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The impact of co-administration of ketoconazole and rifampicin on the pharmacokinetics of apremilast in healthy volunteers

Liu, Y, Zhou, S, Wan, Y, Wu, A and Palmisano, M (2014) The impact of co-administration of ketoconazole and rifampicin on the pharmacokinetics of apremilast in healthy volunteers. British Journal of Clinical Pharmacology. pp. 1050-1057.


AimsTwo clinical studies were conducted to determine possible drug-drug interactions between apremilast and a strong CYP3A4 inhibitor, ketoconazole, or a potent CYP3A4 inducer, rifampicin. The main objectives of these two studies were to evaluate the impact of multiple doses of ketoconazole on the pharmacokinetics of apremilast and its metabolites, and the effect of multiple oral doses of rifampicin on the pharmacokinetics of apremilast.MethodsThese single centre, open label, sequential treatment studies in healthy subjects included two treatment periods for ketoconazole and three treatment periods for rifampicin. Apremilast was administered as a 20mg (ketoconazole study) or 30mg (rifampicin study) single oral dose.ResultsKetoconazole increases overall exposure (AUC(0,)) of apremilast by approximate to 36% (2827 vs. 2072ngml(-1)h, 90% CI = 126.2, 147.5) and peak exposure (C-max) by 5% (247 vs. 236ngml(-1)). Multiple doses of rifampicin increase apremilast clearance approximate to 3.6-fold and decrease apremilast mean AUC(0,) by approximate to 72% (3120 vs. 869ngml(-1)h, 90% CI = 25.7, 30.4) and C-max (from 290 vs. 166ngml(-1)) relative to that of apremilast given alone. A 30min intravenous infusion of rifampicin 600mg had negligible effects on the overall exposure (AUC(0,)) of apremilast (2980 vs. 3120ngml(-1)h, 90% CI = 88.0, 104.1).ConclusionKetoconazole slightly decreased apremilast clearance, resulting in a small increase in AUC which is probably not meaningful clinically. However, the effect of CYP3A4 induction by rifampicin on apremilast clearance is much more pronounced than that of CYP3A4 inhibition by ketoconazole. Strong CYP3A4 inducers may result in a loss of efficacy of apremilast because of decreased drug exposure

Item Type: Article
Additional Information: NIBR author: Wu, A institute: NIBR contributor address: Celgene Corp, Summit, NJ 2842 USA; Roche PRED, Pharma Res & Early Dev, Shanghai, Peoples R China ; Novartis Inst BioMed Res, Early Dev Asia, Shanghai, Peoples R China ; Celgene Corp, Summit, NJ 2842 USA; Palmisano, M; Celgene Corp, Translat Dev Clin Pharmacol, 86 Morris Ave, Summit, NJ 2842 USA
Date Deposited: 13 Oct 2015 13:11
Last Modified: 13 Oct 2015 13:11


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