of risperidone (another atypical agent), the appearance of side effects might reflect excessively high blood levels and might be associated with poor clinical response. Therefore, reducing doses to abate adverse events could decrease the blood drug levels to the therapeutic range, perhaps thus yielding better clinical efficacy. For the schizophrenic patients who were able to tolerate a 2-week, drug-free period (N = 18), their urinary dextromethorphan/dextrorphan metabolic ratios were measured after the washout. They then received 2-week, 10-mg/day haloperidol for determination of steady-state plasma levels of haloperidol and its active metabolite, reduced haloperidol. Plasma concentrations of these compounds were assayed by high performance liquid chromatography (HPLC). The relationships between plasma haloperidol levels, reduced haloperidol levels, and reduced haloperidol/haloperidol ratios vs. dextromethorphan phenotyping activity were analyzed. For the treatment-resistant patients (N = 162), who were usually unsuitable for long-duration washout, clozapine therapy was instituted. Steady-state plasma levels of clozapine and its main metabolites (norclozapine and clozapine-N-oxide) were also assayed by HPLC. Multiple linear regression was applied to evaluate the effects of gender, age, body weight, and doses on the plasma levels. To overcome the skewness problem, the logarithm of the plasma drug level was adopted for the statistics. Finally, in the risperidone study, 31 newly admitted schizophrenic patients with acute exacerbation entered a prospective, 6-week open trial. Risperidone doses were titrated to 6 mg/day (if tolerable) over 3 days, but were lowered thereafter if side effects appeared. Efficacy and side-effect assessments were conducted on day 0, day 4, day 14, day 28, and day 42. Endpoint steady-state plasma levels of risperidone and 9-hydroxyrisperidone were analyzed by HPLC too. In the enzyme-phenotyping study, dextromethorphan metabolic ratios in urine were significantly correlated with haloperidol levels, reduced haloperidol levels, and reduced haloperidol to haloperidol ratios in plasma. Ten patients who experienced extrapyramidal side effects had higher reduced haloperidol concentrations and reduced haloperidol/haloperidol ratios than the other patients. These results suggested that the higher the dextromethorphan/dextrorphan ratio (the lower the phenotyping activities of drug-metabolizing enzymes), the higher haloperidol plasma concentration (and much higher reduced haloperidol concentration) will be. In the study regarding patients’demographic characteristics, aging, female gender, and higher clozapine doses, all significantly raised plasma levels of clozapine (and perhaps the metabolites), after adjusting the effects of other variables. Body weight did not influence the levels of these compounds. In the study concerning risperidone’s side effects, 30 patients completed the trial. Of them, 17 tolerated the 6-mg target dose well, while the other 13 received lower final doses (mean 3.6 +/- .9 mg) for curtailing side effects. At endpoint, 92.3% of the 13 low-dose individuals responded to treatment, compared with 52.9% of the 17 high-dose subjects (p < .05). These results suggested that side effects might be caused by excessively high plasma concentrations of antipsychotic agents. Of note, endpoint plasma levels of the active moiety (risperidone plus 9-hydroxyrisperidone) were similar between the low- and the high-dose groups. Phenotypic activities of drug-metabolizing enzymes, patients’ demographic characteristics, and adverse drug reactions all have the potential to assist clinicians in predicting blood drug concentrations. These factors should be taken into account for efficient and safe therapy with the lowest possible dose. Contents………………………………………………………………………………. I List of Tables…………………………………………………………………………II List of Figures……………………………………………………………………….III List of Abbreviations………………………………………………………………IV List of Appendixes……………………………………………………..……………..V Chinese Abstract……………………………………………………………………..VI English Abstract………………………………………………………………….VIII Introduction……………………………………………………………………………1 Methods…………………………………………………………………………….11 Results………………………………………………………………………………..22 Discussion……………………………………………………………………………38 Conclusions…………..………………………………………………………………50 References……………………………………………………………………………52 List of Tables Table 1 Patient Demographics and Plasma Concentrations of Haloperidol and Reduced Haloperidol.………………………………………………….....27 Table 2 Multivariate Regression Analysis of Dose, Sex, Age, and Body Weight on the Natural Logarithm of the Plasma Clozapine level…………….….28 Table 3 Multivariate Regression Analysis of Dose, Sex, Age, and Body Weight on the Natural Logarithm of the Plasma Norclozapine Level……………29 Table 4 Multivariate Regression Analysis of Dose, Sex, Age, and Body Weight on the Natural Logarithm of the Plasma Clozapine-N-Oxide Level……..30 Table 5 Characteristics of Schizophrenic Patients Treated with Low or High Doses of Risperidone…..………………………………….……………...31 Table 6 Change in the Positive and Negative Syndrome Scale of Schizophrenic Patients Treated with Low or High Doses of Risperidone.……………....32 Table 7 Change in the Extrapyramidal Symptom Rating Scale of Schizophrenic Patients Treated with Low or High Doses of Risperidone….……………33 Table 8 Adverse Events (Evaluated by the UKU scale) Reported by 10% or More of Schizophrenic Patients Treated with Low or High Doses of Risperidone at Endpoint…………………………….....….………...……34 Table 9 Plasma Drug Indices in 30 Haloperidol-Treated Patients with Extrapyramidal Symptoms and 18 Without Extrapyramidal Symptoms...47 Table 10 Percentages of Poor Metabolizers of Dextromethorphan in Various Populations………..…...…………………………………………………48 List of Figures Fig. 1 Frequency Distribution of Plasma Haloperidol Levels (ng/mL) in 88 Schizophrenic Patients Treated With Haloperidol 20 mg/day……………...9 Fig. 2 Frequency Distribution of Reduced Haloperidol/Haloperidol Ratios in Four Dosage Groups of Schizophrenic Patients…………………………..10 Fig. 3 The Distribution of the Steady-State Plasma Levels of Clozapine in 162 Schizophrenic Patients ……………………………………………………35 Fig. 4 The Distribution of the Natural Logarithms of the values of the Steady-State Plasma Clozapine Levels in 162 Schizophrenic Patients…...36 Fig. 5 The Normal Quantile-Quantile Plot of the Natural Logarithms of the values of the Steady-State Plasma Clozapine Levels in 162 Schizophrenic Patients………...………………………………………......37 Fig. 6 Frequency Distribution of Logarithmic Dextromethorphan Metabolic Ratio (log Dextromethorphan/Dextrorphan) in 175 Chinese Subjects……49 List of Abbreviations BPRS Brief Psychiatric Rating Scale CGI Clinical Global Impression DSM Diagnostic and Statistical Manual EM Extensive Metabolizer EPS Extrapyramidal Side Effects ESRS Extrapyramidal Symptom Rating Scale GAF Global Assessment of Functioning HPLC High Performance Liquid Chromatography ICC Intraclass Correlation Coefficient NOSIE Nurses’ Observation Scale for Inpatients Evaluation PANSS Positive and Negative Syndrome Scale PM Poor Metabolizer Q-Q plot Quantile-Quantile plot UKU Udvalg for Kliniske Underso-gelser (Side Effect Rating Scale) List of Appendixes Appendix 1 博士學位候選人資格考試 Appendix 2 博士論文研究進度報告 Appendix 3 Lane HY, Chiu WC, Chou JCY, Wu ST, Su MH, and Chang WH. Risperidone in acutely exacerbated schizophrenia: dosing strategies and plasma levels. J. Clin. Psychiatry 61: 209-214, 2000. Appendix 4 Lane HY, Chang YC, Chang WH, Lin SK, Tseng YT, and Jann MW. Effects of gender and age on plasma levels of clozapine and its metabolites: analyzed by critical statistics. J. Clin. Psychiatry 60: 36-40, 1999. Appendix 5 Lane HY, Hu OYP, Jann MW, Deng HC, Lin HN, and Chang WH. Dextromethorphan phenotyping and haloperidol disposition in schizophrenic patients. Psychiatry Res. 69: 105-111, 1997. Appendix 6 Lane HY, Chang WH, Chang YC, Hu OPY, Lin HN, Jann MW, and Hu WH. Dose-dependent reduced haloperidol/haloperidol ratios: influence of patient-related variables. Psychiatry Res. 72: 127-132, 1997. Appendix 7 Lane HY, Lin HN, Hu OYP, Chen CC, Jann MW, and Chang WH. Blood levels of reduced haloperidol versus clinical efficacy and extrapyramidal side effects off haloperidol. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 21: 299-311, 1997. Appendix 8 Lane HY, Deng HC, Huang SM, Hu WH, Chang WH, and Hu OYP. Low frequency of dextromethorphan O-demethylation deficiency in a Chinese population. Clin. Pharmacol. Ther. 60: 696-698, 1996.