title: Everolimus drug interactions: application of a classification system for clinical decision making.
abstract: More than half of all drugs used in medical practice are metabolized by cytochrome CYP3A. Coadministration of drugs that share this elimination pathway may lead to pharmacokinetic drug interactions. Efforts are underway by clinical, drug development and regulatory scientists to classify CYP3A-related drug interactions with the ultimate goal of improving guidance for clinical intervention. The CYP3A inhibitory classification system ranks inhibitors according to the fold-increase in area-under-the-curve (AUC) of a probe substrate as: strong (> or =5-fold), moderate (>2.0- to 4.9-fold), or weak (< or =2.0-fold). This classification system was applied to characterize everolimus as a CYP3A substrate.Methods. Five open-label crossover drug interaction studies were performed in 12-16 healthy subjects each. Subjects received a single 2 mg dose of everolimus alone and again during single- or multiple-dose treatment with the probe inhibitors ketoconazole, erythromycin, verapamil, cyclosporine and atorvastatin.Results. The fold-increase in everolimus AUC was: 15.0 with the strong inhibitor ketoconazole; 4.4, 3.5 and 2.7 with the moderate inhibitors erythromycin, verapamil and cyclosporine; and no change with the weak inhibitor atorvastatin. Subjects with low baseline AUCs when everolimus was given alone tended to have AUC increases of a higher magnitude (more potent interaction) in the presence of an inhibitor.Conclusions. Strong CYP3A inhibitors should be avoided when possible during everolimus treatment as compensatory everolimus dose reductions could be difficult to manage. Everolimus therapeutic drug monitoring should be used to guide individualized dose adjustments when moderate CYP3A inhibitors are added to or withdrawn from the regimen. Routine everolimus therapeutic drug monitoring should be sufficient to determine whether dose adjustments are needed when weak CYP3A inhibitors are coadministered. This rational and systematic approach to drug interactions on everolimus yielded clinically useful, structured guidelines for dose adjustment.
authors.affiliation: Novartis Pharmaceuticals, Basel, Switzerland and East Hanover, NJ, USA. john.kovarik@Novartis.com
authors.forename: John M
authors.initials: JM
authors.lastname: Kovarik
authors.forename: Doris
authors.initials: D
authors.lastname: Beyer
authors.forename: Robert L
authors.initials: RL
authors.lastname: Schmouder
mesh_terms: D019540:Area Under Curve; D018592:Cross-Over Studies; D065692:Cytochrome P-450 CYP3A Inhibitors; D003657:Decision Making; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000145:classification*; D000068338:Everolimus; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D000068338:Everolimus; D020123:Sirolimus