ARI, apart from being described as an antipsychotic drug, is also a mood stabilizer. ARI has become a frequently used drug for treating of TD due to its effectiveness and less adverse effects compared to other dopamine-modulating agents such as haloperidol and risperidone[6, 19, 20]. So far, there was limited data about population pharmacokinetics of ARI in pediatrics. This work successfully explored the relationship between CYP2D6 genetic polymorphisms and pharmacokinetic parameters, including MR, V and CL in children of TD. MRs of Cmax, Cmin and AUC0 − t, CL of ARI were statistically different between different genotypes of rs1135840 (P<0.05). In the study of Zhang’s[14], it revealed that Cmax, Tmax and AUC0–∞ were substantially influenced by CYP2D6 rs1135840. Belmonte et al[15] found that MR was influenced by CYP2D6 phenotypes and CYP3A5*3. As for V of ARI or DARI, just rs5030865 showed statistically difference in V of DARI. The CYP2D6 SNPs that influenced CL of ARI and DARI were: rs1135840, rs5030865, rs1080989, rs16947, rs29001518, rs1080985 respectively. A recent study in Chinese subjects shown that CYP2D6 rs1058164 and rs28371699 influenced the pharmacokinetics of ARI, such as T1/2, and AUC0−∞[14]. Similarly, variants of rs1058164 effected MR of AUC0 − t in this research. This study, together with the findings from Jukic et al’s[21] strongly supported that CYP2D6 genetic testing would be an important and necessary means in the clinical treatment process. Comparisions with previous researches were shown in Table 3.
Table 3
Summary of the latest researches on the correlation between CYP2D6/ABCB1 gene polymorphisms and pharmacokinetics of ARI
Gene | Research | Variants(phenotypes/genotypes) | Associated | Not associated |
CYP2D6 | Zhang et al[14](2021) | rs1135840 | Cmax, Tmax and AUC0–∞ of ARI | T1/2 |
| | rs28371702 | Tmax and AUC0–∞ | Cmax, T1/2 |
| | rs1058164, rs28371699 | Cmax, Tmax and AUC0–∞, T1/2 | —— |
| | EMs (extensive metabolizers) & IMs (intermediated metabolizers) | T1/2, AUC0–∞ | Cmax, T1/2 |
| Belmonte et al[15](2018) | PMs (poor metabolizers) | Cmax, T1/2 | |
ABCB1 | Belmonte et al[15](2018) | G2677T/A (rs2032582) | CL/F of ARI AUC0 − t of DARI | AUC0-t, Cmax, T1/2 of ARI CL/F, Cmax, T1/2of DARI |
| | C1236T (rs1128503) | CL of ARI AUC0-t and Cmax of the DARI | —— |
| | C3435T(rs1045642) | Ratio of DARI/ARI | ARI&DARI AUC0-t, Cmax, T1/2, CL/F |
| Rafaniello et al[24](2018) | 2677TT/3435TT | concentration/dose(C/D) | —— |
PMs, poor metabolizers; IMs, intermediated metabolizers; EMs, extensive metabolizers;CL/F, apparent clearance rate |
ABCB1 protein is involved in processes of drug absorption, distribution, and elimination. ARI and DARI are substrates of P-gp which is encoded by ABCB1 gene[22]. Is was reported that the pharmacokinetic parameters of ARI and DARI were not only influenced by polymorphisms of genes encoding metabolizing enzymes (CYP2D6, CYP3A4, and CYP3A5), but also the drug transporter (ABCB1 protein)[15]. Belmonte et al[15] concluded that ABCB1 C1236T (rs1128503) and G2677T/A (rs2032582) polymorphisms affected CL of ARI, while no correlation was found between CL of ARI or DARI and variants of rs2032582 and rs1045642 in this research. Further research would be probed for ABCB1 rs1128503 variants in tic disorders. Carring ABCB1 C3435T T allele showed greater AUC than C/C homozygotes was proposed in Koller et al’s report[23]. T allele carriers for G2677T/A and C3435T polymorphisms had significantly lower plasma concentration/dose ratio(C/D) for ARI related to patients with other ABCB1 genotypes in Rafaniello et al’s report[24]. In this study, there was significantly difference in V of DARI in rs1045642 T/T and rs1045642 C/T subjects with multiple post hoc comparisons while ABCB1 polymorphisms showed no effect on MRAUC0−t, MRCmin, as well as MRCmax. The greater influence of rs1045642 on V of the DARI than parent drug could be attributed to the higher affinity of metabolite DARI to P-gp[25]. Nonetheless, these results were controversial probably due to difference of sample sizes and ethnicity of participants. Up to now, researches focused on the role of ABCB1 polymorphisms on the pharmacokinetics of ARI have been discordant, consequently further and deeper research is required. Comparisions with previous researches were shown in Table 3.
This research also analyzed the correlation between CYP2D6 and ABCB1 SNPs and therapeutic response which was rare in previous studies. Regarding DRD2/ ANKK1 gene polymorphisms—C957T polymorphism, schizophrenic patients with C/C genotype were associated with poor ARI response for excitement symptoms when compared with T/T patients[26]. Yan P et al concluded that genetic polymorphism of CYP2D6 rs1065852, rs1799732, rs1800497 and their interactions affected the clinical efficacy of aripiprazole in the treatment of schizophrenia[27]. It was also reported that ABCB1 G2677T/A (rs2032582) influenced the clinical response to antipsychotics like risperidone and haloperidol[28]. However, the subjects in those studies were schizophrenia different from TD pediatrics treated with ARI. After treatment with ARI, therapeutic efficacy was significantly different in the homozygosity or heterozygosity of CYP2D6 rs1065852, rs1080989 mutations. As shown above, both rs1065852 and rs1080989 variants influenced MRs of Cmax, Cmin and AUC0 − t. Moreover, ABCB1 gene polymorphism was not associated with therapeutic effects in this study. Due to lack of similar studies and the small sample sizes, researches with larger sample sizes were expected to further elucidate the correlation between CYP2D6 and ABCB1 SNPs and clinical response of ARI in TD patients.
Limitations
1. The sample size of this research is small. 2.YGTSS score is somewhat objective during treatment response observation. 3. It is difficult to make comparison since limited evidence in previous study.
To the best of our knowledge, this was the first exploratory research to investigate the relationships between CYP2D6, ABCB1 SNPs, and pharmacokinetic parameters, as well as clinical response of ARI treatment in pediatric patients with TD. Different from previous studies, ABCB1 genetic polymorphisms were not prominently influenced pharmacokinetic parameters and clinical response in TD patients. CYP2D6 genetic polymorphisms were associated with pharmacokinetic parameters of ARI such as MRs and CL. CYP2D6 rs1065852, rs1080989 were correlated to clinical response to some extent. Therefore, CYPD6 genotype testing should be implemented alongside other characteristics such as sex, liver and renal functions and concomitant medications before clinical therapeutic drug monitoring and treatment. Although significant differences in the pharmacokinetic parameters between the different genotypes could be observed, more thorough researches describing pharmacokinetic interactions and environmental conditions, among other variables, are needed to fully comprehend these pharmacogenetic interactions. Despite of the limitations of our study, CYP2D6 genetic testing is fully needed to comprehend these pharmacokinetic, pharmacogenetic, pharmacodynamic interactions during treatment of ARI in clinics.