Effect of Co-medication on the Serum Concentrations of Aripiprazole and the Main Metabolite Dehydroaripiprazole

Abstract

Abstract

Background: Aripiprazole is a relatively new antipsychotic drug with a partial dopamine agonist activity. It is metabolized by cytochrome P450 2D6 (CYP2D6) and CYP3A4 to an active metabolite, dehydroaripiprazole. Studies on pharmacokinetic drug interactions are so far limited. Thus, the aim of the present study was to investigate the impact of different co-medications on the serum concentration of aripiprazole and the active metabolite dehydroaripiprazole in psychiatric patients in a clinical setting.

Method: Psychiatric patients that had routine drug monitoring of aripiprazole performed at the Department of Psychopharmacology, Diakonhjemmet Hospital, as part of clinical follow-up and control of drug treatment were included in the study. A total of 360 patient samples were distributed in different co-medication groups according to information of co-medication given on the requisition forms. Patient samples with no co-medication constituted the control group. Steady state dose-adjusted serum concentrations (concentration/dose ratios) of aripiprazole, dehydroaripiprazole and the sum of aripiprazole and dehydroaripiprazole, and the metabolic ratio (dehydroaripiprazole/aripiprazole) in the different co-medication groups were compared to the control group.

Results: The present analysis showed that co-administration of a CYP3A4 inducer decreased the mean concentration/dose ratio (C/D ratio) of aripiprazole, dehydroaripiprazole and the sum of aripiprazole and dehydroaripiprazole by 69% (p<0.01), 75% (p<0.001) and 70% (p<0.001), respectively. Further, combination with a CYP2D6 inhibitor increased the C/D ratio of aripiprazole by 35% (p<0.05), with a corresponding decrease in dehydroaripiprazole by 26% (p<0.05). When aripiprazole was co-administered with lithium, a 43% (p<0.05) increase in aripiprazole C/D ratio was obtained, whereas there was no effect on the C/D ratio of dehydroaripiprazole. Olanzapine, perphenazine, risperidone injection, escitalopram and lamotrigine also obtained statistically significant effects on aripiprazole disposition, but to a lesser extent. The other psychotropic drugs assessed (clozapine, quetiapine, risperidone tablets, mirtazapine, sertraline, venlafaxine, clonazepam and valproate) did not show an apparent effect on aripiprazole disposition.

Conclusion: In the present study, the drugs most commonly used in combination with aripiprazole were investigated with respect to possible pharmacokinetic drug interactions. The only co-medications which appeared to require dosage adjustments for aripiprazole were the CYP3A4 inducers and, surprisingly, lithium. The other drug interactions observed were of uncertain clinical importance.