Drug-Drug Interactions

Jim Hoehns, Pharm.D.

Objectives

Identify mechanisms for specific clinically relevant drug interactions

Identify methods to predict and prevent drug interactions

Recognize common inducers and inhibitors of CYP450 interactions

Drug Interactions

Pharmacokinetic One drug alters the kinetic properties of another

• Absorption• Distribution• Metabolism• Elimination

Pharmacodynamic One drug alters the sensitivity or responsiveness of

tissues to another

Question

A patient has the following meds. Her doctor wants to start calcium carbonate 500mg BID Synthroid 0.1 mg QD Metoprolol 50 mg BID Procardia XL 60 mg QD

Any drug-drug interaction concerns?

Calcium and Levothyroxine

20 patients with hypothyroidism

Added 1200mg calcium QAM with Synthroid

13/20 pts had reduced free T4

13/20 pts had increased TSH

4 pts had TSH >nl range

0

0.5

1

1.5

2

2.5

3

Baseline Month 3 End

Free T4 TSH

Calcium added

JAMA 2000;283:2822-2825.

Mechanisms - GI Absorption

Drug binding in GI tractformation of insoluble complexes

• iron salts: tetracyclines, Sinemet• antacids/Carafate: quinolone antimicrobials• Questran/Colestid: Coumadin, Synthroid,

Lanoxin

ALENDRONATE: EFFECT OF FOOD ON ORAL BIOAVAILABILITY

1.0

0.90.80.7

0.60.50.4

0.30.2

0.10.0

2 hBefore

Breakfast

1/2 hBefore

Breakfast

<0.11

2 hAfter

Breakfast

<0.11

Time of Dose(after overnight fast)

Bio

avai

lab

ilit

y(%

)

1 hBefore

Breakfast

WithBreakfast

0.460.46

0.76

Gertz BJ et al. Clin Pharmacol Ther. 1995;58:288-298.

Mechanisms - GI Absorption

Effects on intestinal floradigoxin and erythromycin/Biaxin? oral contraceptives and oral antibiotics

Drug metabolism within intestinal wallCYP3A4 is abundant in intestinal epithelium

Avoidance of GI drug interactionsadjustment of dosing times

Question

A patient is on the following meds. His doctor wants to start Glucophage 500mg BID. Cimetidine 400 mg BID ASA 325 mg QD Terazosin 10 mg QD Imdur 60 mg QD

Any drug-drug interaction concerns?

Mechanisms - Drug Excretion Interactions

Active tubular secretionacidic drugs

• probenecid (Benemid) and penicillins/cephalosporins

• probenecid and methotrexate• thiazide diuretics and lithium

basic drugs• quinidine and Lanoxin• cimetidine and procainamide (Pronestyl)• trimethoprim

Question

A patient has the following meds. Her doctor wants to start Rifampin 600 mg QD and INH 300 mg QD for TB. Trazodone 50 mg QHS Prozac 20 mg QD Ortho Tri-Cyclen 1 tab QD

Any drug-drug interaction concerns?

Mechanisms - Enzyme Induction

Increased hepatic P450 enzymes Examples

barbiturates: phenobarbitalTegretol (carbamazepine) or Dilantinrifampincigarette smoking, St. John’s wort

Characteristicstime course: gradualdose dependency

Cytochrome P450 Superfamily

CYP 2 D 6

root termfamily subfamily

individualenzyme

Terminology

Cytochrome P450 Superfamily

C Y P 1A 2

C Y P 1

E M s P M s

C Y P 2D 6 C Y P 2C 9

E M s P M s

C Y P 2C 19

C Y P 2

C Y P 3A 3/4

C Y P 3

C ytochrom e P 450

Shimada T et al. J Pharmacol Exp Ther 1994;270(1):414.

CYP3A

CYP2D6

CYP2C

CYP1A2CYP2E1

Relative Importance ofP450s in Drug Metabolism

CYP3A

CYP2C

CYP1A2

CYP2E1

?

CYP2D6

Relative Quantities of P450s in Liver

CYP450

CYP Genetic Variation

CYP2D6 Absent in 7% of Caucasians; 1-2% non-Caucasians

CYP2C9 Absent in 1% Caucasians & African-Americans

CYP2C19 Absent in 20-30% Asians; 3-5% Caucasians

Drugs That Decrease the Effectiveness of OCs

American College of Obstetrics and Gynecology Practice Bulletin Number 18, July 2000

Anticonvulsants Barbiturates

(including phenobarbital and primidone)

Phenytoin Carbamazepine Topiramate Vigabatin

Anti-infectives Rifampin Griseofulvin

www.contraceptiononline.org

Drugs That Do Not Decrease the Effectiveness of OCs

American College of Obstetrics and Gynecology Practice Bulletin Number 18, July 2000

Anti-infectives Tetracycline Doxycycline Ampicillin Metrondiazole Quinolone

antibiotics

www.contraceptiononline.org

Question

A patient has the following meds. His doctor wants to start Sporanox pulse therapy for onychomycosis. Atenolol 50 mg QD Ativan 1mg BID Felodipine 20mg QD

Any drug-drug interaction concerns?

Mechanisms - Enzyme Inhibition

Inhibition of hepatic P450 activity Most common drug-drug interaction Characteristics

time course: maximum inhibition in 24 hrsdose dependencyspecificity

CYP2D6

CYP3A3/4

Mechanisms - Enzyme Inhibition

CYP3A inhibitorsDiltiazemVerapamilItraconazoleKetoconazoleClarithromycinErythromycinGrapefruit juice

CYP2D6 inhibitors Clomipramine Quinidine Fluoxetine Haloperidol Paroxetine

CYP2C9 inhibitors Amiodarone Fluconazole

Substrates, Inhibitors & Inducers

CYP Substrate Inhibitor Inducer

2C9 warfarin fluconazole, amiodarone

rifampin

2C19 omeprazole, lansoprazole, pantoprazole

omeprazole, fluvoxamine

rifampin

2D6 desipramine paroxetine, fluoxetine

none identified

3A4/3A5 midazolam, buspirone, felodipine, lovastatin,

simvastatin, sildenafil

atazanavir, clarithromycin,

indinavir, itraconazole, ketoconazole,

ritonavir

rifampin, carbamazepine

fda.gov

CYP3A Inhibitors

Strong CYP3A Inhibitors

Moderate CYP3A Inhibitors

Weak CYP3A Inhibitors

≥ 5-fold increase in AUC ≥2, but ≤ 5-fold increase in AUC

≥1.25, but < 2-fold increase in AUC

atazanavir, clarithromycin, indinavir,

itraconazole, ketoconazole,

nefazodone, nelfinavir, ritonavir, telithromycin

diltiazem, erythromycin, fluconazole, grapefruit

juice, verapamil

cimetidine

fda.gov

Case #5

72 y.o. male with HIV, Afib, CAD, and hyperlipidemia presents with pain, fatigue, and dark orange urine X3 days.

Labs: CK 66,680 U/L BUN 93 mg/dL Creatinine 4.6 mg/dL AST 1,579 U/L ALT 738 U/L

Dx: rhabdomyolysis Treatment: hydration and dialysis X 1 month

Case #5

Meds Simvastatin 80mg/d (27 days prior) Amiodarone 200mg/d (19 days prior) Atazanavir 400mg/d (>2 yrs) Stavudine 40mg BID Delavirdine 600mg BID Imdur 60mg BID Plavix 75mg QD Lopressor 50mg BID Hytrin 5mg QHS Pepcid 20mg BID

Simvastatin Label Update

Interacting Drug Previous Label Updated Label

Strong 3A4 inhibitors (e.g. itraconazole, keto, posaconazole HIV protease inhibitors, erythromycin, clarithromycin)

Avoid Contraindicated; posaconazole added to list of examples

Gemfibrozil, cyclosporine, danazol

Do not exceed 10mg simvastatin daily

Contraindicated

Amiodarone, verapamil Do not exceed 20mg simvastatin daily

Do not exceed 10mg simvastatin daily

Diltiazem Do not exceed 40mg simvastatin daily

Do not exceed 10mg simvastatin daily

Amlodipine, ranolazine No dose cap Do not exceed 20mg simvastatin daily

FDA Early Communication

“The FDA is aware of published reports that clopidogrel (marketed as Plavix) is less effective in some patients than it is in others. Differences in effectiveness may be due to genetic differences in the way the body metabolizes clopidogrel, or that using certain drugs with clopidogrel can interfere with how the body metabolizes clopidogrel.”

January 26, 2009

CYP2C19 Variants

White(n=1356)

Black (n=966)

Chinese (n=573)

Extensive metabolism2C19*1/*1

74 66 38

Intermediate metabolism2C19*1/*2 or *1/*3

26 29 50

Poor metabolism2C19*2/*2, *2/*3 or *3/*3

2 4 14

CYP2C19 Phenotype and Genotype Frequency (%)

Clopidogrel + PPI Controversy

Where are we now? COGENT: only RCT to compare PPI with clopidogrel

in patients taking clopidogrel• Summary: No concern for interaction

Considerations Confounding may have contributed to cohort study

findings of interactions with PPIs Did COGENT have adequate power? Is this controversy now over?

No need to modify PPI regimens in patients receiving clopidogrel at this time?

Warfarin

Increased INR Metronidazole Sulfamethoxazole Amiodarone Cimetidine Fluconazole Erythromycin Voriconazole

Decreased INR Phenobarbital Rifampin Carbamazepine Phenytoin Cholestyramine St. John’s wort

Patient Case #3

72 y.o. male (FPC patient)Coumadin 10 mg QD (goal INR 2.5-3.5)erythromycin 250 mg TID (bronchitis)4 days later

• epistaxis, ecchymosis, hematuria• INR = 55.4• vitamin K (phytonadione) given

Patient Case #4

61 y.o. femalemedications:

• lithium 300 mg QD, Nardil 15 mg TID, Sinequan 75 mg QD, Mellaril 50 mg QD, & others

Zoloft 100 mg QD startedwithin 3 hours of first dose:

• semi-comatose, T 41 C, BP 140/110, HR 154, RR 40

ER treatment: ice-packs, dantrolene, Versed and Valium• 3 days later patient was extubated

Serotonin syndrome

Summary

Understand common mechanisms Know the “red flag” drugs

Inhibitors• Oral antifungals, Biaxin, Emycin, Prozac, Paxil,

AmiodaroneInducers

• Rifampin, Tegretol, Dilantin, Phenobarbital, St. John’s wort

Special caution for narrow therapeutic index drugs digoxin, warfarin, lithium, Synthroid

Websites

www.drug-interactions.org www.torsades.org www.arizonacert.org

Inducer or Inhibitor?

ErythromycinItraconazoleCarbamazepineRifampinPhenytoinFluoxetineAmiodaroneSt. John’s WortPhenobarbitalFluvoxamine

DI Questions

A 47 y.o. female is newly diagnosed with PE while an inpatient. Her BMI is 58. She is on rifampin 450mg BID and Bactrim DS 1 BID for MRSA infection after hip arthroplasty. What might we anticipate about her warfarin dosage requirement?

A 77 y.o. female with Afib now has UTI. Her most recent INR was 3.0. Now MD prescribed Cipro 250mg BID x 14 days. Current warfarin dose is: 2mg M,W,F,Sat and 3 mg all other days. Plan?

Patient Case 1

A 25 y.o. female saw her physician and was diagnosed with a sinus infection. He prescribed a Zpak.

PMedHx: Morbid obesity, depression, headaches

Meds: Citalopram 20mg QD, Implanon, Ibuprofen 600mg PRN

Patient Case 2

87 y.o. male presents with Rx for Levaquin 500mg QD x 7 days for UTI. He has also been treated for Cdiff colitis recently and has lost 25 lbs over the past 2 months.

PMedHx: Afib, lymphoma, polymyalgia rheumatica, osteoporosis

Meds: amiodarone 200mg QD, aspirin 81mg QD, prednisone 10mg QD

Allergies: Sulfa