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.
BACKGROUND
Fenofibrate has been prescribed concomitantly with 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 determine the 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-infinity)) 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-infinity) 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-infinity) 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-infinity) and AUC(0-infinity) 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 approximately 12 to approximately 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 single dose 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.
Penn
Ruth
R
Bioanalytical Systems, Inc., Baltimore, Maryland 21201, USA.
Williams
Robert X
RX
Guha-Ray
Dilip K
DK
Sawyers
William G
WG
Braun
Sandra L
SL
Rains
Keith T
KT
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000069059:Atorvastatin; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D004359:Drug Therapy, Combination; D050171:Dyslipidemias / Q000097:blood / Q000517:prevention & control*; D005260:Female; D005500:Follow-Up Studies; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D009525:Niacin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011758:Pyrroles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012016:Reference Values; D019821:Simvastatin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016896:Treatment Outcome
D003692:Delayed-Action Preparations; D004337:Drug Carriers; D006538:Heptanoic Acids; D000960:Hypolipidemic Agents; D011758:Pyrroles; D009525:Niacin; D000069059:Atorvastatin; D019821:Simvastatin