Alarcan Hugo, Cannet Pauline, Camus Vincent, Fond Guillaume, Zendjidjian Xavier, Guilhaumou Romain, Quaranta Sylvie
CHRU de Tours, 2 boulevard Tonnellé, Tours, France.
UMR 1253 iBrain, Université de Tours, Inserm, 10 boulevard Tonnellé, Tours, France.
Br J Clin Pharmacol. 2023 May;89(5):1665-1671. doi: 10.1111/bcp.15636. Epub 2022 Dec 29.
Cytochrome P450 1A2 (CYP1A2) is involved in the metabolism of antipsychotic drugs such as clozapine and olanzapine. Personalization of these treatments requires an accurate estimation of CYP1A2 activity. In this study, we aimed (1) to evaluate the correlation between activity score (AS), covariate-corrected activity score (CCS) and the phenotype of CYP1A2 using a caffeine test probe and (2) to investigate their relationship with dose-adjusted clozapine concentrations in a subgroup of the cohort.
A multicentric, retrospective and observational study was carried out in the French university hospitals of Marseille and Tours. CYP1A2 activity was calculated by the paraxanthine/caffeine (17X/137X) ratio determined 4 h after an oral intake of 100 mg caffeine. AS was calculated according to the CYP1A21F alleles. CCS was calculated according to the CYP1A21F alleles, smoking status and the presence of concomitant inhibitors.
As expected, among the 89 patients included, the 17X/137X ratio was significantly higher in patients who smoked. We found a significant but modest correlation between the 17X/137X ratio and CCS (R = 0.3, P = 1.74 × 10 ) but none between the 17X/137X ratio and AS (R = -0.007, P = 0.52). AS was not correlated with dose-adjusted clozapine levels, contrary to CCS (R = 0.19, P = 0.016) and especially the 17X/137X ratio (R = 0.42, P = 1.7 × 10 ).
Correlation with clozapine concentrations showed the advantage of the 17X/137X ratio over the CCS in clozapine dose optimization. CYP1A2 activity, especially when determined by the caffeine probe, may be used to personalize clozapine dosing for patients experiencing treatment failure.
细胞色素P450 1A2（CYP1A2）参与氯氮平、奥氮平等抗精神病药物的代谢。这些治疗的个体化需要准确评估CYP1A2活性。在本研究中，我们旨在：（1）使用咖啡因测试探针评估活性评分（AS）、协变量校正活性评分（CCS）与CYP1A2表型之间的相关性；（2）在队列的一个亚组中研究它们与剂量调整后的氯氮平浓度之间的关系。
在法国马赛和图尔的大学医院进行了一项多中心、回顾性观察研究。通过口服100毫克咖啡因4小时后测定的副黄嘌呤/咖啡因（17X/137X）比值计算CYP1A2活性。AS根据CYP1A21F等位基因计算。CCS根据CYP1A21F等位基因、吸烟状态和同时存在的抑制剂计算。
正如预期的那样，在纳入的89名患者中，吸烟者的17X/137X比值显著更高。我们发现17X/137X比值与CCS之间存在显著但适度的相关性（R = 0.3，P = 1.74×10），但17X/137X比值与AS之间无相关性（R = -0.007，P = 0.52）。与CCS相反，AS与剂量调整后的氯氮平水平无相关性（R = 0.19，P = 0.016），尤其是与17X/137X比值无相关性（R = 0.42，P = 1.7×10）。
与氯氮平浓度的相关性表明，在氯氮平剂量优化方面，17X/137X比值优于CCS。CYP1A2活性，尤其是通过咖啡因探针测定时，可用于为治疗失败的患者个体化调整氯氮平剂量。
