Drug Interactions Pharm 560 2 October 2002 Philip D. Hansten, PharmD Professor, School of Pharmacy...

Drug InteractionsPharm 560

2 October 2002

Philip D. Hansten, PharmDProfessor, School of Pharmacy

University of Washington

Drugs Removed from the Market Due to Drug-Drug

Interactions•Cerivastatin (Baycol): Rhabdomyolysis

when combined with gemfibrozil•Terfenadine (Seldane): Ventricular

arrhythmias with CYP3A4 inhibitors•Astemizole (Hismanal): Ventricular

arrhythmias with CYP3A4 inhibitors•Cisapride (Propulsid): Ventricular

arrhythmias with CYP3A4 inhibitors•Mebefradil (Posicor): Rhabdomyolysis

when combined with simvastatin

Hospital Admissions due to Drug Interactions in Elderly

(France)•Prospective study of 1000 patients

> 70 yo admitted to geriatric unit

•538 patients exposed to DDIs

•130 patients developed ADIs

•Most common drugs involved were cardiovascular and psychotropic

Doucet J et al. J Am Geriatr Soc. 1996;44:944-948.

Severe Cimetidine Adverse Drug Interactions

Are Rare•VA Hospital switched from ranitidine to

cimetidine as cost-saving measure

•Retrospective study of 4570 patients on cimetidine (10% got interacting drugs)

•Only 4 patients had adverse interactions– 2 theophylline (nausea, vomiting,

arrhythmia)– 1 procainamide (arrhythmia)– 1 warfarin (fatal intracerebral hemorrhage)

Scott MA et al. Am J Health-Syst Pharm. 1999;56:1890-91.

Uncommon Adverse Drug Interactions

For an adverse drug interaction that occurs once in 1000 cases, one would have to study 3000 cases to have a 95% chance of

observing the event.

David Hume (1711-1776)

•Scientific certainty is not possible using induction–“All swans are white.”

•Absence of proof is not proof of absence–“Bigfoot does not exist.”–“Those drugs do not interact.”

NO ADR OBSERVED

Drug A + Drug B

Assessing Drug Interactions Using

Induction

25 Patients

Usual Conclusion: This interaction is not clinically important.

NO ADR OBSERVED

Drug A + Drug B 25

Patients

Correct Conclusion: Available information is insufficient to determine clinical importance.

Assessing Drug Interactions Using

Induction

Prescriber’s Knowledge

Computer Screening

Pharmacist’s Knowledge

Patient Risk Factors

Patient EducationMonitoring

ADR

Drug Interaction Defenses

Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990

Drug Administration

Pharmacogenetics

Drug A +Drug B

Defenses

Prescriber’s KnowledgeComputer Screening

Pharmacist’s Knowledge

Latent Failures

Patient Risk Factors

Patient EducationMonitoring

ADR

A + B

Drug Interactions: “When the Holes Line

Up”

Defenses

Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990

Drug Administration

Prescriber’s Knowledge

Computer Screening

Pharmacist’s Knowledge

Patient Risk Factors

Patient EducationMonitoring

NO ADR

A + B

Drug Interaction Errors

Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990

Drug Administration

NSAIDs + SSRIs: Increased Risk of Bleeding?

• Case-control study of 1651 incident cases compared to 10,000 matched controls

• “The concurrent use of NSAIDs with SSRIs greatly increases risk of upper GI bleeding”

• SSRIs platelet uptake of serotonin

0

2

4

6

8

10

12

14

16Relative Risk

Neither DrugNSAIDSSRINSAID + SSRI

De Abajo FJ et al. Br Med J 1999;319:1106-1109.

1

Clarithromycin (Biaxin)-Induced Digoxin Toxicity

•70 YO woman on digoxin 0.25 mg/day for 4 years started on clarithromycin

•After 4 days, hospitalized with nausea, vomiting, weakness, brown spots in vision, ECG abnormalities

•Serum digoxin = 5.4 ng/mLTrevedi S et al. Ann Intern Med 1998;128:604. Letter

P-glycoprotein (P-gp)

•Efflux pump: exposure to xenobiotics•Found in numerous tissues:

– Intestinal Epithelium– Biliary canaliculi – Renal proximal tubules – Blood-brain barrier – Tumor cells

•Promiscuous: interacts with wide variety of chemical structures

Kovarik JM et al. Clin Pharmacol Ther 1999;66:391-400.

P-Glycoprotein Actively Transports Drugs Out of Cell

Wall

Inside Cell

Cell Wall

Outside CellEntry via passive diffusion

PGP

= Lipophilic Drug

P-glycoprotein Involved in Digoxin

Pharmacokinetics P-glycoprotein protects against

digoxin toxicity by:

•Decreasing G.I. absorption

•Increasing biliary excretion

•Increasing renal tubular secretion

•Decreasing access to the brain

Tanigawara Y. Ther Drug Monit 2000;22:137-140.

Itraconazole Increases Levels of

Methylprednisolone• Randomized

crossover study of 14 subjects, 4 days of itraconazole, then single dose of:– Methylpred. 48mg– Prednisolone 60 mg

• Marked effect on methylprednisolone, but not prednisolone

0

2

4

6

8

Methylprednisolone AUC

Methylprednisolone AloneMethylprednisolone + Itra.

Lebrun-Vignes B. Br J Clin Pharmacol. 2001;51:443-450.

Prescriber’s Knowledge

Computer Screening

Pharmacist’s Knowledge

Patient Risk Factors

Patient EducationMonitoring

NO ADR

A + B

Drug Interaction Errors

Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990

Drug Administration

“Asthma Sufferer Wins $28.6 Million Award” (Seattle Times 9/3/94)

“Asthma Sufferer Wins $28.6 Million Award” (Seattle Times 9/3/94)

•24-year-old man on theophylline went into ER with infection, and the ER physician gave him ciprofloxacin

•Theophylline levels doubled, and he was left with permanent brain damage

•Physician was awarded $22.5 million for “damage to his reputation”

•24-year-old man on theophylline went into ER with infection, and the ER physician gave him ciprofloxacin

•Theophylline levels doubled, and he was left with permanent brain damage

•Physician was awarded $22.5 million for “damage to his reputation”

St. John’s Wort Reduces Simvastatin (Zocor) Levels

• 16 subjects took 10mg simvastatin alone and after St. John’s Wort 900 mg/day X 14 days

• AUC of Simvastatin & its active metabolite substantially reduced

• Induction of CYP3A4 and P-glycoprotein?

• No effect on Pravastatin

0

5

10

15

Simvastatin Alone

Simvastatin + SJ W

Sugimoto K et al. Clin Pharmacol Ther 2001;70:518-24.

Simvastatin Acid AUC

St. John’s Wort Increases CYP3A4 Activity

• 12 subjects took probe drugs with St. John’s Wort 900mg/d X 14d– Caffeine (1A2)– Tolbutamide (2C9)– Dextromethorphan

(2D6)– Midazolam (3A4)

• Only midazolam was affected (PO > IV)

0

10

20

30

40

50

60

70

80

90

100

Serum Midazolam (% Control)

Midazolam AloneMidazolam IVMidazolam PO

Wang Z et al. Clin Pharmacol 2001;70:317-26.

Garlic Supplements Decrease Saquinavir (Invirase) Levels

• 9 subjects took 1200 mg saquinavir TID alone and after garlic capsules BID X 20 days

• Allicin content of garlic capsules confirmed

• Garlic associated with 51% decrease in AUC of saquinavir

0

500

1000

1500

2000

2500

3000

3500

Saquinavir AUC

SaquinavirSaquinavir + Garlic

Piscitelli SC et al. 8th Conf. On Retroviruses, 2001, Abst. 743

Ibuprofen (Advil) Inhibits the Antiplatelet Effects of AspirinIbuprofen (Advil) Inhibits the Antiplatelet Effects of Aspirin

Catella-Lawson F et al. New Engl J Med. 2001;345:1809-17.

• Subjects took 81 mg ASA in AM for 6 days with 3 ibuprofen dosing schedules:– 400 mg 2 hours before ASA ( platelet effect) – 400 mg 2 hours after ASA (No effect on ASA)– 400 mg 2, 7 & 12 h after ASA ( platelet effect)

• Other agents did not reduce platelet effect:– Rofecoxib (Vioxx) 25 mg before or after ASA– Diclofenac DR 75 mg BID (2 & 10 h after ASA)– Acetaminophen 1000 mg before or after ASA

• Subjects took 81 mg ASA in AM for 6 days with 3 ibuprofen dosing schedules:– 400 mg 2 hours before ASA ( platelet effect) – 400 mg 2 hours after ASA (No effect on ASA)– 400 mg 2, 7 & 12 h after ASA ( platelet effect)

• Other agents did not reduce platelet effect:– Rofecoxib (Vioxx) 25 mg before or after ASA– Diclofenac DR 75 mg BID (2 & 10 h after ASA)– Acetaminophen 1000 mg before or after ASA

Prescriber’s Knowledge

Computer Screening

Pharmacist’s Knowledge

Patient Risk Factors

Patient EducationMonitoring

NO ADR

A + B

Drug Interaction Errors

Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990

Drug Administration

Rifampin Markedly Reduces Simvastatin Plasma Levels

• 10 subjects took 40 mg simvastatin alone & after rifampin 600 mg/day for 5 days

• Simvastatin acid AUC decreased by 93%

• No effect on half-life of simvastatin; primary effect on first pass metabolism

0

2

4

6

8

10

12

14

16

18

Simvastatin Acid AUC

Simvastatin AloneSimvastatin + Rifampin

Kyrklund et al. Clin Pharmacol Ther 2000;68:592-597..

Sertraline (Zoloft) Levels Reduced by Enzyme Inducers

(PHT, CBZ)• Sertraline serum

levels compared in 9 patients on phenytoin (PHT) or carbamazepine (CBZ) versus 54 patients on just sertraline

• Concentration/daily dose ratios considerably lower with enzyme inducers

0

20

40

60

80

100

Sertraline Alone

Sertraline + Inducers

Pihlsgard M, Eliasson E. Eur J Clin Pharmacol 2002;57:915-916.

Sertraline C/D Ratio

Cushing’s Syndrome with Ritonavir + Nasal

Fluticasone• 30 YO HIV (+) man on

ritonavir and nasal fluticasone developed Cushingoid facies

• Positive dechallenge and rechallenge

• Similar case reported by Chen (1998)

0

100

200

300

400

500

600

700

Plasma Cortisol

Fluticasone aloneFluticasone + RitonavirFluticasone alone (3 weeks)

Hillebrand-Haverkort et al. AIDS 1999;13:1803.

Fluticazone Susceptible to CYP3A4 Inhibitors?

•Fluticasone metabolized by CYP3A4 to inactive metabolite

•Bioavailability of fluticasone after inhalation = 12 to 26%

•CYP3A4 inhibitors theoretically would increase systemic effects of fluticasone

Prescriber’s Knowledge

Computer Screening

Pharmacist’s Knowledge

Patient Risk Factors

Patient EducationMonitoring

NO ADR

A + B

Drug Interaction Errors

Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990

Drug Administration

Factors Influencing Drug Interaction Outcomes

CLINICALOUTCOMEOF DRUG

INTERACTIONS

PATIENT FACTORS

DRUGADMINISTRATION

Genetics

Diseases

Diet/Nutrition

Environment

Smoking

Alcohol

Dose

Duration

Dosing Times

Sequence

Route

Dosage FormHIGH VARIABILITY

Adapted from Hansten. Science & Medicine. 1998;5:16-25.

Fluconazole (Diflucan) + Warfarin (Coumadin)

0

10

20

30

40

50

60

70

1 2 3 4 5 6 7

% Increase in Pro-Time

mean

Patients

•7 people on warfarin given fluconazole 100 mg daily X 7 d

•Marked increase in the PT response (but high variability)

•No bleeding occurred

Crussell-Porter LL et al. Arch Intern Med 1993;153:102-104.

Fatal Hyperkalemia After Amiloride + ACE Inhibitors

• 5 patients presented to ER with 5 patients presented to ER with severe hyperkalemia (on ACE severe hyperkalemia (on ACE inhibitor with amiloride added 8 to inhibitor with amiloride added 8 to 18 days earlier)18 days earlier)

• All 5 were over 50 & had diabetes All 5 were over 50 & had diabetes and 4 had renal impairmentand 4 had renal impairment

• Potassium levels = 9.4 to 11 mEq/LPotassium levels = 9.4 to 11 mEq/L

• 2 patients died (authors recommend 2 patients died (authors recommend avoiding combination)avoiding combination)

Chiu T-F et al. Ann Emerg Med 1997;30:612-615.

Hyperkalemia Risk Estimates With Various Combinations of

Drugs

0%

20%

40%

60%

80%

100%

Amiloride(Alone)

Amiloride(+ACEI)

Amiloride(+ACEI + K)

Amiloride(+ACEI + K)

Symtomatic

Hyperkalemia

Normal K

Hypokalemia

Patients Predisposed

to Hyperkalemia

** e.g., Diabetes, Renal impairment, High dietary potassium, etc.