Itraconazole, a P-glycoprotein and CYP3A4 inhibitor, markedly raises the plasma concentrations and enhances the renin-inhibiting effect of aliskiren

• Published in: Journal of clinical pharmacology Vol. 51; no. 3; p. 359
• Main Authors: Tapaninen, Tuija, Backman, Janne T, Kurkinen, Kaisa J, Neuvonen, Pertti J, Niemi, Mikko
• Format: Journal Article
• Language: English
• Published: England 01.03.2011
• Subjects: Adult; Amides - blood; Amides - pharmacokinetics; Amides - pharmacology; Amides - urine; Antifungal Agents - pharmacology; Antihypertensive Agents - blood; Antihypertensive Agents - pharmacokinetics; Antihypertensive Agents - pharmacology; Antihypertensive Agents - urine; ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors; Biotransformation - drug effects; Cross-Over Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Enzyme Inhibitors - blood; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - urine; Female; Fumarates - blood; Fumarates - pharmacokinetics; Fumarates - pharmacology; Fumarates - urine; Half-Life; Humans; Itraconazole - analogs & derivatives; Itraconazole - blood; Itraconazole - pharmacology; Male; Metabolic Clearance Rate; Renin - antagonists & inhibitors; Renin - blood; Young Adult
• ISSN: 1552-4604
• DOI: 10.1177/0091270010365885

In a randomized crossover study, 11 healthy volunteers took 100 mg (first dose 200 mg) of the antifungal drug itraconazole, a P-glycoprotein and CYP3A4 inhibitor, or placebo twice daily for 5 days. On day 3, they ingested a single 150-mg dose of aliskiren, a renin inhibitor used in the treatment of hypertension. Itraconazole raised the peak plasma aliskiren concentration 5.8-fold (range, 1.1- to 24.3-fold; P < .001) and the area under the plasma aliskiren concentration-time curve 6.5-fold (range, 2.6- to 20.5-fold; P < .001) but had no significant effect on aliskiren elimination half-life. Itraconazole increased the amount of aliskiren excreted into the urine during 12 hours 8.0-fold (P < .001) and its renal clearance 1.2-fold (P = .042). Plasma renin activity 24 hours after aliskiren intake was 68% lower during the itraconazole phase than during the placebo phase (P = .011). In conclusion, itraconazole markedly raises the plasma concentrations and enhances the renin-inhibiting effect of aliskiren. The interaction is probably mainly explained by inhibition of the P-glycoprotein-mediated efflux of aliskiren in the small intestine, with a minor contribution from inhibition of CYP3A4. Concomitant use of aliskiren and itraconazole is best avoided.