Drug Interactions: An Update for 2010

John R. Horn, Pharm.D., FCCP

Professor, Department of Pharmacy

Associate Director Pharmacy Services

University of Washington

Seattle, Washington

Drug Interactions: Risk / Benefit of Coadministration

Is never constant

» Varies with each occurrence

» Patient and drug variables

“Prediction is very

difficult. Especially if it’s

about the future.”

Niels Bohr

Prediction

Factors Influencing Drug

Interaction Outcomes

CLINICAL

OUTCOME

OF DRUG

INTERACTIONS

PATIENT

FACTORSDRUG

FACTORSGenetics

Diseases

Diet/Nutrition

Environment

Smoking

Alcohol

Dose

Duration

Dosing Times

Sequence

Route

Dosage Form

HIGH VARIABILITY Adapted from Hansten.

Science & Medicine. 1998;5:16-25.

Cytochrome P4501A2

• Substrates» Caffeine (Starbucks)

» Clozapine (Clozaril)

» Olanzapine (Zyprexa)

» Tacrine (Cognex)

» Theophylline

» Tizanidine (Zanaflex)

» R-warfarin* (Coumadin)

» Zileuton (Zyflo)

• Inhibitors» Cimetidine (Tagamet)

» Ciprofloxacin (Cipro)

» Enoxacin (Penetrex)

» Erythromycin

» Fluvoxamine (Luvox)

» Mexiletine (Mexitil)

» Tacrine (Cognex)

Hansten and Horn, The Top 100 Drug Interactions, 2010, www.hanstenandhorn.com

Mexiletine - Tizanidine

• 12 subjects took

2 mg tizan alone

and after mexil 50

mg bid for two

days

• Half-life incr from

1.3 to 1.8 hrs

• Mexil inhibits

CYP1A2

Momo K et al. J Clin Pcol 2010;50:331

Cytochrome P4502C9

Substrates» Diclofenac (Voltaren)

» Ibuprofen (Ibuprofen)

» Naproxen (Naprosyn)

» Fluvastatin (Lescol)

» Phenytoin (Dilantin)

» Tolbutamide (Orinase)

» S-warfarin (Coumadin)

Inhibitors» Amiodarone (Cordarone)

» Cimetidine (Tagamet)

» Fluoxetine (Prozac)

» Fluvastatin (Lescol)

» Metronidazole (Flagyl)

» Sulfaphenazole

» TMP/SMX (Bactrim)

» Voriconazole (Vfend)

Hansten and Horn, The Top 100 Drug Interactions, 2010, www.hanstenandhorn.com

Oral Hypoglycemic Agents

Generic Trade CYP Substrate

Chlorpropamide Diabinese 2C9

Glimepiride Amaryl 2C9

Glipizide Glucotrol 2C9

Glyburide DiaBeta 2C9

Tolbutamide Orinase 2C9

Hansten and Horn, The Top 100 Drug Interactions, 2010, www.hanstenandhorn.com

Drug Interactions with Oral Hypoglycemic Agents

Case control study of patients >60 yo taking

glyburide (DiaBeta)

Incidence of hospitalization for hypoglycemia

within 7 days of receiving co-trimoxazole or

amoxicillin

OR for co-trimoxazole 6.6 (4.5-9.7)

OR for amoxicillin 1.5 (0.8-2.9)

Juurlink DN. JAMA.2003;289;1652

Warfarin (Coumadin) +Miscellaneous Anti-infectives

• Many cases of marked in INR and bleeding

reported with anti-infectives that are not known

to inhibit CYP2C9

• Macrolides (eg, erythromycin)

• Quinolones (eg, ciprofloxacin, levofloxacin)

• Azoles antifungals (eg, itraconazole)

• Cephalosporins (without NMTT side chain)

• Penicillins

• Tetracyclines

Warfarin (Coumadin) + Anti-infectives Possible Mechanisms

• Fever: catabolism of clotting factors

• Infection: cytokines (TNF , IL-1, IL-6,

Interferon), that inhibit isozymes (eg. CYP2C9)

• Acute illness: vomiting, diarrhea, decreased

dietary vitamin K

• Reduced bacterial vitamin K in gut

• Inhibition of R-warfarin metabolism by other

CYP450 isozymes (eg, 3A4, 1A2)

Horn JR et al. Pharmacy Times. 2004;70:70

Warfarin and Antibiotics

Case-controlled study of Medicaid patients on warfarin

who had GI bleed while on concurrent antibiotic therapy

Controlled for demographics, diseases, drugs affecting

CYPs 1A2, 3A4 or 2C9, drugs affecting bleeding

All antibiotics (cipro-, levo-, gatifloxacin, cotrimoxazole,

fluconazole, cephalexin, amoxicillin) exhibited elevated

odds ratios vs no exposure

When controlled for cephalexin, only cotrimoxazole

(OR=1.68) and fluconazole (OR 2.09) remained

Schelleman et al. CPT. 2008;84:581

Cytochrome P4503A4

Alfentanil

Alprazolam

Astemizole

Atorvastatin

Ca-Blockers

Carbamazepine

Cerivastatin

Cisapride

Cyclosporine

Diltiazem

Ergotamine

Substrates:

Ethinyl

estradiol

Felodipine

Loratadine

Lovastatin

Midazolam

Quinidine

Simvastatin

Tacrolimus

Terfenadine

Triazolam

Inhibitors:

Amiodarone

Clarithromycin

Cyclosporine

Delavirdine

Diltiazem

Erythromycin

Fluoxetine

Fluvoxamine

Grapefruit

Juice

Indinavir

Itraconazole

Ketoconazole

Mibefradil

Miconazole

Nefazodone

Propoxyphene

Ritonavir

Saquinavir

TAO

Verapamil

Zafirlukast

Hansten and Horn, The Top 100 Drug Interactions, 2010, www.hanstenandhorn.com

CYP3A4 Drug Metabolism: Both Intestine and Liver

small

intestine

Parent

drugMetabolite

CYP3A4

P-Glycoprotein

Intestinal Lumen Portal Vein

LIVER

CYP3A4

Systemic

CirculationAdapted from Hansten.

Science & Medicine. 1998;5:16-25.

Effect of GFJ on Object Drugs vs Bioavailability

0

2

4

6

8

10

12

14

16

18

0 10 20 30 40 50 60 70

Increase in Object Drug AUC

Bioavailability of Object Drug (%)

Horn et al. Pharmacy Times.2006;72:84

Diltiazem + Lovastatin: High Variability in Magnitude

0

200

400

600

800

1000

1 2 3 4 5 6 7 8 9 10 Mean

Lovastatin AUC (% Control)

Azie NE et al. Clin Pharmacol Ther 1998;64:369.

Cytochrome P4502C19

SubstratesCitalopram (Celexa)

Clopidogrel (Plavix)

Diazepam (Valium)

Desmethyldiazepam

Esomeprazole (Nexium)

Lansoprazole (Prevacid)

Omeprazole (Prilosec)

Pantoprazole (Protonix)

Phenytoin (Dilantin)

InhibitorsEsomeprazole (Nexium)

Fluoxetine (Prozac)

Fluvoxamine (Luvox)

Omeprazole (Prilosec)

Voriconazole (Vfend)

Hansten and Horn, The Top 100 Drug Interactions, 2010, www.hanstenandhorn.com

Drug Interaction: Clopidogrel and PPI Properties

Clopidogrel

»Substrate for CYP3A4, 2C19, 1A2, 2B6, p-

gp, others

»Inhibitor of CYP2B6 and 2C19

»Substrate for Carboxylesterase 1

PPIs

»Substrate for CYP2C19, 3A4

»Inhibitor of CYP2C19 (esp omep)

Metabolism of Clopidogrel –In Vitro

Clopidogrel

Active Thiol

CYP2C19 44.9%

CYP1A2 35.8%

CYP2B6 19.4%

Kazui et al. Drug Metab Dispos. 2010;38:92

2-oxo-clopidogrel (inactive)

CYP3A4 39.8%

CYP2B6 32.9%

CYP2C19 20.9%

CYP2C9 3.7%Carboxylesterase 1

Carboxylic Acid

Derivative

(Inactive)

Carboxylic Acid

2-Oxo-Clopidogrel

(Inactive)

Esterase

80%

20%

50% 50%

Are PPIs Competitive Inhibitors of CYP2C19?

PPI Ki (uM) Cmax (uM) Fu (%) Cmaxu (uM)

Omeprazole 2.4-6.2 1-3 3 0.03 – 0.09

Lansoprazole 0.4-0.75 2-5 3 0.06-0.15

Pantoprazole 15-69 5-10 2 0.1-0.2

Rabeprazole 19-21 1-2 4 0.04-0.08

Ki and Cmax from Li etal. Drug Metab Dispos.2004;32:821-7

Clopidogrel and PPIs: Affect on Platelet Activity

1425 pts with CAD and stent placement

PPI (Ome 8.4%, Eso 25.6%, Panto 66%) use for

>7d before procedure

Clopidogrel 600 mg – 75mg/d + ASA 100 mg/d

PPI patients were older, more female, higher rate

of acute coronary syndrome and took fewer

statins. Equal nos of smokers, diabetics, ACEI,

BB, CCBs. No genetics, control for CYP2C19 or

CYP3A4 inhibitors.Zuern etal. Thromb Res. 2010;125:e51

Clopidogrel and PPIs: Affect on Platelet Activity

Maximal (~20 hours after LD) ADP-induced platelet

aggregation (ADP-IPA) was 41.1% and 40.3% for

PPI users and non-users, respectively. p<0.005

Final ADP-IPA 34.0% and 29.8% for PPI users and

non-users, respectively. p<0.001

No differences between PPIs

Poor response to clopid was defined as ADP-IPA

>49.4%, but no data on numbers of pts by Rx group

Zuern etal. Thromb Res. 2010;125:e51

Studies of Clopidogrel & PPIs CVA, AMI, CV-death as Endpoints

Trial Pts Rate

Clopidogrel

%

Rate PPI +

Clopidogrel

%

Difference

%

Pazella

(Aetna)

AMIs over 1yr 2.6 11.4 8.8

Aubert S/P Stent 1yr

Major CV event

21.2 32.5 11.3

Ho S/P ACS –

Mortality or ACS

20.8 29.8 9.0

Juurlink S/P AMI – AMI 90

d

20.6 26.4 5.8

Studies of Clopidogrel & PPIs CVA, AMI, CV-death as Endpoints

Trial Pts Rate

Clopidogrel %

Rate PPI +

Clopidogrel

%

Difference

%

Stanek

(SCAI

abstract)

AMIs over 1yr 17.9 25.1 7.2

Omeprazole 25.1

Esomeprazole 24.9

Pantoprazole 29.2

Lansoprazole 24.3

Effects of Clopidogrel vs PPI-Interaction

Study

Efficacy

Difference Study

Interaction

Difference

Charisma 1.7 Pazella 8.8

Cure 2.1 Aubert 11.3

PCI-CURE 3.8 Ho 9.0

CREDO 3.0 Juurlink 5.8

Stanek 7.2

Average 2.65 8.4

0%

2%

4%

6%

8%

10%

12%

14%

0 100 200 300 400

No PPI PPI

PPI No PPI

CV

death

, M

I or

str

oke

Days

CLOPIDOGREL PPI vs no PPI: Adj HR 0.94, 95% CI 0.80-1.11

PPI use at randomization (n= 4529)

Clopidogrel

Prasugrel

PRASUGREL PPI vs no PPI: Adj HR 1.00, 95% CI 0.84-1.20

TRITON-TIMI 38: Primary CVD Endpoint

by PPI

O’Donoghue ML, Braunwald E, Antman EM, et al. Lancet. 2009.

Clopidogrel – PPI StudiesVariables to Control

Concurrent use of ASA / other platelet inhibitors

Concurrent disease states

Drugs / herbals that are CYP3A4, 3A5, 2C19,

1A2, P-gp inhibitors / inducers (substrates)

Genotype for P-gp, CYP3A5, CYP2C19

Dose and timing of PPI / Clopidogrel

administration

Baseline Co-morbidities in Clopidogrel – PPI Reports

Trial More Patients in PPI or Control Groups

Male Cigs DM MI Lipids CrCl CHF

O’Donoghue C NS NS NS NS PPI NS

Juurlink NS NR PPI NR NR PPI PPI

Ho NS NR PPI PPI NR PPI PPI

Stanek C NR PPI NR PPI PPI PPI

C = Control Group PPI = PPI group

NS = Not significantly different NR = Not reported

Concurrent Drug Use in Clopidogrel – PPI Reports

Trial More Patients in PPI or Control Groups

Beta-

Blockers

Calcium

Chanel

Blockers

Statins ASA ACEI

O’Donoghue NS NR PPI NS NR

Juurlink C PPI C NR

(7-9% Rx)

C

Ho NS NR NS C NS

Stanek NR NR PPI NR NR

C = Control Group PPI = PPI group

NS = Not significantly different NR = Not reported

COGENT: Study Design

Bhatt et al. Transcath Cardiovasc Ther. 2009

Multicenter, international, randomized, double-

blind, double-dummy, placebo-controlled, parallel

group, study of a fixed-dose combination of

clopidogrel (75 mg) and omeprazole (20 mg),

compared with clopidogrel. Started 12/07; Ended

2009 with 3627/5000 enrolled, mean follow-up 133

days.

All patients were to receive enteric coated aspirin

at a dose of 75 to 325 mg

COGENT: Study Design

Bhatt et al. Transcath Cardiovasc Ther. 2009

GI endpoint: Upper GI bleeding, symptomatic gastroduodenal ulcer confirmed by endoscopy or radiography, pain of presumed GI origin with underlying multiple erosive disease confirmed by endoscopy, obstruction, or perforation.

CV endpoint: Composite of cardiovascular death, non-fatal MI, CABG or PCI, or ischemic stroke

COGENT: Outcomes by Treatment Group

CV events:

» Placebo 67/ 1821

» PPI 69/1806 HR = 1.02, NS

GI events:

» Placebo 67/1895

» PPI 38/1878 HR = 0.55, p= 0.007

Bhatt et al. Transcath Cardiovasc Ther. 2009

FDA Drug Safety Information:November 2009

Omeprazole reduces the anti-blood clotting

effect of clopidogrel by almost half when these

two medicines are taken by the same patient.

Separating the dose of clopidogrel and

omeprazole in time will not reduce this drug

interaction.

BMS Clopidogrel – Omeprazole Study

Clopidogrel 300 mg LD followed by 75 mg/d for 4 days

Placebo or Omeprazole 80 mg/d for 5 days

Omep admin concurrently or 12 hours after clopidogrel

Max ADP-induced platelet aggregation intensity –change from baseline (MAI) or VASP platelet reactivity index [Less is better]

BMS Med Info, November, 2009

Estimated Omeprazole Plasma Concentrations, 20 mg vs 80 mg

80 mg

20 mg

Hours

Conc

mg/L

Cytochrome P4502D6

Substrates

» Codeinemorphine

» Desipramine (Norpramin)

» Dextromethorphan

» Haloperidol (Haldol)

» Hydrocodone (Vicodin)

» Metoprolol (Lopressor)

» Thioridazine (Mellaril)

» Tramadol (Ultram)

Inhibitors

» Amiodarone (Cordarone)

» Cimetidine (Tagamet)

» Fluoxetine (Prozac)

» Paroxetine (Paxil)

» Propafenone (Rythmol)

» Propoxyphene (Darvon)

» Quinidine (Quinidex)

» Ritonavir (Norvir)

Hansten and Horn, The Top 100 Drug Interactions, 2010, www.hanstenandhorn.com

Codeine – A Prodrug

Codeine Morphine

% of codeine dose converted to morphine

» PM <0.5%

» EM 2-8%

» UEM 15%

O-Demethylation

CYP2D6

Enzyme Induction

Gradual onset and offset - one to two

weeks or more

Requires increased enzyme production

Offset follows drug elimination

Reduces drug efficacy unless induction of

active metabolite formation

Hansten & Horn, Current Topics in Drug Interactions,

www.hanstenandhorn.com

St. John’s Wort - Simvastatin

St. John’s wort 300 mg or placebo daily x 14 days

10 mg simvastatin on day 14

No effect on pravastatin AUC

0

2

4

6

8

10

12

14

16

Simva Lactone Simva Acid

Placebo

SJW

AUC ng/mL/h

Sugimoto et al. CPT. 2001;70:518

St. John’s Wort and Oral Contraceptives

Estrogens and Progestins are CYP3A4

substrates

St. John’s Wort can increase the metabolism

of OCs

Breakthrough bleeding and unplanned

pregnancy has been reported

Be careful to avoid “wrongful birth” findings

Questions