Pharmacokinetics of the Oral Direct Renin Inhibitor Aliskiren in Combination With Digoxin, Atorvastatin, and Ketoconazole in Healthy Subjects: The Role of P-Glycoprotein in the Disposition of Aliskiren

¹ Novartis Pharmaceuticals Corporation
² Novartis Pharma AG
³ Novartis Pharma SAS
⁴ Novartis Institutes for Biomedical Research

^* To whom correspondence should be addressed. E-mail: bill.dole{at}novartis.com.

	Abstract

This study investigated the potential pharmacokinetic interaction between the direct renin inhibitor aliskiren and modulators of P-glycoprotein and cytochrome P450 3A4 (CYP3A4). Aliskiren stimulated in vitro P-glycoprotein ATPase activity in recombinant baculovirusinfected Sf9 cells with high affinity (K_m 2.1 µmol/L) and was transported by organic anion-transporting peptide OATP2B1-expressing HEK293 cells with moderate affinity (K_m 72 µmol/L). Three open-label, multiple-dose studies in healthy subjects investigated the pharmacokinetic interactions between aliskiren 300 mg and digoxin 0.25 mg (n = 22), atorvastatin 80 mg (n = 21), or ketoconazole 200 mg bid (n = 21). Coadministration with aliskiren resulted in changes of <30% in AUC and C_max,ss of digoxin, atorvastatin, o-hydroxy-atorvastatin, and -hydroxy-atorvastatin, indicating no clinically significant interaction with P-glycoprotein or CYP3A4 substrates. Aliskiren AUC was significantly increased by coadministration with atorvastatin (by 47%, P < .001) or ketoconazole (by 76%, P < .001) through mechanisms most likely involving transporters such as P-glycoprotein and organic anion-transporting peptide and possibly through metabolic pathways such as CYP3A4 in the gut wall. These results indicate that aliskiren is a substrate for but not an inhibitor of P-glycoprotein. On the basis of the small changes in exposure to digoxin and atorvastatin and the <2-fold increase in exposure to aliskiren during coadministration with atorvastatin and ketoconazole, the authors conclude that the potential for clinically relevant drug interactions between aliskiren and these substrates and/or inhibitors of P-glycoprotein/CPY3A4/OATP is low.
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