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.
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 baculovirus-infected Sf9 cells with high affinity (K(m) 2.1 micromol/L) and was transported by organic anion-transporting peptide OATP2B1-expressing HEK293 cells with moderate affinity (K(m) 72 micromol/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(tau) and C(max,ss) of digoxin, atorvastatin, o-hydroxy-atorvastatin, and rho-hydroxy-atorvastatin, indicating no clinically significant interaction with P-glycoprotein or CYP3A4 substrates. Aliskiren AUC(tau) 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.
Vaidyanathan
Sujata
S
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
Camenisch
Gian
G
Schuetz
Helmut
H
Reynolds
Christine
C
Yeh
Ching-Ming
CM
Bizot
Marie-Noelle
MN
Dieterich
Hans Armin
HA
Howard
Dan
D
Dole
William P
WP
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000328:Adult; D000577:Amides / Q000009:adverse effects / Q000493:pharmacokinetics*; D000818:Animals; D000935:Antifungal Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D000069059:Atorvastatin; D018938:Caco-2 Cells; D002460:Cell Line; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004077:Digoxin / Q000009:adverse effects / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005260:Female; D005650:Fumarates / Q000009:adverse effects / Q000493:pharmacokinetics*; D006538:Heptanoic Acids / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D007654:Ketoconazole / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D027361:Organic Anion Transporters / Q000378:metabolism; D011758:Pyrroles / Q000009:adverse effects / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D055815:Young Adult; D000092502:Renin Inhibitors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000577:Amides; D000935:Antifungal Agents; D000069059:Atorvastatin; D051544:Cytochrome P-450 CYP3A; D004077:Digoxin; D005650:Fumarates; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007654:Ketoconazole; D027361:Organic Anion Transporters; D011758:Pyrroles; D000092502:Renin Inhibitors; C450859:SLCO2B1 protein, human; C446481:aliskiren; C510163:CYP3A4 protein, human