FibrateFibrate SafetySafety && MetabolismMetabolism
ThomasThomas Dayspring,Dayspring, MD,MD, FACPFACP Clinical Assistant Professor of Medicine University of Medicine and Dentistry of New Jersey New Jersey Medical School Attending in Medicine: St Joseph’s Regional Medical Center, Paterson and Wayne, NJ
Certified Menopause Practitioner: North American Menopause Society North Jersey Institute of Menopausal Lipidology Wayne, New Jersey FDAFDA IndicationsIndications forfor TriCorTriCor
TriCorTriCor isis indicatedindicated asas adjunctiveadjunctive therapytherapy toto dietdiet toto reducereduce elevatedelevated LDLLDL--CC,, TotalTotal cholesterolcholesterol,, TriglyceridesTriglycerides andand ApoApo BB,, andand toto increaseincrease HDLHDL--CC inin adultadult patientspatients withwith primaryprimary hypercholesterolemiahypercholesterolemia oror mixedmixed dyslipidemiadyslipidemia TriCorTriCor (fenofibrate)(fenofibrate) TabletsTablets
) ContraindicatedContraindicated inin thosethose withwith aa hypersensitivityhypersensitivity toto fenofibrate,fenofibrate, hepatichepatic oror severesevere renalrenal dysfunctiondysfunction andand prepre--existingexisting GBGB disease.disease. ) IsIs associatedassociated withwith risesrises inin aminases:aminases: periodicperiodic LFTLFT monitoringmonitoring isis requiredrequired ) MayMay leadlead toto cholelithiasis:cholelithiasis: ifif confirmedconfirmed TriCorTriCor shouldshould bebe discontinueddiscontinued ) MayMay increaseincrease effectseffects ofof coumadincoumadin FibrateFibrate ChemicalChemical StructuresStructures
O CH3 CH3 Cl C O C COO CH
CH3 Fenofibrate CH3
CH3
Cl OCCOOC2H5
Clofibrate CH3 CH 3 CH3
O CH2 CH2 CH2 CH2 C COOH
Gemfibrozil CH3 CH3 FDAFDA IndicationsIndications forfor TriCorTriCor
Lipoprotein Phenotype Occurrence Present in Chol Trig Excess I Rare Chylomicrons 250-400 >2500 IIA Common LDL >250 <150 IIB Most common LDL,VLDL >250 150-400 III Rare VLDL remnants 375-500 600-800 IV Common VLDL 225-275 375-500 V Rare Chylomicrons, 350-400 1700-2500 VLDL
TriCorTriCor isis indicatedindicated inin IIA,IIA, IIB,IIB, IV,IV, VV DrugDrug--DrugDrug InteractionsInteractions Statins/FibratesStatins/Fibrates
)CombinedCombined useuse ofof fibratesfibrates andand statinsstatins hashas beenbeen associatedassociated withwith rhabdomyolysis,rhabdomyolysis, markedlymarkedly elevatedelevated creatinecreatine kinasekinase levels,levels, andand myoglobinuriamyoglobinuria
)TheThe combinedcombined useuse ofof fenofibratefenofibrate andand statinsstatins shouldshould bebe avoidedavoided unlessunless thethe benefitbenefit ofof furtherfurther alterationsalterations inin lipidlipid levelslevels isis likelylikely toto outweighoutweigh thethe increasedincreased riskrisk ofof thisthis drugdrug combinationcombination
Fenofibrate prescribing information, Abbott Laboratories, 1998. FenofibrateFenofibrate PharmacokineticsPharmacokinetics
) WellWell absorbedabsorbed fromfrom GIGI tracttract ) PeakPeak plasmaplasma levelslevels withinwithin 66--88 hourshours ) ExcretedExcreted mainlymainly inin thethe urineurine ) HalfHalf--lifelife ofof 2020 hourshours ) InIn vivovivo datadata indicateindicate thatthat neitherneither fenofibratefenofibrate nornor fenofibricfenofibric acidacid undergoesundergoes oxidativeoxidative metabolismmetabolism (eg,(eg, cytochromecytochrome P450)P450) toto aa significantsignificant extentextent
Fenofibrate prescribing information, Abbott Laboratories, 1998. DrugDrug--DrugDrug InteractionsInteractions
)PotentiationPotentiation ofof coumarincoumarin--typetype anticoagulantsanticoagulants hashas beenbeen observed,observed, withwith prolongationprolongation ofof thethe INRINR •• CautionCaution shouldshould bebe exercisedexercised whenwhen coumarincoumarin anticoagulantsanticoagulants areare givengiven inin conjunctionconjunction withwith TriCorTriCor )FenofibrateFenofibrate shouldshould bebe takentaken atat leastleast 11 hourhour before,before, oror 44--66 hourshours after,after, takingtaking aa bilebile acidacid-- bindingbinding resin,resin, toto avoidavoid impedingimpeding itsits absorptionabsorption
Fenofibrate prescribing information, Abbott Laboratories, 1998. FenofibrateFenofibrate PharmacokineticsPharmacokinetics ))InIn vivovivo datadata indicateindicate thatthat neitherneither fenofibratefenofibrate nornor fenofibricfenofibric acidacid undergoesundergoes oxidativeoxidative metabolismmetabolism (eg,(eg, cytochromecytochrome P450)P450) toto aa significantsignificant extent.extent.
Fenofibrate prescribing information, Abbott Laboratories, 2003. FDAFDA PackagePackage InsertInsert forfor FenofibrateFenofibrate
InIn aa singlesingle--dosedose drugdrug interactioninteraction studystudy inin 2323 healthyhealthy adultsadults thethe concomitantconcomitant administrationadministration ofof TriCorTriCor andand pravastatinpravastatin resultedresulted inin nono clinicallyclinically importantimportant differencedifference inin thethe pharmacokineticspharmacokinetics ofof fenofibricfenofibric acid,acid, pravastatinpravastatin oror itsits activeactive metabolites,metabolites, 3a3a--hydroxyhydroxy isoiso--pravastatinpravastatin whenwhen comparedcompared toto eithereither drugdrug givengiven alonealone FenofibrateFenofibrate DoesDoes notnot IncreaseIncrease PravastatinPravastatin PlasmaPlasma ConcentrationsConcentrations
Three 67-mg fenofibrate 100 capsules + one 40-mg pravastatin tablet One 40-mg pravastatin tablet 10
1 Pravastatin Plasma Pravastatin Plasma Concentration, ng/mL Concentration, ng/mL .1
0 051015 Time (hours) Pan W-J, et al. J Clin Pharmacol . 2000;40:316-323. SimvastatinSimvastatin ProductProduct InformationInformation SheetSheet
) TheThe useuse ofof simvastatinsimvastatin shouldshould notnot exceedexceed 1010 mgmg dailydaily inin patientspatients receivingreceiving concomitantconcomitant gemfibrozil.gemfibrozil. TheThe combinedcombined useuse ofof simvastatinsimvastatin andand gemfibrozilgemfibrozil shouldshould bebe avoidedavoided unlessunless benefitsbenefits areare likelylikely toto outweighoutweigh thethe risksrisks ) CautionCaution shouldshould bebe usedused whenwhen prescribingprescribing simvastatinsimvastatin withwith otherother lipidlipid loweringlowering drugsdrugs (fibrates(fibrates oror >> 1gm1gm niacin)niacin) ) TheThe benefitsbenefits ofof furtherfurther alterationsalterations inin lipidslipids withwith combinedcombined useuse ofof fibratesfibrates andand niacinniacin shouldshould bebe weighedweighed carefullycarefully againstagainst thethe potentialpotential riskrisk ofof thesethese combinationscombinations EffectsEffects ofof HighHigh--DoseDose StatinsStatins Atorvastatin Lovastatin Simvastatin 10 mg 20 mg 40 mg 80 mg 20 mg 40 mg 80 mg 20 mg 40 mg 80 mg C C - - 0 -10 -20 -30 -40 -50 Decrease in LDL Decrease in LDL Additional LDL-C lowering benefit of high-dose statins may be -60 outweighed by the LFTs and increased risk of myositis. 2.5
2.0 (% of (% of
1.5 LFTs LFTs 1.0 Patients) Patients) 0.5
0.0 Elevated Elevated Elevated Elevated 10 mg 20 mg 40 mg 80 mg 20 mg 40 mg 80 mg 20 mg 40 mg 80 mg
Davidson MH. Am J Cardiol. 2002;90(suppl):50K-60K. Glucuronidation:Glucuronidation: ExplanationExplanation ofof Fibrate/StatinFibrate/Statin InteractionInteraction
) ““GlucuronidationGlucuronidation isis aa pathwaypathway forfor thethe eliminationelimination ofof thethe activeactive hydroxyhydroxy acidacid metabolitesmetabolites ofof simvastatin,simvastatin, atorvastatin,atorvastatin, andand cerivastatincerivastatin”” ) ““TheThe mostmost recentrecent evidenceevidence suggestssuggests thatthat gemfibrozilgemfibrozil inhibitsinhibits simvastatin,simvastatin, atorvastatin,atorvastatin, and,and, moremore prominently,prominently, cerivastatincerivastatin glucuronidation.glucuronidation.”” ) ““FenofibratesFenofibrates,, however,however, appearappear toto havehave aa significantlysignificantly lessless inhibitoryinhibitory effecteffect onon statinstatin glucuronidationglucuronidation,, andand thisthis maymay explainexplain thethe lacklack ofof significantsignificant drugdrug interactioninteraction betweenbetween fenofibratefenofibrate andand statins.statins.””
Davidson MH. Am J Cardiol. 2002;90(suppl):50K-60K. Glucuronidation:Glucuronidation: ?? ExplanationExplanation ofof Fibrate/StatinFibrate/Statin InteractionInteraction
) “Glucuronidation is a pathway for the elimination of the active hydroxy acid metabolites of simvastatin, atorvastatin, and cerivastatin” ) “Initially, the PK interaction between statins and gemfibrozil was thought to be the result of an interaction with cytochrome P450 pathways.” ) “The most recent evidence suggests that gemfibrozil inhibits simvastatin, atorvastatin, and, more prominently, cerivastatin glucuronidation.” ) “Fenofibrates, however, appear to have a significantly less inhibitory effect on statin glucuronidation, and this may explain the lack of significant drug interaction between fenofibrate and statins.”
Davidson MH. Am J Cardiol. 2002;90(suppl):50K-60K. GemfibrozilGemfibrozil InteractsInteracts withwith StatinStatin GlucuronidationGlucuronidation
) “Further studies conducted in human liver microsomes with atorvastatin showed that, as with simvastatin, gemfibrozil was a less potent inhibitor of the CYP3A4-mediated oxidation of this drug than its glucuronidation.” ) “However, with cerivastatin, the glucuronidation as well as the CYP2C8- and CYP3A4-mediated oxidation pathways were much more susceptible to inhibition by gemfibrozil than was observed with simvastatin or atorvastatin.” ) “Collectively, the results of these studies provide metabolic insight into the nature of drug-drug interaction betweenbetween gemfibrozil and statins, and a possible explanation for the enhanced susceptibility of cerivastatin to interactions with gemfibrozil.” Prueksaritanont T, et al. JPET. 301:1042-1051, 2002. GemfibrozilGemfibrozil IncreasesIncreases SimvastatinSimvastatin PlasmaPlasma ConcentrationsConcentrations
8 Gemfibrozil Placebo
6
4
2 Simvastatin Acid, ng/mL Simvastatin Acid, ng/mL
0 01234 6 8 1012 Time, h
Backman JT, et al. Clin Pharmacol Ther. 2000;68:122-129. GemfibrozilGemfibrozil IncreasesIncreases CerivastatinCerivastatin PlasmaPlasma ConcentrationsConcentrations
10
8
6
4 + Gemfibrozil Cerivastatin (Acid) ng/mL Cerivastatin (Acid) ng/mL 2 + Placebo
0 0 2 4 6 8 10 12 24 Time, hours Backman JT, et al. Clin Pharmacol Ther. 2002;72:685-691. Gemfibrozil,Gemfibrozil, butbut notnot Bezafibrate,Bezafibrate, IncreasesIncreases LovastatinLovastatin PlasmaPlasma ConcentrationsConcentrations
Gemfibrozil 8 Placebo Bezafibrate 6
4
2 Lovastatin Acid, ng/mL Lovastatin Acid, ng/mL
0 024681012 Time, h Kyrklund C, et al. Clin Pharmacol Ther. 2001;69:340-345. GlucuronidationGlucuronidation ofof FibratesFibrates GemfibrozilGemfibrozil andand FenofibrateFenofibrate Statins utilize UGT 1A1 and 1A3 for metabolism 3000 UGT = UDP Glucuronyl transferase 2500 2000 Gemfibrozil 1500 Fenofibrate Fenofibrate primarily 1000 utilizes UGT 1A9 and 500 2B7 for metabolism 50 pmo/min/mg pmo/min/mg Glucuronide Formation, Glucuronide Formation, Glucuronide Formation, Glucuronide Formation,
0 HLM 1A1 1A3 1A10 1A9 2B7 2B15 Gemfibrozil competitively competes with statins for UGT 1A1 and 1A3 Prueksaritanont T, et al. Drug Metab Dispos. 2002;30:1280-128 EffectEffect onon GlucuronidationGlucuronidation ofof StatinStatin HydroxyHydroxy AcidsAcids -- GemfibrozilGemfibrozil VersusVersus FenofibrateFenofibrate
Inhibitor
Substrate Gemfibrozil IC50* (μM) Fenofibrate IC50* (μM) Simvastatin Hydroxy 354 682 Acid Atorvastatin 316 Not Done Cerivastatin 82 433
Gemfibrozil Cmax† (μM) Fenofibrate Cmax † (μM) § 100-300 15-55§
*Obtained following coincubation of fibrates and simvastatin hydroxy acid in human liver microsomes. †Reported values following 600 mg BID gemfibrozil or 200 mg QD fenofibrate in humans. §Measured as fenofibric acid.
Prueksaritanont T, et al. Poster presented at 2002 AHA. EffectEffect onon GlucuronidationGlucuronidation ofof StatinStatin HydroxyHydroxy AcidsAcids -- GemfibrozilGemfibrozil VersusVersus FenofibrateFenofibrate
) Although glucuronidation of all statins is inhibited by gemfibrozil: simvastatin, atorvastatin, and rosuvastatin appear to be less susceptible than cerivastatin ) Initial studies indicate the fenofibrate is much less inhibitory than gemfibrozil on statin glucuronidation ) For rosuvastatin, the significant effect of gemfibrozil on both glucuronidation and oxidation is similar to cerivastatin, suggestion the potential for a pharmacokinetic interaction between this new statin and gemfibrozil
Prueksaritanont T, et al. Poster presented at 2002 AHA. LipophilicityLipophilicity -- HydrophilicityHydrophilicity
Most Lipophilic Hydrophilic (low lipophilicity) Simvastatin statins may have greater Lovastatin accumulation in the liver via selective membrane carriers Fluvastatin and decreased accumulation Atorvastatin in peripheral tissues through passive diffusion and thus Rosuvastatin inhibit greater selective Pravastatin inhibition of liver HMG-CoA reductase. Most Hydrophilic
J Pharm Sci 1991;80:830-834Trends Pharmacol Sci 1998;19:26-37 Am J Cardiol 2001;97(suppl):28B-32B EffectEffect ofof GemfibrozilGemfibrozil andand FenofibrateFenofibrate onon RosuvastatinRosuvastatin PlasmaPlasma ConcentrationsConcentrations
1.90 2 1.8 1.6 1.4 1.07 1.2 Gemfibrozil 1 Fenofibrate AUC ratio AUC ratio 0.8 0.6 0.4 0.2 0 Gemfibrozil Fenofibrate Ratio of rosuvastatin AUC in fibrate-treated patients to AUC in placebo- treated patients FenofibrateFenofibrate DoesDoes NotNot IncreaseIncrease RosuvastatinRosuvastatin PlasmaPlasma ConcentrationsConcentrations
Rosuvastatin (10 mg QD) 10 Rosuvastatin (10 mg QD) + Fenofibrate 200 mg (67 mg TID)
1 Plasma Concentration (ng/mL) Plasma Concentration Plasma Concentration (ng/mL) Plasma Concentration 0.1 0 5 10 15 20 25 30 35
Time (h) Geometric mean (SD) plasma concentrations of rosuvastatin over time on day 7 after dosing of rosuvastatin alone and rosuvastatin in combination with fenofibrate
Martin PD, et al. Clin Ther. 2003;25:459-470. CombinationCombination Therapy:Therapy: PharmacokineticPharmacokinetic InteractionsInteractions
GemfibrozilGemfibrozil FenofibrateFenofibrate
PravastatinPravastatin ↑↑ inin ccmax NoNo effecteffect FluvastatinFluvastatin NoNo effecteffect NotNot availableavailable
SimvastatinSimvastatin ↑↑ ccmax byby 112%112% NoNo effecteffect
CerivastatinCerivastatin ↑↑ ccmax byby 22--33--foldfold NoNo effecteffect RosuvastatinRosuvastatin NotNot availableavailable NoNo effecteffect
Davidson MH. Am J Cardiol. 2002;90(suppl):50K-60K. Statin/FibrateStatin/Fibrate CombinationCombination Therapy:Therapy: PharmacokineticPharmacokinetic InteractionsInteractions
Gemfibrozil Fenofibrate Atorvastatin Not available No effect
Simvastatin ↑ in Cmax by 2-fold No effect
Pravastatin ↑ in Cmax by 2-fold No effect
Rosuvastatin ↑ in Cmax by 2-fold No effect Fluvastatin No effect No effect
Lovastatin ↑ in Cmax by 2.8-fold No effect
Cerivastatin ↑ in Cmax by 2-3–fold No effect
Backman JT, et al. Clin Pharmacol Ther. 2002;72:685-691. TriCor [package insert]. Abbott Laboratories;2004. Abbott Laboratories. Data on file; 2005. Kyrklund C, et al. Clin Pharmacol Ther. 2001;69:340-345. Davidson MH. Am J Cardiol. 2002;90(suppl):50K-60K. Pan W-J, et al. J Clin Pharmacol. 2000;40:316-323. Prueksaritanont T, et al. Drug Metab Dispos. 2002;30:1280-1287. Backman JT, et al. Clin Pharmacol Ther. 2000;68:122-129. Martin PD, et al. Clin Ther. 2003;25:459-471. Bergman AJ, et al. J Clin Pharmacol. 2004;44:1054-1062. LLipidsipids inin DDiabetesiabetes SStudytudy ((LDSLDS))
) 4,1914,191 diabeticdiabetic patientspatients withoutwithout knownknown CHDCHD andand LDLLDL--CC << 160160 mg/dLmg/dL fromfrom 3030 centerscenters inin UKUK • Fenofibrate 200 mg + placebo • Cerivastatin .4mg + placebo • Cerivastatin.4mg + fenofibrate 200mg • Placebo + placebo ) BeganBegan MayMay 19991999 andand closedclosed AugustAugust 20012001 ) DataData onon 19491949 followedfollowed forfor aa yearyear havehave beenbeen analyzedanalyzed • No myositis or rhabomyolysis cases
ADA abstract 317 Neil A et al. The Endocrinologist 2003;13(suppl3):S17 Fibrate/StatinFibrate/Statin RiskRisk ofof RhabdomyolysisRhabdomyolysis
NumberNumber ofof CasesCases ofof RhabdomyolysisRhabdomyolysis
# Cases # Rx # Cases Medication Reported Dispensed 2,3 Reported per Million 1 Fenofibrate + Any Statin 16 3,519,000 4.55 Fenofibrate + Cerivastatin 14 100,000 140.00 Fenofibrate + Other Statins 2 3,419,000 0.58
Gemfibrozil + Any Statin 590 6,757,000 87.32 Gemfibrozil + Cerivastatin 533 116,000 4,594.83 Gemfibrozil + Other Statins 57 6,641,000 8.58
1Adverse Event Reporting System, U.S. Food and Drug Administration. 2National Prescription Audit Plus report, IMS Health. 3Concomitancy Report, VERISPAN, LLC. RiskRisk ofof RhabdomyolysisRhabdomyolysis withwith FibratesFibrates andand StatinsStatins
vs statins other than cerivastatin vs cerivastatin 10 5000 4600 9 8.6 4500
8 Fenofibrate 4000 Fenofibrate resulted in 15 resulted in 33 7 3500 times lower times lower 6 rhabdomyolysis 3000 rhabdomyolysis 5 reporting than 2500 reporting than 4 did gemfibrozil 2000 did gemfibrozil
3 1500 2 1000 0.58 1 500 140
No.Million Prescriptions Cases Reported per 0 0 No.Million Prescriptions Cases Reported per Fenofibrate Gemfibrozil Fenofibrate Gemfibrozil
Number of cases of rhabdomyolysis Number of cases of rhabdomyolysis reported per million prescriptions reported per million prescriptions dispensed of statins other than dispensed of cerivastatin in combination cerivastatin in combination with fibrates. with fibrates.
Jones PH & Davidson MH. A J Card 2005;95:120-122 NumberNumber ofof CasesCases ofof RhabdomyolysisRhabdomyolysis inin CombinationCombination TherapyTherapy WithWith CerivastatinCerivastatin
5000 4600 4500 4000 3500 3000 2500 2000 1500
No. Cases Reported No. Cases Reported 1000 per Million Prescriptions 500 140 0 Fenofibrate Gemfibrozil
Jones PH, et al. Am J Cardiol. 2005;95:120-122. NumberNumber ofof CasesCases ofof RhabdomyolysisRhabdomyolysis inin CombinationCombination TherapyTherapy WithWith Statins*Statins*
10 9 8.6 8 7 6 5 15-Fold Increase 4 3 2 No. Cases Reported
per Million Prescriptions 1 0.58 0 Fenofibrate Gemfibrozil
*Excludes cases involving cerivastatin Jones PH, et al. Am J Cardiol. 2005;95:120-122. RiskRisk ofof AdverseAdverse EventsEvents withwith FibratesFibrates
120 Reviewed adverse events reported to OR 1.24* the United States Food and Drug 100 OR 2.41* Administration (FDA)
80 OR 10.84* Gemfibrozil 60 Fenofibrate
40 OR 0.95 OR 1.78* 20 AERs/One Million Rx AERs/One 0 s is s ty is it R R i it s E E ic s o A A x o y y r to y m n o o M o A j t d a a b M p a e h H R
Alsheikh-Ali, A. et al. Amer J Card 2004;59:935-938 RiskRisk ofof AdverseAdverse EventsEvents withwith FibratesFibrates
100 Cerivastatin Available 80
60 Gemfibrozil 40 Fenofibrate
20 AERs/One Million Rx AERs/One
0 1994 1995 1996 1997 1998 1999 2000 2001 2002 Year
Alsheikh-Ali, A. et al. Amer J Card 2004;59:935-938 EzetimibeEzetimibe -- FenofibrateFenofibrate PharmacokineticPharmacokinetic StudyStudy
) EzetimibeEzetimibe hadhad nono clinicallyclinically significantsignificant effecteffect onon thethe pharmacokineticspharmacokinetics (e.g.(e.g. absorbtionabsorbtion,, metabolismmetabolism andand excretion)excretion) oror pharmacodynamicspharmacodynamics (e.g.(e.g. bindingbinding actionaction ofof thethe drugdrug toto certaincertain receptorsreceptors andand consequentconsequent effectseffects onon CNS,CNS, GIGI tracttract andand otherother CVCV parameters)parameters) ofof fenofibratefenofibrate oror vicevice versaversa..
www.sch-plough.com/news/2001/research/20010521.html EzetimibeEzetimibe -- FenofibrateFenofibrate PharmacokineticPharmacokinetic StudyStudy 32 patients with hypercholesterolemia for 14 days: on strict diet
LDL-C TG (median) HDL-C
0% Mean % Change From Baseline -20%
-30% -32% Placebo Zetia -36%* TriCor *P≤0.03 vs placebo or either drug. Combo FenofibrateFenofibrate –– EzetimibeEzetimibe PharmacodynamicPharmacodynamic andand PharmacokineticPharmacokinetic InteractionInteraction StudyStudy
Placebo (n = 8) Ezetimibe 10 mg (n = 8) Patients have no physical 30 activity and are on a high Fenofibrate 200 mg (n = 8) carbohydrate low fat diet which lowers HDL-C 20 Fenofibrate 200mg + 10 Ezetimibe 10 mg (n = 8)
0
-10
-20
-30
Change from Baseline (%) -40
-50 TC LDL-C HDL-C TG Mean (SE) percentage change from baseline in serum lipids on day 14 following oral administration of fenofibrate monotherapy, ezetimibe monotherapy, fenofibrate-ezetimibe co- administration therapy or placebo once daily to 14 healthy subjects with hypercholesterolemia
Kosoglou T et al. Curr Med Res & Opin 2004;20:1185-1195 FenofibrateFenofibrate –– EzetimibeEzetimibe PharmacodynamicPharmacodynamic andand PharmacokineticPharmacokinetic InteractionInteraction StudyStudy
Placebo (n = 8) 30 Ezetimibe 10 mg (n = 8) Fenofibrate 200 mg (n = 8) Combination therapy 20 produced significantly Fenofibrate 200mg + 10 Ezetimibe 10 mg (n = 8) greater reductions in 0 LDL-C and in small LDL-III -10 Levels of apoCIII were -20 also reduced greater -30 than monotherapy with
Change from Baseline (%) Change from Baseline either drug -40
-50 LDL-C LDL-1 LDL-II LDL-III Large Intermed Small
Kosoglou T et al. Curr Med Res & Opin 2004;20:1185-1195 FenofibrateFenofibrate –– EzetimibeEzetimibe PharmacodynamicPharmacodynamic andand PharmacokineticPharmacokinetic InteractionInteraction StudyStudy
8.0 180 Ezetimibe 10 mg (n = 8) 7.0 160 Fenofibrate 200mg + Ezetimibe 10 mg (n = 8) Ezetimibe 10 mg (n = 8) 6.0 140 Fenofibrate 200mg + 120 5.0 Ezetimibe 10 mg (n = 8)
100 4.0 80 3.0 60 1.0 40 Ezetimibe Conc (ng/ml) 20 1.0 Total Ezetimibe Conc (ng/ml) Total Ezetimibe Conc 0 0 0 4812 16 20 24 0 4 81216 20 24 Time (hr) Time (hr) Mean (+SD) plasma concentration-time profiles of total ezetimibe (ezetimibe + ezetimibe glucuronide) and ezetimibe on day 14 following multiple dose, once-daily oral administration of either ezetimibe alone or co-administered with fenofibrate
Concomitant fenofibrate administered as a 200 mg micronized capsule formulation resulted in a significant (~50%) increase in the steady state total ezetimibe exposure. However, this exposure is probably not clinically important. The increased plasma total ezetimibe appear to be due to an increase in ezetimibe bioavailability rather than inhibition of clearance
Kosoglou T et al. Curr Med Res & Opin 2004;20:1185-1195