Evaluating the Landscape of Statin Drug Interactions with Select Cardiovascular Medications:  What you need to know

Barbara S. Wiggins, Pharm.D., FCCP, FAHA, FNLA, AACC, BCPS (AQ Cardiology), CLSClinical Specialist‐ Cardiology, Medical University of South CarolinaAdjunct Professor,  South Carolina College of PharmacyCharleston, South Carolina

Disclosures

No Conflicts of Interest

Objectives• Review the various type of pharmacokinetic interactions that can occur with medications

• Describe drug interactions that occur with the CYP 450 enzymes and P‐glycoprotein. 

• Discuss specific drug interactions with statins and other lipid lowering agents as well as clinical management

• Review drug interactions with select cardiovascular agents and statins as well as clinical management

Metabolism of Select Statins

Copyright to PharmGKB, with permission by PharmGKB and Stanford University. https://www.pharmgkb.org/pathway/PA145011109

Classifying the Degree of the Interaction

Minor Moderate Severe

AUC 1.2 ‐2 > 2 to 4.9  > 5

Metabolism of Select Statins (CYP 450 Enzymes and P‐glycoprotein)

Statin Bioavail T ½ (hours) Metabolism Pro‐drug P‐Glycoprotein

Pravastatin 17% 1.5‐2 n/a No

Fluvastatin 24% 1 CYP 2C9 No

Lovastatin <5% 2‐3 CYP 3A4 Yes ? Substrate and inhibitor

Simvastatin <5% 2 CYP 3A4 Yes ? Substrate and inhibitor

Atorvastatin 12% 14 CYP 3A4 No ? Substrate and inhibitor

Rosuvastatin 20% 20 Limited 2C9 No

Pitavastatin 51% 12 CYP 2C9,2C8 Yes ? Substrate and inhibitor

Adapted from Corsini et al. Pharmacol Ther 1999;84: 413-428.White CM. J Clin Pharmacol 2002;42:963-970.

N.A. = not availableLog D class = distribution of drug into octanol:water

Clinical Pharmacokinetics of Statins

Parameter Atorva Rosuva Fluva Lova Prava Simva

DistributionFraction bound(%)

80 - 90 88 > 99 > 95 43 - 55 94 - 98

Lipophilic YES NO YES YES NO YES

Log D class 1 to 1.25 -0.25 to -0.5 NA -0.75 to -1.0 1.5 to 1.751 to 1.25

Clinical Pharmacokinetics of Statins

Parameter Atorva Rosuva Fluva Lova Prava Simva

Metabolism

Hepatic extraction (%)

> 70 63 > 68 > 70 46 - 66 78 - 87

Metabolism CYP3A4 CYP2C9, 2C19 (minor)

CYP2C9 CYP3A4 Sulf/Gluc CYP3A4

Systemic metabolites

Active Active Inactive Active Inactive Active

Clearance (L/hr/kg)

0.25 0.63 0.97 0.26 – 1.1 0.81 0.45

Adapted from Corsini et al. Pharmacol Ther 1999;84: 413-428.White CM. J Clin Pharmacol 2002;42:963-970.

Clinical Pharmacokinetics of Statins

Parameter Atorva Rosuva Fluva Lova Prava Simva

Excretion

t ½ (hr) 15 - 30 20.8 0.5 – 2.3 2.9 1.3 – 2.8 2 - 3

Urinary excretion (%)

Negligible 10 6 10 20 13

Fecal excretion (%)

Major route

90 90 83 71 58

Adapted from Corsini et al. Pharmacol Ther 1999;84: 413-428.White CM. J Clin Pharmacol 2002;42:963-970.

Fibrates

Which of the following statins levels is increased the most when combined with Gemfibrozil? 

A. Fluvastatin

B. Atorvastatin

C. Pravastatin

D. Rosuvastatin

Statin/Fibrate Combination Therapy: Pharmacokinetic Interactions

GEMFIBROZIL FENOFIBRATEAtorvastatin in Cmax 1.4 fold  No effect

Simvastatin in Cmax 2‐3 fold No effect

Pravastatin in Cmax 2.02‐fold No effect

Rosuvastatin in Cmax 1.56‐1.88‐fold  No effect

Fluvastatin No effect  No effect 

Lovastatin in Cmax by 2‐3‐fold Not available

Pitavastatin in Cmax by 1.45–fold No effectTriCor [package insert]. Abbott Laboratories. 2004; Kyrklund C et al. Clin Pharmacol Ther. 2001;69:340‐345;Pan WJ et al. J Clin Pharmacol. 2000;40:316‐323; Backman JT et al. Clin Pharmacol Ther. 2000;68:122‐129;

Backman JT et al. Clin Pharmacol Ther. 2002;72:685‐691; Abbott Laboratories. Data on file. 2005;Davidson MH. Am J Cardiol. 2002;90:50K‐60K; Prueksaritanont T et al. Drug Metab Dispos. 2002;30:1280‐1287;

Martin PD et al. Clin Ther. 2003;25:459‐471; Bergman AJ et al. J Clin Pharmacol. 2004;44:1054‐1062

Davidson MH. Am J Cardiol. 2002;90(suppl):50K‐60K.Kyrklund C, et al. Clin Pharmacol Ther. 2001;69:340‐345.

Glucuronidation: Possible Explanation for Fibrate/Statin Interaction

Glucuronidation is a pathway for the elimination of the active hydroxy acid metabolites of atorvastatin, lovastatin, simvastatin, and cerivastatin

Clinical and preclinical studies indicate that gemfibrozil inhibits statin glucuronidation

Fenofibrate appears to have significantly less inhibitory effect on statin glucuronidation, and this may explain the lack of significant drug interaction between fenofibrate and statins

Niacin

Increased risk of skeletal muscle effectsDose of niacin > 1 gram in combination with statins should be avoided

Clinical ImplicationsPertains to “immediate release” niacinER‐ Niacin can be used up to 2 grams daily

Calcium Channel Blockers

Which of the following in correct regarding diltiazem/verapamil and why they interact with statins?A. They are strong inhibitors of CYP3A4 and inducers of P‐glycoproteinB. They are substrates for CYP3A4 and substrates and inducers of P‐glycoproteinC. They are moderate‐to‐weak inhibitors of CYP3A4 and substrates for CYP3A4 and P‐glycoproteinD. They are strong inhibitors of CYP3A4 and substrates for CYP3A4 and P‐glycoprotein

Diltiazem/VerampamilDiltiazem co‐administered with simvastatinC‐max of simvastatin increasedAUC of simvastatin increased by 5 foldElimination t1/2 increased by 2.3 foldDiltiazem co‐administered with lovastatinAUC increased 3.6 foldNo effect of half‐life

Amlodipine

Substrate of CYP3A4Amlodipine 10 mg co‐administered with 80 mg of simvastatin‐ 77% in simvastatin exposure

Calcium Channel Blockers

Statin CCB Increase in AUC

Simvastatin Diltiazem 3.7 fold

Lovastatin Diltiazem 3.6 fold

Simvastatin Verapamil 2.5 fold

Lovastatin Diltiazem 3.6 fold

Simvastatin Amlodipine 1.76 fold

Lovastatin Amlodipine 1.76 fold

Anti‐arrhythmics

Amiodarone/DronedaroneAmiodaroneMetabolized by CYP3A4 and CYP2C8Inhibitor of CYP3A4 and P‐glycoproteinSome level of inhibition of CYP1A2, CYP2C9, CYP2D6DronedaroneMetabolized extensively by CYP3A4Moderate inhibitor of CYP3A4 and CYP2D6Also inhibits P‐glycoprotein

Amiodarone/Dronedarone

AmiodaroneAUC increase of simvastatin by 75%Cmax increase of 75%DronedaroneAUC increase of simvastatin by 4 foldAUC increase of simvastatin acid by 2 fold

Antiarrhythmics

Statin Interacting Agent Increase in AUC

Simvastatin Amiodarone 1.76 fold

Lovastatin Amiodarone 1.76 fold

Simvastatin Dronedarone 3.9 fold

Lovastatin Dronedarone 3.9 fold

Ranolazine

Which of the following in true regarding  ranolazine?

A.  Inhibitor of CYP3A4 and CYP2D6 and inhibitor of P‐glycoproteinB.  Metabolized by CYP3A4 and CYP2D6 and weak inhibitor of CYP3A4C.  Metabolized by CYP3A4 and CYP2D6 and weak inhibitor of CYP2D6D.  Inhibitor of CYP3A4 and CYP2D6 and substrate for P‐glycoprotein

Ranolazine

Metabolized predominately by CYP3A4 and to a lessor extent by CYP2D6Weak inhibitor of CYP3A4Co‐administration with simvastatinApproximately a 50% increase in AUC of simvastatinDoubles Cmax

Anti‐Anginals

Statin Interacting Agent Increase in AUC

Simvastatin Ranolazine 1.86 fold

Antiplatelet Agents

TicagrelorPredominantly metabolized by CYP3A4 and to a lesser extent by CYP3A5Substrate for P‐glycoprotein Weak inhibitor of CYP3A4 and P‐glycoprotein

Ticagrelor

23% increase in AUC of atorvastatin35% increase in Cmax with atovastatin81% increase in Cmax with simvastatin56% increase in AUC of simvastatin

Antiplatelet Agents

Statin Interacting Agent Effect on AUC

Simvastatin Ticagrelor 2‐3 fold

Atorvastatin Ticagrelor 1.36 fold

Lovastatin Ticagrelor 2‐3  fold

Immunosupressive AgentsCyclosporine/TacrolimusExtensively metabolized by hepatic and intestinal CYP3A4Inhibitor and substrate of P‐glycoprotein and OATP‐1B1

SirolimusExtensively metabolized by hepatic and intestinal CYP3A4 and P‐glycoprotein

Immunosupressive AgentsStatin Interacting Agent Effect in AUC

Simvastatin Cyclosporine/everolimus/sirolimus 6‐8 fold

Atorvastatin Cyclosporine/everolimus/sirolimus 6‐15 fold

Lovastatin Cyclosporine/everolimus/sirolimus 5‐10 fold

Fluvastatin Cyclosporine/everolimus/sirolimus 2‐4 fold

Pitavastatin Cyclosporine/everolimus/sirolimus 5 fold

Rosuvastatin Cyclosporine/everolimus/sirolimus 5‐10 fold

Pravastatin Cyclosporine/everolimus/sirolimus 5‐10 fold

Immunosupressive AgentsStatin Interacting Agent Effect in AUC

Simvastatin Tacrolimus 6‐8 fold

Atorvastatin Tacrolimus 6‐15 fold

Lovastatin Tacrolimus 5‐10 fold

Fluvastatin Tacrolimus 2‐4 fold

Pitavastatin Tacrolimus 5 fold

Rosuvastatin Tacrolimus 5‐10 fold

Pravastatin Tacrolimus 5‐10 fold

Summary

Many cardiovascular agents have significant interactions with statinsUnderstanding the magnitude can assist with clinical decision makingHigh intensity statin may not be an option for all patients

Take Home Message

Varying degrees of interactions with statinMost significant occur with simvastatin and lovastatinClinical practice may dictate combinations that are not ideal