Pharmacy Department, Vilardebó Hospital, Avenida Millán 2515, 11800 Montevideo, Uruguay.
Pharmaceutical Sciences Department, Faculty of Chemistry, Universidad de la República, Avenida General Flores 2124, P. O. Box 1157, 11800 Montevideo, Uruguay.
Biomed Res Int. 2019 Mar 6;2019:3163502. doi: 10.1155/2019/3163502. eCollection 2019.
Clozapine (CZP) is an atypical antipsychotic agent commonly used in the treatment of schizophrenia. It is metabolized primarily by CYP1A2 enzyme, yielding a pharmacologically active metabolite, norclozapine (NCZP). Significant intra- and interindividual pharmacokinetic (PK) variability for CZP and NCZP has been observed in routine therapeutic drug monitoring. So the goal of this study was to evaluate the magnitude and variability of concentration exposure to CZP and its active metabolite NCZP on pharmacokinetic parameters in Uruguayan patients with schizophrenia with a focus on covariates such as cigarette smoking, age, sex, caffeine consumption, brands available of CZP, and comedication using population PK (PPK) modeling methodologies. Patients with a diagnosis of schizophrenia treated with brand-name CZP (Leponex®) for more than a year were included in the study. Then these patients were switched to the similar brand of CZP (Luverina®). Morning predose blood samples for determination of CZP and NCZP using a HPLC system equipped with a UV detector were withdrawn on both occasions at steady state and under the same comedication. Ninety-eight patients, 22 women and 76 men, took part in the study. Mean ± standard deviation for CZP and NCZP concentration was 421 ± 262 ng/mL and 275 ± 180 ng/mL, respectively. After covariate evaluation, only smoking status remained significant in CZP apparent clearance, inducing a mean increment of 32% but with no clinical impact. The results obtained with the two brands of CZP should ensure comparable efficacy and tolerability with the clinical use of either product. Smoking was significantly associated with a lower exposure to CZP due to higher clearance. The results obtained with the two brands commercialized in our country hint a bioequivalence scenario in the clinical setting.
氯氮平（CZP）是一种常用于治疗精神分裂症的非典型抗精神病药物。它主要通过 CYP1A2 酶代谢，生成具有药理活性的代谢物去甲氯氮平（NCZP）。在常规治疗药物监测中，已经观察到 CZP 和 NCZP 的个体内和个体间药代动力学（PK）变异性很大。因此，本研究的目的是评估在乌拉圭精神分裂症患者中，CZP 和其活性代谢物 NCZP 的浓度暴露对 PK 参数的影响程度和变异性，并重点关注吸烟、年龄、性别、咖啡因摄入、可用 CZP 品牌和合并用药等协变量。使用群体 PK（PPK）建模方法。本研究纳入了使用品牌名氯氮平（Leponex®）治疗超过一年的精神分裂症患者。然后，这些患者被转换为类似的氯氮平品牌（Luverina®）。在稳态和相同合并用药下，从这两个时间点采集早晨的 CZP 和 NCZP 血样，使用配备 UV 检测器的 HPLC 系统进行测定。共有 98 名患者（22 名女性和 76 名男性）参与了这项研究。CZP 和 NCZP 浓度的平均值±标准差分别为 421±262ng/mL 和 275±180ng/mL。在协变量评估后，只有吸烟状态仍然与 CZP 的表观清除率显著相关，导致平均增加 32%，但无临床影响。这两种 CZP 品牌的结果应该可以确保在临床使用中，任何一种产品都具有可比较的疗效和耐受性。吸烟与 CZP 暴露降低显著相关，这是由于清除率升高所致。在我们国家上市的两种品牌的结果提示在临床环境中存在生物等效性的情况。
