An open-label, crossover study of the pharmacokinetics of Insoluble Drug Delivery®-MicroParticle fenofibrate in combination with atorvastatin, simvastatin, and extended-release niacin in healthy volunteers

Abstract

Background: Fenofibrate has been prescribed concomitantlywith other lipid-lowering agents as a treatment for dyslipidemia. However, combination therapy, particularly a statin-fibrate combination, may be associated with an increased risk of myopathy, although this risk appears to be less with fenofibrate than with other fibrates. Objective: The objective of this study was to determinethe effect of administering a single dose of atorvastatin, simvastatin, or extended-release (ER) niacin on the pharmacokinetics and safety of a single dose of fenofibrate Insoluble Drug Delivery®-MicroParticle (IDD-P). Methods: This was an open-label, single-center,randomized, 4-treatment, 4-period crossover study in healthy adult volunteers. Subjects were randomized to 1 of 4 treatment sequences, administered 1 week apart, that included all 4 of the following treatments: 1 IDD-P fenofibrate 160-mg tablet alone; 1 IDD-P fenofibrate 160-mg tablet plus 1 atorvastatin 10-mg tablet; 1 IDD-P fenofibrate 160-mg tablet plus 1 simvastatin 10-mg tablet; and 1 IDD-P fenofibrate 160-mg tablet plus 1 ER niacin 500-mg tablet. Blood samples for pharmacokinetic analysis were obtained immediately before and up to 72 hours after administration during each of the 4 treatment periods. If the 90% CI for the log-transformed parameter was between 0.80 and 1.25, and the 90% CI for the nontransformed parameter was between 0.80 and 1.20, then the absence of a clinically significant drug interaction was assumed. However, the absence of a drug interaction was not to be ruled out if one or more of the CIs exceeded the boundary, provided the CI included 1.00. Results: Twenty healthy subjects were enrolled.Sixteen (80%) of the subjects were male and 17 (85%) were black; mean (SD) age was 35 (9.3) years. The mean C max, AUC from the time of administration to the last quantifiable concentration (AUC 0−t), and AUC from the time of administration to infinity (AUC 0−∞) were 5%, 6%, and 2% lower, respectively, with IDD-P fenofibrate plus atorvastatin than with IDD-P fenofibrate alone; the mean C max, AUC 0−t, and AUC 0-∞ were 6% lower, and 10% and 9% higher, respectively, with IDD-P fenofibrate plus simvastatin than with IDD-P fenofibrate alone; and the mean C max, AUC 0−t, and AUC 0−∞ were 12%, 6%, and 5% lower, respectively, with IDD-P fenofibrate plus ER niacin than with IDD-P fenofibrate alone. The 90% CIs surrounding the mean ratios for AUC 0−∞ and AUC 0−∞ for all 3 comparisons were between 0.80 and 1.25, suggesting the absence of a drug interaction for these parameters. For C max, an absence of a drug interaction was observed between concomitantly administered IDD-P fenofibrate and both atorvastatin and simvastatin; absence of drug interaction was not found for IDD-P fenofibrate plus ER niacin. All treatments were well tolerated; headache was the most common adverse event (AE) (10%). One subject with creatinine kinase levels of 1300 IU/L (>6 times the upper limit of normal) at baseline experienced a seizure ≈12 to ≈13 hours after administration of IDD-P fenofibrate plus atorvastatin; this serious AE was deemed to be possibly related to study drug. Conclusions: Concomitant administration of a singledose of either atorvastatin or simvastatin had no significant effect on the pharmacokinetics of a single dose of IDD-P fenofibrate. A drug interaction between concomitantly administered single doses of IDD-P fenofibrate and ER niacin could not be ruled out.