卡利拉嗪及其主要代谢物的群体药代动力学。
Population Pharmacokinetics of Cariprazine and its Major Metabolites.
机构信息
Allergan, 5 Giralda Farms, Madison, NJ, USA.
Cognigen Corporation, Buffalo, NY, USA.
出版信息
Eur J Drug Metab Pharmacokinet. 2021 Jan;46(1):53-69. doi: 10.1007/s13318-020-00650-4.
BACKGROUND AND OBJECTIVES
Cariprazine, a dopamine D-preferring D/D receptor partial agonist, is approved for the treatment of adults with schizophrenia (1.5-6 mg/day) and manic/mixed (3-6 mg/day) episodes associated with bipolar I disorder. This population pharmacokinetic analysis describes the concentration-time profiles of cariprazine and its two major active metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR). Additionally, the potential impact of patient characteristics, creatinine clearance, and cytochrome P450 2D6 (CYP2D6) metabolizer status on the pharmacokinetics of cariprazine and its metabolites was evaluated.
METHODS
Data from three phase 1 and ten phase 2/3 studies in adult patients with schizophrenia or bipolar mania were included. Nonlinear mixed-effects pharmacokinetic modeling was performed using the NONMEM software package. Compartmental modeling was performed sequentially with the cariprazine elimination rate used as the DCAR formation rate and likewise the elimination rate of DCAR used with a delay as the DDCAR formation rate.
RESULTS
Cariprazine pharmacokinetics were described by a three-compartment model with zero-order input of the dose to a depot compartment followed by first-order absorption and first-order elimination. DCAR and DDCAR pharmacokinetics were described by two-compartment models with linear elimination. Statistically significant predictors of pharmacokinetic parameters included weight, sex, and race, though differences in exposures were not large enough to require an adjustment in dose. Creatinine clearance was not a statistically significant predictor of drug clearance, and a post hoc analysis found that CYP2D6 metabolizer status was not associated with changes in exposure levels for cariprazine, DCAR, or DDCAR. The median time to 90% of steady state was approximately 1 week for cariprazine and DCAR and 3 weeks for DDCAR.
CONCLUSIONS
Population pharmacokinetic modeling provided a quantitative description of the concentration-time profile of cariprazine and its metabolites.
背景和目的
卡利拉嗪是一种多巴胺 D 受体优先激动剂/部分激动剂，适用于治疗成人精神分裂症（1.5-6mg/天）和双相 I 障碍相关的躁狂/混合发作（3-6mg/天）。这项群体药代动力学分析描述了卡利拉嗪及其两种主要活性代谢物去甲卡利拉嗪（DCAR）和双去甲卡利拉嗪（DDCAR）的浓度-时间曲线。此外，还评估了患者特征、肌酐清除率和细胞色素 P450 2D6（CYP2D6）代谢物状态对卡利拉嗪及其代谢物药代动力学的潜在影响。
方法
纳入了三项成人精神分裂症或双相躁狂症的 I 期和 10 项 II/III 期研究的数据。使用 NONMEM 软件包进行非线性混合效应药代动力学建模。依次进行房室模型建模，卡利拉嗪的消除率用作 DCAR 形成率，同样地，DCAR 的消除率延迟用作 DDCAR 形成率。
结果
卡利拉嗪药代动力学特征描述为三房室模型，零级输入剂量至储存室，随后为一级吸收和一级消除。DCAR 和 DDCAR 药代动力学特征描述为二房室模型，具有线性消除。药代动力学参数的统计学显著预测因子包括体重、性别和种族，尽管暴露差异不大，无需调整剂量。肌酐清除率不是药物清除率的统计学显著预测因子，事后分析发现 CYP2D6 代谢物状态与卡利拉嗪、DCAR 或 DDCAR 的暴露水平变化无关。达到 90%稳态的中位时间约为卡利拉嗪和 DCAR 的 1 周，DDCAR 的 3 周。
结论
群体药代动力学模型提供了卡利拉嗪及其代谢物浓度-时间曲线的定量描述。
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