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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
top related