Cumming School of Medicine, University of Calgary, Calgary, AB.
College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB.
Pharmacogenet Genomics. 2024 Jul 1;34(5):149-153. doi: 10.1097/FPC.0000000000000529. Epub 2024 Mar 20.
Amphetamine-based medications are recommended as a first-line pharmacotherapy for the treatment of attention-deficit/hyperactivity disorder in children and adolescents. However, the efficacy and tolerability of these medications vary across individuals, which could be related to interindividual differences in amphetamine metabolism. This study examined if genotype-predicted phenotypes of the cytochrome P450 isozyme CYP2D6 were associated with self-reported side effects and symptom improvement in youth treated with amphetamines.
Two hundred fourteen participants aged 6-24 who had a history of past or current amphetamine treatment were enrolled from Western Canada. Amphetamine dose and duration information was collected from the participants along with questions regarding adherence, concomitant medications, symptom improvement and side effects. DNA was extracted from saliva samples and genotyped for CYP2D6 . Binomial logistic regression models were used to determine the effect of CYP2D6 metabolizer phenotype with and without correction for phenoconversion on self-reported symptom improvement and side effects.
Genotype-predicted CYP2D6 poor metabolizers had significantly higher odds of reporting symptom improvement when compared to intermediate metabolizers (OR = 3.67, 95% CI = 1.15-11.7, P = 0.029) after correction for phenoconversion and adjusting for sex, age, dose, duration, and adherence. There was no association between CYP2D6 metabolizer phenotype and self-reported side effects.
Our findings indicate that phenoconverted and genotype-predicted CYP2D6 poor metabolizer phenotype is significantly associated with higher odds of symptom improvement in children and adolescents treated with amphetamine. If replicated, these results could inform the development of future dosing guidelines for amphetamine treatment in children and adolescents.
安非他命类药物被推荐为治疗儿童和青少年注意缺陷/多动障碍的一线药物。然而，这些药物在个体间的疗效和耐受性存在差异，这可能与安非他命代谢的个体间差异有关。本研究考察了细胞色素 P450 同工酶 CYP2D6 的基因型预测表型是否与接受安非他命治疗的青少年的自我报告副作用和症状改善相关。
从加拿大西部招募了 214 名年龄在 6-24 岁之间、有过去或目前安非他命治疗史的参与者。参与者提供了安非他命剂量和持续时间的信息，以及关于依从性、伴随药物、症状改善和副作用的问题。从唾液样本中提取 DNA 并进行 CYP2D6 基因分型。使用二项逻辑回归模型确定 CYP2D6 代谢表型的基因型预测与不校正表型转化对自我报告症状改善和副作用的影响。
校正表型转化并调整性别、年龄、剂量、持续时间和依从性后，基因型预测的 CYP2D6 弱代谢者报告症状改善的几率明显高于中间代谢者（OR=3.67，95%CI=1.15-11.7，P=0.029）。CYP2D6 代谢表型与自我报告的副作用之间没有关联。
我们的研究结果表明，表型转化和基因型预测的 CYP2D6 弱代谢表型与接受安非他命治疗的儿童和青少年症状改善的几率增加显著相关。如果得到证实，这些结果可以为儿童和青少年安非他命治疗的未来剂量指南的制定提供信息。
