Effects of the combination of second-generation antipsychotics on serum concentrations of aripiprazole and dehydroaripiprazole in Chinese patients with schizophrenia

Abstract

Background Aripiprazole (ARI) is often prescribed alone or in combination with other second-generation antipsychotics (SGAs) to treat patients with schizophrenia. However, this may increase the potential clinical significance of drug-drug interactions. Therapeutic drug monitoring (TDM) is an important and fundamental tool both when administering ARI alone and in combination with other SGAs to monitor ARI pharmacokinetics, adjust the dosage and thereby achieve more effective and safer treatment. Aims This study retrospectively investigated the effects of four SGA comedications (clozapine, risperidone, quetiapine (QTP) and olanzapine) and other potential factors (sex, age and ARI dose) on the serum concentrations of ARI and dehydroaripiprazole (DARI) in Chinese patients with schizophrenia using TDM data. Methods High-performance liquid chromatography was used to test the serum concentrations of ARI, DARI and ARI+DARI. In addition, steady-state dose-adjusted serum concentrations (ie, concentration-to-dose ratios, C:D ratios) of ARI, DARI and ARI+DARI; sex; age; ARI dose and SGA comedication dose between 299 inpatients with schizophrenia who received ARI or SGA comedication were all collected and analysed. Spearman's correlation and multiple linear regression analysis were used to evaluate bivariate associations between ARI dose and serum ARI and DARI concentrations and describe the effect of independent variables on serum ARI and DARI concentrations, respectively. Results There were significant differences in the C:D ratios of ARI (χ 2 =-3.21, p=0.001) and ARI+DARI (χ 2 =-2.50, p=0.01) between the ARI and SGA groups, as well as in the C:D ratios of ARI (χ 2 =-3.59, p<0.001) and ARI+DARI (χ 2 =-3.10, p=0.002) between the female patients in the two groups. Of the four SGAs, only QTP had significant effects on the C:D ratios of ARI (Z=-4.12, p<0.001) and ARI+DARI (Z=-3.62, p<0.001) when compared with the ARI group in the whole sample and on the C:D ratios of ARI, DARI and ARI+DARI (Z=-3.96, p<0.001; Z=-2.22, p=0.03; Z=-3.75, p<0.001, respectively) in women when compared with their counterparts in the ARI group. Conclusion Comedication with SGAs resulted in lower C:D ratios of ARI and ARI+DARI compared with ARI monotherapy, and comedication with QTP resulted in lower C:D ratios of ARI and ARI+DARI than ARI monotherapy. Despite this statistical significance of our findings, whether the presently observed effect has clinical significance requires exploration by further research. TDM and dosage regulation of ARI should be performed in Chinese inpatients with schizophrenia who are receiving SGA comedication (especially QTP) to maintain a safe and effective dose-adjusted serum concentration of ARI and DARI.