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

Penn, Ruth; R, Williams; Guha-Ray, Dilip K.; Sawyers, William; Braun, Sandra; Rains, Keith T.

doi:10.1016/j.clinthera.2005.12.004

Cited by 11 publications

(6 citation statements)

References 19 publications

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“…Moreover, recent studies showed that combined oral administration of fenofibrate and simvastatin is devoid of any possible pharmaceutical or intestinal absorption interactions after single oral doses (Penn et al, 2006).The same schedule of treatment was used to evaluate the longterm effects of combination on neurological deficits and brain lesion induced by TBI. The neurological assessments were performed 3 and 7 days after TBI, and then rats were killed for brain lesion determination.…”

Section: Experimental Protocolsmentioning

confidence: 99%

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Combination Therapy with Fenofibrate, a Peroxisome Proliferator-Activated Receptor α Agonist, and Simvastatin, a 3-Hydroxy-3-methylglutaryl-Coenzyme A Reductase Inhibitor, on Experimental Traumatic Brain Injury

Chen

Besson²,

Béziaud³

et al. 2008

J Pharmacol Exp Ther

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We and others have demonstrated that fibrates [peroxisome proliferator-activated receptor (PPAR)␣ agonists] and statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) exerted neuroprotective and pleiotropic effects in experimental models of traumatic brain injury (TBI). Because the combination of statins and fibrates synergistically enhanced PPAR␣ activation, we hypothesized that the combination of both drugs may exert more important and/or prolonged beneficial effects in TBI than each alone. In this study, we examined the combination of fenofibrate with simvastatin, administered 1 and 6 h after injury, on the consequences of TBI. First, our dose-effect study demonstrated that the most efficient dose of simvastatin (37.5 mg/kg) reduced post-traumatic neurological deficits and brain edema. Then, the effects of the combination of fenofibrate (50 mg/kg) and simvastatin (37.5 mg/kg), given p.o. at 1 and 6 h after TBI, were evaluated on the TBI consequences in the early and late phase after injury. The combination exerted more sustained neurological recovery-promoting and antiedematous effects than monotherapies, and it synergistically decreased the post-traumatic brain lesion. Furthermore, a delayed treatment given p.o. at 3 and 8 h after TBI with the combination was still efficient on neurological deficits induced by TBI, but it failed to reduce the brain edema at 48 h. The present data represent the first demonstration that the combination of fenofibrate and simvastatin exerts prolonged and synergistic neuroprotective effects than each drug alone. Thus, these results may have important therapeutic significance for the treatment of TBI. Traumatic brain injury (TBI) remains one of the leading causes of death and disability in industrialized countries. Despite numerous studies on animal models of TBI that investigated therapeutic strategies, no neuroprotective therapy is currently available (Bramlett and Dietrich, 2004). TBI leads to important and deleterious neuroinflammation, as evidenced by edema, free radicals, cytokine production, induction of nitric-oxide synthase and cyclooxygenase type 2, and leukocyte infiltration. Strategies blocking each inflammatory and oxidative mediator have been shown to induce neuroprotective, anti-inflammatory and antioxidative effects after brain injury (Ray et al., 2002). Drugs that were able to modulate only one molecular pathway implicated in inflammation or oxidative stress induced beneficial effects in experimental studies, but they failed in clinical trials. Thus, one key to success in neuroprotection would be to simultaneously modulate many pathophysiological pathways with pharmacological agent inducing pleiotropic effects.One pleiotropic strategy is to activate peroxisome proliferator-activated receptor (PPAR) ␣. PPAR␣ is one of the three subtypes of the nuclear receptor PPAR family, which can be activated by natural ligands, such as polyunsaturated fatty acids, and synthetic ligands (drugs belonging to fibrate's family). PPARs are implicated in several...

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Section: Experimental Protocolsmentioning

confidence: 99%

“…Last but not the least, combined oral administration of fenofibrate and simvastatin is devoid of any possible pharmaceutical or intestinal absorption interactions after a single dose (Penn et al, 2006). Therefore, translating this strategy to a clinical context may potentially have important therapeutic significance.…”

Section: Downloaded Frommentioning

confidence: 99%

Combination Therapy with Fenofibrate, a Peroxisome Proliferator-Activated Receptor α Agonist, and Simvastatin, a 3-Hydroxy-3-methylglutaryl-Coenzyme A Reductase Inhibitor, on Experimental Traumatic Brain Injury

Chen

Besson²,

Béziaud³

et al. 2008

J Pharmacol Exp Ther

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“…No clinically relevant pharmacokinetic interaction between fenofibrate and simvastatin combination has been shown [139][140][141].…”

Section: Brief Description Of Drug Interactionsmentioning

confidence: 99%

Safety considerations with fenofibrate/simvastatin combination

Filippatos

Elisaf

2015

Expert Opinion on Drug Safety

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Large randomized clinical trials show that the combined administration of fenofibrate with simvastatin is not associated with significantly increased incidence of serious adverse events compared with simvastatin monotherapy. The incidence of rhabdomyolysis is slightly increased with fibrate/statin combination compared with monotherapy but the actual risk is very low. Although fenofibrate increases creatinine and homocysteine serum levels, the incidence of diabetic nephropathy and thrombotic events was not significantly increased with fenofibrate/simvastatin combination compared with simvastatin monotherapy in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid trial. Furthermore, a decrease in albuminuria was observed with fenofibrate in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and ACCORD Lipid trials. Overall, the combined administration of fenofibrate with simvastatin appears to be safe, unless clinicians give fenofibrate/simvastatin combination to patients with predisposing risk factors for the occurrence of adverse events.

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“…Differences in the potential for pharmacokinetic interaction are most likely responsible for these findings. Whereas gemfibrozil can increase plasma concentrations of (and hence exposure to) commonly prescribed statins [43–47], fenofibrate, and although less studied, bezafibrate, do not appear to influence significantly the pharmacokinetics of statins [48–52] (Table 2). Recent experimental evidence indicates that most statins undergo glucuronidation, involving the same family of enzymes as those involved in the metabolism of gemfibrozil [53, 54].…”

Section: Dual Combination Therapy: What Are the Options?mentioning

confidence: 99%