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 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