The relationship between clinical pharmacokinetics of aripiprazole and CYP2D6 genetic polymorphism: effects of CYP enzyme inhibition by coadministration of paroxetine or fluvoxamine

Abstract

PurposeTo investigate the effects of coadministration of paroxetine or fluvoxamine on the pharmacokinetics of aripiprazole in healthy adult Japanese with different CYP2D6 genotypes.MethodsFourteen CYP2D6 extensive metabolizer (EM) and 14 CYP2D6 intermediate metabolizer (IM) subjects were coadministered a single oral dose of aripiprazole 3 mg after steady-state plasma concentrations of the SSRIs paroxetine (20 mg/day) or fluvoxamine (100 mg/day) were reached by repeated oral doses for 6–7 days. The pharmacokinetics of aripiprazole with and without coadministration of SSRIs were compared according to CYP2D6 genotypes.ResultsCoadministration of paroxetine, a potent CYP2D6 inhibitor, decreased systemic clearance (CL/F) of aripiprazole by 58 and 23% in CYP2D6 EMs and IMs, respectively, demonstrating that the percentage inhibition of CYP2D6 activity by coadministration of paroxetine was apparently greater in CYP2D6 EMs than in IMs. Coadministration of fluvoxamine, a less potent CYP3A4 inhibitor, decreased the CL/F of aripiprazole by 39% in CYP2D6 EMs and 40% in IMs, indicating the same inhibitory effect on CYP enzymes, regardless of the CYP2D6 genotype. Percent contribution of CYP2D6 to total CL/F (CYP2D6 plus CYP3A4) of aripiprazole estimated as a reduced percentage of CL/F by CYP enzyme inhibition was 62% for CYP2D6 EMs and 24% for IMs in paroxetine coadministration, and 40% for CYP2D6 EMs and 18% for IMs in fluvoxamine coadministration.ConclusionsThere were marked differences in the degree of influence of paroxetine coadministration on the pharmacokinetics of aripiprazole between CYP2D6 EMs and IMs, but no apparent differences were found between two CYP2D6 genotypes in fluvoxamine coadministration. Aripiprazole can be used safely in combination with SSRIs that have a CYP enzyme-inhibitory action.

Clinically relevant interactions between newer antidepressants and second-generation antipsychotics

“…These effects are probably due to the potent inhibitory effect of paroxetine on CYP2D6, the isoform responsible, together with CYP3A4, for aripiprazole biotransformation. Consistent with these findings, in a study of healthy subjects, coadministration of paroxetine (20 mg/day) decreased systemic clearance of aripiprazole by 58 --23% in CYP2D6 EMs and intermediate metabolizers (IMs), respectively, demonstrating that the percentage of inhibition of CYP2D6 activity by coadministration of paroxetine was apparently greater in CYP2D6 EMs than in IMs [53].…”

“…Inhibition of CYP1A2 [63][64][65][66] Risperidone No significant changes in plasma risperidone concentrations at fluvoxamine dosage of 100 mg/day, increase by 26% at fluvoxamine dose of 200 mg/day Inhibition of CYP2D6 and CYP3A4 [68] Quetiapine Increase in plasma concentrations of quetiapine by 159% Inhibition of CYP3A4 [45] Aripiprazole Decrease by 40% in systemic clearance of aripiprazole Inhibition of CYP3A4 [53] Asenapine Increase by 29% in the AUC of asenapine at fluvoxamine dosage of 50 mg/day Inhibition of CYP1A2 [25,26] Sertraline Risperidone Increased plasma concentrations of risperidone (36 --52%) only at high doses of sertraline (150 mg/day) Inhibition of CYP2D6 [69] Citalopram/ escitalopram Aripiprazole Minimal increase (by 20%) in plasma concentrations of aripiprazole and dehydroaripiprazole Inhibition of CYP2D6 [46] Duloxetine Risperidone Minimal increase (by 26%) in plasma concentrations of the active moiety of risperidone Inhibition of CYP2D6 [83] Olanzapine No change or minimal increase in plasma olanzapine concentrations Inhibition of CYP2D6 (?) [82,83] AUC: Area under the curve; CYP: Cytochrome P450.…”

“…Inhibition of CYP2D6 [52,53] Iloperidone Increase (up to twofold) in plasma iloperidone concentrations…”

Study of pharmacokinetic interaction of paroxetine and roxithromycin on bencycloquidium bromide in healthy subjects

“…The overall increase of only 33% in AUC with individual data within the ''No Effect Boundary'' indicated that no relevant clinical drug interactions were expected from subjects regardless of their CYP2D6 polymorphism, when BCQB is co-administered with paroxetine. Recent studies on drug interactions between paroxetine and aripiprazole and between clarithromycin and ambrisentan showed similar inhibition extent (30%), and found clinically minor and likely irrelevant (Azuma et al, 2012;Markert et al, 2013). Roxithromycin is known as anti-infective but also as immunomodulator, and widely used in the management and treatment of infective and/or inflammatory diseases, particularly in upper respiratory tract infections (Itkin and Menzel, 1970;Kadota et al, 1993;Plewig and Schopf, 1975).…”

Selective Serotonin Reuptake Inhibitor Drug Interactions in Patients Receiving Statins

“…51 However, the pharmacokinetic effects of an enzyme inhibitor are more apparent in intermediate to extensive metabolizers than in poor metabolizers. 52 Therefore, given that the wild type of CYP genes code for intermediate to extensive metabolism status, and given that (as already discussed) SSRIs have little effect on the CYP enzymes that metabolize the statins, it is unlikely that CYP gene polymorphisms will influence the risk of SSRI-related drug interactions in patients receiving statins.…”