title: Pharmacokinetic and pharmacodynamic assessments of HMG-CoA reductase inhibitors when coadministered with everolimus.
abstract: The authors assessed the mutual influence of the immunosuppressant everolimus (Certican) and the HMG-CoA reductase inhibitors atorvastatin and pravastatin when coadministered based on pharmacokinetic and pharmacodynamic measures. In this randomized, open-label, three-way crossover study, 24 healthy men received three single-dose oral treatments: 2 mg everolimus, 20 mg atorvastatin (n = 12) or 20 mg pravastatin (n = 12), and the respective statin coadministered with everolimus. Consecutive treatments were separated by a 14-day washout. The pharmacokinetics of all three drugs and total HMG-CoA reductase inhibitors were measured. Everolimus Cmax was reduced by 9% and 10% with atorvastatin and pravastatin coadministration; the corresponding decreases in everolimus AUC were 5% and 6%, respectively. Everolimus coadministration increased the Cmax of atorvastatin by 11% but had no influence on atorvastatin AUC. Coadministration of everolimus with pravastatin was associated with a 10% decrease in pravastatin Cmax and a 5% decrease in the AUC. The elimination half-lives of the two statins were unaffected by everolimus. Changes in total HMG-CoA reductase inhibitors in plasma exhibited generally similar patterns as for the parent statin exposures. Single-dose administrations of everolimus with either atorvastatin or pravastatin did not influence the pharmacokinetics of everolimus, atorvastatin, pravastatin, or total HMG-CoA reductase inhibitors in plasma to a clinically relevant extent.
authors.affiliation: Novartis Pharmaceuticals, Basel, Switzerland.
authors.forename: John M
authors.initials: JM
authors.lastname: Kovarik
authors.forename: Stefan
authors.initials: S
authors.lastname: Hartmann
authors.forename: Martine
authors.initials: M
authors.lastname: Hubert
authors.forename: Stephane
authors.initials: S
authors.lastname: Berthier
authors.forename: Werner
authors.initials: W
authors.lastname: Schneider
authors.forename: Bernd
authors.initials: B
authors.lastname: Rosenkranz
authors.forename: Christiane
authors.initials: C
authors.lastname: Rordorf
mesh_terms: D000328:Adult; D019540:Area Under Curve; D000069059:Atorvastatin; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004347:Drug Interactions; D000068338:Everolimus; D005260:Female; D006207:Half-Life; D006538:Heptanoic Acids / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D017035:Pravastatin / Q000493:pharmacokinetics / Q000494:pharmacology; D011758:Pyrroles / Q000493:pharmacokinetics / Q000494:pharmacology; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents; D011758:Pyrroles; D000068338:Everolimus; D000069059:Atorvastatin; D017035:Pravastatin; D020123:Sirolimus