Pharmacokinetic interaction of the direct renin inhibitor aliskiren with furosemide and extended-release isosorbide-5-mononitrate in healthy subjects.
This study investigated the pharmacokinetics, safety, and tolerability of aliskiren administered alone or in combination with either the loop diuretic furosemide or an oral extended-release formulation of isosorbide-5-mononitrate (ISMN). In separate studies, 22 healthy subjects (ages 18-45 years) received either ISMN 40 mg or furosemide 20 mg once-daily for 3 days followed by a 3-day washout. Subjects then received aliskiren 300 mg once-daily for 7 days followed by combination therapy for 3 days. Pharmacokinetic assessments were taken at regular intervals over 24 h after dosing on the last day of each treatment period. At steady state, aliskiren AUC(tau) was decreased by 7% (geometric mean ratio [90% CI], 0.93 [0.84, 1.04]), and C(max) by 20% (0.80 [0.65, 0.97]) with furosemide coadministration compared with aliskiren administration alone. Aliskiren coadministration reduced furosemide AUC(tau) by 28% (0.72 [0.64, 0.81]) and C(max) by 49% (0.51 [0.39, 0.66]) compared with furosemide alone. Coadministration of aliskiren and ISMN was associated with only minor changes in the pharmacokinetic parameters of aliskiren (AUC(tau) 1.03 [0.90, 1.18]; C(max) 0.94 [0.69, 1.29]) and ISMN (AUC(tau) 0.88 [0.71, 1.10]; C(max) 0.94 [0.79, 1.13]). Headache and dizziness were the most common adverse events in both studies; dizziness and BP values below normal (SBP < 90 and/or DBP < 50 mmHg) were more frequent with aliskiren and ISMN coadministration than with either agent alone. Coadministration of aliskiren and ISMN had no clinically relevant effect on either aliskiren or ISMN pharmacokinetics. In conclusion, coadministration of aliskiren and furosemide reduced furosemide exposure and had a minor effect on aliskiren pharmacokinetics. The clinical significance of reduced systemic exposure to furosemide during coadministration of aliskiren is uncertain.
Vaidyanathan
Sujata
S
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
Bartlett
Michael
M
Dieterich
Hans Armin
HA
Yeh
Ching-Ming
CM
Antunes
Ana
A
Howard
Dan
D
Dole
William P
WP
D000293:Adolescent; D000328:Adult; D000577:Amides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004232:Diuretics / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D005650:Fumarates / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D005665:Furosemide / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D007548:Isosorbide Dinitrate / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D055815:Young Adult; D000092502:Renin Inhibitors
D000577:Amides; D003692:Delayed-Action Preparations; D004232:Diuretics; D005650:Fumarates; D005665:Furosemide; D007548:Isosorbide Dinitrate; D014665:Vasodilator Agents; D000092502:Renin Inhibitors; C446481:aliskiren; C030397:isosorbide-5-mononitrate