Association between aripiprazole pharmacokinetics and CYP2D6 phenotypes: A systematic review and meta-analysis

Abstract

What is known and objective: The FDA has provided recommendations for aripiprazole use in CYP2D6 poor metabolizers (PMs); however, PMs make up <1% of the Asian population and no recommendation has been provided for intermediate metabolizers (IMs), who comprise a considerable proportion of the Asian population (64%-70% occurrence of CYP2D6*10). This study aimed to investigate the characteristics of aripiprazole metabolism in IMs and other phenotypes by conducting the first meta-analysis of the association among CYP2D6 phenotypes and aripiprazole pharmacokinetics (PK). Methods: We searched four electronic databases for studies published through February 2018, investigating the association between aripiprazole and CYP2D6 gene polymorphisms. Gene polymorphism information was extracted, and CYP2D6 phenotypes were determined according to a unified classification standard. The associations between three aripiprazole PK-related outcomes and CYP2D6 phenotype were analysed. Meta-analyses were used to compare ultra-rapid metabolizers (UMs) vs extensive metabolizers (EMs), EMs vs IMs and IMs vs poor metabolizers (PMs) for each outcome. The aripiprazole serum concentration funnel plot and the Egger's and Begg's tests were used to assess publication bias. Results and discussion: Altogether, 10 studies were included in this analysis (n = 649). Aripiprazole serum concentration differed significantly between EMs and IMs (EM vs IM pooled SMD: −0.383; 95% CI: −0.735 to −0.031, P = 0.03 < 0.05), but not between IMs and PMs (IM vs PM pooled SMD: −0.425; 95% CI: −0.933 to 0.082, P = 0.10 > 0.05). However, aripiprazole plus dehydroaripiprazole serum level did not significantly differ among EMs, IMs and PMs (EM vs IM pooled SMD: −0.285; 95% CI: −0.724 to 0.154, P = 0.20 > 0.05; IM vs PM pooled SMD: −0.302; 95%CI: −0.810 to 0.205, P = 0.24 > 0.05). Overall, aripiprazole serum level and the sum level of aripiprazole plus dehydroaripiprazole in different phenotypes followed the trend UMs < EMs < IMs < PMs, whereas dehydroaripiprazole serum level followed the trend UMs < EMs > IMs > PMs. What is new and conclusion: Aripiprazole serum concentration differed significantly between EMs and IMs, but not between PMs. Whether this has clinical significance requires further evaluation by randomized trials.