Drug InteractionsDrug Interactions

Cara L. Alfaro, Pharm.D.Cara L. Alfaro, Pharm.D.Clinical ReviewerClinical Reviewer

Division of Neuropharmacological Drug ProductsDivision of Neuropharmacological Drug Products

Food and Drug AdministrationFood and Drug Administration

This presentation was prepared by Dr. Alfaro in her private capacity.No official support or endorsement by the FDA is intended or should be inferred.

Incidence of Drug-Drug InteractionsIncidence of Drug-Drug Interactions

True incidence difficult to determineTrue incidence difficult to determine Data for drug-related hospital admissions do not Data for drug-related hospital admissions do not

separate out drug interactions, focus on ADRsseparate out drug interactions, focus on ADRs Lack of availability of comprehensive and easy to Lack of availability of comprehensive and easy to

access databasesaccess databases Difficulty in assessing OTC and herbal drug therapy useDifficulty in assessing OTC and herbal drug therapy use Difficulty in determining contribution of drug interaction Difficulty in determining contribution of drug interaction

in morbidity of medically complicated patientsin morbidity of medically complicated patients

Drug InteractionsDrug Interactions

PharmacodynamicPharmacodynamic Related to the drug’s effects in the bodyRelated to the drug’s effects in the body

Receptor site occupancyReceptor site occupancy

PharmacokineticPharmacokinetic Related to the body’s effects on the drugRelated to the body’s effects on the drug

Absorption, distribution, metabolism, elimination, Absorption, distribution, metabolism, elimination,

Pharmacodynamic InteractionsPharmacodynamic Interactions

Pharmacodynamic Drug InteractionsPharmacodynamic Drug Interactions

Additive, synergistic, or antagonistic Additive, synergistic, or antagonistic effects from co-administration of two or effects from co-administration of two or more drugsmore drugs Synergistic actions of antibioticsSynergistic actions of antibiotics Overlapping toxicities - ethanol & Overlapping toxicities - ethanol &

benzodiazepinesbenzodiazepines Antagonistic effects - anticholinergic Antagonistic effects - anticholinergic

medications (oxybutinin or amitriptyline w/ medications (oxybutinin or amitriptyline w/ acetylcholinesterase inhibitors)acetylcholinesterase inhibitors)

Pharmacokinetic Drug InteractionsPharmacokinetic Drug Interactions

Alteration in absorptionAlteration in absorption Protein binding effectsProtein binding effects Alteration in eliminationAlteration in elimination Changes in drug metabolismChanges in drug metabolism

PharmacokineticPharmacokineticAbsorption InteractionsAbsorption Interactions

Alterations in AbsorptionAlterations in Absorption

Administration with foodAdministration with food For many drugs, decrease rate of absorption For many drugs, decrease rate of absorption

but not extentbut not extent Indinavir - rapidly absorbed in fasted state, Indinavir - rapidly absorbed in fasted state,

AUC and Cmax decreased by ~80% with high AUC and Cmax decreased by ~80% with high calorie/fat/protein mealcalorie/fat/protein meal

Saquinavir - administration with high fat meal Saquinavir - administration with high fat meal increases AUC by ~570% for this low F drug increases AUC by ~570% for this low F drug (4%)(4%) Patient issues??Patient issues??

Alterations in AbsorptionAlterations in Absorption

ChelationChelation Irreversible binding of drugs in the GI tractIrreversible binding of drugs in the GI tract Tetracyclines, quinolone antibiotics - ferrous sulfate Tetracyclines, quinolone antibiotics - ferrous sulfate

(Fe(Fe+2+2), antacids (Al), antacids (Al+3+3, Ca, Ca+2+2, Mg, Mg+2+2), dairy products (Ca), dairy products (Ca+2+2))

Usually separating administration of chelating Usually separating administration of chelating drugs by 2+ hours decreases interaction effectdrugs by 2+ hours decreases interaction effect Dose tetracycline 1 hour before or 2 hours after dairy Dose tetracycline 1 hour before or 2 hours after dairy

productsproducts

Thyroxine and Ferrous SulfateThyroxine and Ferrous Sulfate

TSH on stable thyroxine TSH on stable thyroxine dose before and after 12 dose before and after 12 weeks co-ingestion with weeks co-ingestion with 300 mg FeSO4300 mg FeSO4

TSH 1.6 ± 0.4 beforeTSH 1.6 ± 0.4 before TSH 5.4 ± 2.8 afterTSH 5.4 ± 2.8 after 9/14 had clinical 9/14 had clinical

symptoms of symptoms of hypothyroidismhypothyroidism

Thyroxine + FeSO4 Thyroxine + FeSO4 invitro - complexationinvitro - complexation

Mgmt??Mgmt??

0.1

1

10

100

0 12

Study WeekS

eru

m T

SH

(m

U/L

)

Campbell NRC et al. Ann Intern Med 1992;/117:1010-1013Campbell NRC et al. Ann Intern Med 1992;/117:1010-1013

Variability of interaction

Alterations in AbsorptionAlterations in Absorption

Alteration in GI motilityAlteration in GI motility Increased motility - cisapride (R.I.P.), metoclopramideIncreased motility - cisapride (R.I.P.), metoclopramide Decreased motility - narcoticsDecreased motility - narcotics

Altering GI tract pHAltering GI tract pH Increase in GI pH (antacids, omeprazole, cimetidine) Increase in GI pH (antacids, omeprazole, cimetidine)

may decrease absorption of drugs which require may decrease absorption of drugs which require acidic pH for optimal absorption such as acidic pH for optimal absorption such as ketoconazole and itraconazoleketoconazole and itraconazole

Ketoconazole InteractionsKetoconazole InteractionspH-dependent absorptionpH-dependent absorption

0

1

2

3

4

5

6

7

8

0 0.5 1.5 2.5 4 6 12

Hours

Ket

oco

naz

ole

Cp

(m

cg/m

l)

Keto

K + Sucral

K + Ranit

Piscitelli S et al. Antimicrob Agents Chemother 1991;35:1765-1771Piscitelli S et al. Antimicrob Agents Chemother 1991;35:1765-1771

PharmacokineticPharmacokineticProtein Binding Displacement Protein Binding Displacement

InteractionsInteractions

“…“…the overall clinical importance of plasma protein the overall clinical importance of plasma protein binding displacement interactions continues to be binding displacement interactions continues to be overstated…”overstated…”

““Despite the theoretical and experimental data to the Despite the theoretical and experimental data to the contrary, the concept that plasma protein binding contrary, the concept that plasma protein binding displacement is a common cause of clinically significant displacement is a common cause of clinically significant interactions may still be widely taught in some medical interactions may still be widely taught in some medical schools, often appears in textbooks and is accepted by schools, often appears in textbooks and is accepted by many in the medical community and by drug many in the medical community and by drug regulators.”regulators.”

Protein Binding InteractionsProtein Binding Interactions

Sansom LN & Evans AM. Drug Safety 1995;12:227-233.Rolan PE. Br J Clin Pharmacol 1994;37:125-128.

Protein Binding InteractionsProtein Binding Interactions

Competition between drugs for protein or tissue Competition between drugs for protein or tissue binding sitesbinding sites Increase in free (unbound) concentration may lead to Increase in free (unbound) concentration may lead to

enhanced pharmacological effectenhanced pharmacological effect Many interactions previously thought to be PB Many interactions previously thought to be PB

interactions, were found to be primarily interactions, were found to be primarily metabolism interactionsmetabolism interactions Warfarin - sulfamethoxazole (partially metabolism Warfarin - sulfamethoxazole (partially metabolism

interaction)interaction) PB interactions are not usually clinically PB interactions are not usually clinically

significantsignificant

Restrictively cleared drugsRestrictively cleared drugs Small fraction of drug extracted during single Small fraction of drug extracted during single

passage through the eliminating organpassage through the eliminating organ CL is directly proportional to fCL is directly proportional to fuu

Increase in fIncrease in fuu leads to proportional increase in CL and leads to proportional increase in CL and

decrease in Cssdecrease in Css No change in ClNo change in Cluu, Css, Cssuu will return to predisplacement will return to predisplacement

value after transient increasevalue after transient increase phenytoin and valproic acid; decrease in phenytoin Css and phenytoin and valproic acid; decrease in phenytoin Css and

CCuu unchanged unchanged

Protein Binding InteractionsProtein Binding Interactions

Principles of Clinical Pharmacology, pg 64

Nonrestrictively cleared drugsNonrestrictively cleared drugs Eliminating organ removing most of the drug Eliminating organ removing most of the drug

being presented to it, including the fraction being presented to it, including the fraction bound to plasma proteinsbound to plasma proteins

Increase in fu will not lead to a proportional Increase in fu will not lead to a proportional increase in CLincrease in CL

Protein Binding InteractionsProtein Binding Interactions

Protein Binding InteractionsProtein Binding Interactions

Drugs for which pure plasma protein binding Drugs for which pure plasma protein binding displacement interactions will lead to sustained changes displacement interactions will lead to sustained changes in Cssin Cssuu

Extensively bound to plasma proteinsExtensively bound to plasma proteins Nonrestrictively clearedNonrestrictively cleared Administered by non-oral routeAdministered by non-oral route

alfentanil, buprenorphine, lidocaine, verapamilalfentanil, buprenorphine, lidocaine, verapamil

Very few orally administered drugs exhibiting properties Very few orally administered drugs exhibiting properties of extensive plasma protein binding, high hepatic first-of extensive plasma protein binding, high hepatic first-pass extraction and narrow therapeutic indexpass extraction and narrow therapeutic index

PharmacokineticPharmacokineticMetabolism InteractionsMetabolism Interactions

Drug Metabolism InteractionsDrug Metabolism Interactions

Drug metabolism inhibited or enhanced by Drug metabolism inhibited or enhanced by coadministration of other drugscoadministration of other drugs

CYP 450 system has been the most extensively CYP 450 system has been the most extensively studiedstudied CYP3A4, CYP2D6, CYP1A2, CYP2B6, CYP2C9, CYP3A4, CYP2D6, CYP1A2, CYP2B6, CYP2C9,

CYP2C19 and othersCYP2C19 and others Phase 2 metabolic interactions (glucuronidation, Phase 2 metabolic interactions (glucuronidation,

etc.) occur, research in this area is increasingetc.) occur, research in this area is increasing

CYP 450 SubstratesCYP 450 Substrates Metabolism by a single isozyme (predominantly)Metabolism by a single isozyme (predominantly)

Few examples of clinically used drugsFew examples of clinically used drugs Desipramine/CYP2D6Desipramine/CYP2D6

Examples of drugs used primarily in research on Examples of drugs used primarily in research on drug interaction potentialdrug interaction potential

Debrisoquin, sparteine, dextromethorphan, mephenytoinDebrisoquin, sparteine, dextromethorphan, mephenytoin

Metabolism by multiple isozymesMetabolism by multiple isozymes Most drugs metabolized by more than one isozymeMost drugs metabolized by more than one isozyme

Imipramine: CYP2D6, CYP1A2, CYP3A4, CYP2C19Imipramine: CYP2D6, CYP1A2, CYP3A4, CYP2C19

If co-administered with CYP450 inhibitor, some If co-administered with CYP450 inhibitor, some isozymes may “pick up slack” for inhibited isozymeisozymes may “pick up slack” for inhibited isozyme

Proportion of Drugs Metabolized by Proportion of Drugs Metabolized by CYP450 IsozymesCYP450 Isozymes

CYP3A4CYP3A436%36%

CYP2E1CYP2E1 CYP2B6CYP2B6 CYP2A6CYP2A6

CYP1A2CYP1A2

CYP2D6CYP2D619%19%

CYP2C9CYP2C9

CYP2C19CYP2C19

CYP 450 InhibitorsCYP 450 Inhibitors Drugs can inhibit a specific CYP even though they Drugs can inhibit a specific CYP even though they

are not metabolized by that isozymeare not metabolized by that isozyme Quinidine - most potent CYP2D6 inhibitor but Quinidine - most potent CYP2D6 inhibitor but

metabolized primarily by CYP3A4metabolized primarily by CYP3A4 Drugs which are metabolized by a specific CYP Drugs which are metabolized by a specific CYP

may not may not potentlypotently inhibit that CYP inhibit that CYP Venlafaxine is metabolized by CYP3A4 but is not a Venlafaxine is metabolized by CYP3A4 but is not a

potent inhibitor of CYP3A4potent inhibitor of CYP3A4 Determining whether a drug is a substrate or an Determining whether a drug is a substrate or an

inhibitor (or inducer) of a specific CYP are inhibitor (or inducer) of a specific CYP are different questionsdifferent questions

Examples of CYP 450 Examples of CYP 450 Substrates, Inhibitors, & InducersSubstrates, Inhibitors, & Inducers

Substrates*Substrates* InhibitorsInhibitors InducersInducers

CYP3A4CYP3A4 AlprazolamAlprazolam

LovastatinLovastatin

QuetiapineQuetiapine

ClarithromycinClarithromycin

RitonavirRitonavir

KetoconazoleKetoconazole

RifampinRifampin

CarbamazepineCarbamazepine

CYP2D6CYP2D6 RisperidoneRisperidone

DesipramineDesipramine

DonepezilDonepezil

QuinidineQuinidine

FluoxetineFluoxetine

ParoxetineParoxetine

None identifiedNone identified

CYP1A2CYP1A2 ClozapineClozapine

TheophyllineTheophylline

CaffeineCaffeine

FluvoxamineFluvoxamine

CimetidineCimetidine

SmokingSmoking

OmeprazoleOmeprazole

Cruciferous vegCruciferous veg

*Primary metabolic pathway*Primary metabolic pathway

CYP 450 InducersCYP 450 Inducers

The “usual suspects”The “usual suspects” RifampinRifampin RifabutinRifabutin CarbamazepineCarbamazepine PhenobarbitalPhenobarbital PhenytoinPhenytoin

CYP 450 Enzyme InductionCYP 450 Enzyme Induction

Gradual onset and offsetGradual onset and offset Onset - accumulation of inducing agent Onset - accumulation of inducing agent

and increase in enzyme productionand increase in enzyme production Offset - elimination of inducing agent and Offset - elimination of inducing agent and

decay of enzymesdecay of enzymes Results in reduction of plasma Results in reduction of plasma

concentration of substrate drugsconcentration of substrate drugs

CYP 450 InhibitorsCYP 450 Inhibitors

The “usual suspects”The “usual suspects” CimetidineCimetidine ErythromycinErythromycin KetoconazoleKetoconazole

RitonavirRitonavir Fluoxetine, paroxetine (CYP2D6)Fluoxetine, paroxetine (CYP2D6) Nefazodone (CYP3A4)Nefazodone (CYP3A4)

CYP 450 Enzyme InhibitionCYP 450 Enzyme Inhibition

Usually by competitive binding to enzyme siteUsually by competitive binding to enzyme site Onset and offset dependent on the half-life and Onset and offset dependent on the half-life and

time to steady-state of the inhibitortime to steady-state of the inhibitor Fluoxetine & CYP2D6Fluoxetine & CYP2D6

Time to maximum interaction effect dependent Time to maximum interaction effect dependent on time required for substrate drug to reach new on time required for substrate drug to reach new steady-statesteady-state

Fluoxetine, Sertraline & Desipramine InteractionFluoxetine, Sertraline & Desipramine Interaction

0

500

1000

1500

2000

2500

3000

3500

4000

Des

ipra

min

e A

UC

DMI DMI + SSRI 3 wks

DMI

SertralineFluoxetine

Preskorn SH et al. J Clin Psychopharmacol 1994;14:90-98Preskorn SH et al. J Clin Psychopharmacol 1994;14:90-98

3 week SSRI washout

Review of NDAsReview of NDAs

0

100

200

300

400

500

600

87 - 91 92 - 97

# NMEs

# DDIs

# NMEs increased 2-fold# NMEs increased 2-fold# DDI studies increased 4.6 fold# DDI studies increased 4.6 fold

Marroum PJ et al. Clin Pharmacol Ther 2000;68:280-5Marroum PJ et al. Clin Pharmacol Ther 2000;68:280-5

Drug Interaction Studies by Drug Interaction Studies by Medical Division 1992-1997Medical Division 1992-1997

AntiviralsAntivirals15%15%

Cardio-renalCardio-renal17%17%

EndocrineEndocrine13%13%

NeuropharmacolNeuropharmacol24%24%

Anti-infectivesAnti-infectives13%13%

< 10%< 10%PulmonaryPulmonaryAnalgesicsAnalgesicsGIGIOncologyOncologyReproductiveReproductive

NDAs - Drug InteractionsNDAs - Drug Interactions

Most common single agent drug interactionsMost common single agent drug interactions CimetidineCimetidine DigoxinDigoxin AntacidsAntacids WarfarinWarfarin PropranololPropranolol TheophyllineTheophylline

Approaches to drug interaction studies > 1995 Approaches to drug interaction studies > 1995 focused on mechanism based interactionsfocused on mechanism based interactions Effects of drugs on specific CYP isozymesEffects of drugs on specific CYP isozymes Predicting drug interactionsPredicting drug interactions

Investigating Drug InteractionInvestigating Drug InteractionPotential of NMEsPotential of NMEs

cDNA expressed isozymescDNA expressed isozymes Drug probes (in vivo) - drugs with fairly specific Drug probes (in vivo) - drugs with fairly specific

metabolic pathwaysmetabolic pathways Dextromethorphan, debrisoquin - CYP2D6Dextromethorphan, debrisoquin - CYP2D6 Midazolam - CYP3A4Midazolam - CYP3A4 Caffeine - CYP1A2Caffeine - CYP1A2 Bupropion - CYP2B6Bupropion - CYP2B6 Tolbutamide - CYP2C9Tolbutamide - CYP2C9

DextromethorphanDextromethorphan dextrorphandextrorphanCYP2D6CYP2D6

Drug LabelingDrug Labeling

““An in vitro enzyme inhibition study utilizing An in vitro enzyme inhibition study utilizing human liver microsomes showed that human liver microsomes showed that ziprasidone had little inhibitory effect on ziprasidone had little inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and thus would not likely interfere with CYP3A4, and thus would not likely interfere with the metabolism of drugs primarily metabolized the metabolism of drugs primarily metabolized by these enzymes. by these enzymes. In vivo studies have revealed no effect of In vivo studies have revealed no effect of ziprasidone on the pharmacokinetics of ziprasidone on the pharmacokinetics of dextromethorphan…”dextromethorphan…”

Drug WithdrawalsDrug WithdrawalsDrug Interactions & QT ProlongationDrug Interactions & QT Prolongation

TerfenadineTerfenadine(Seldane®)(Seldane®)

FexofenadineFexofenadine(Allegra®)(Allegra®)

CisaprideCisapride(Propulsid®)(Propulsid®)

AstemizoleAstemizole(Hismanal®)(Hismanal®)

+ Norcisapride?+ Norcisapride?

Norastemizole?Norastemizole?

Risk Benefit AnalysisRisk Benefit Analysis

Labeling changes - impact??Labeling changes - impact??

Terfenadine & Ketoconazole InteractionTerfenadine & Ketoconazole Interaction

Terf Cp at usual Terf Cp at usual doses = undetectabledoses = undetectable

QT prolongation QT prolongation correlated to terf Cp correlated to terf Cp (R(R22 = 0.6, p = 0.001) = 0.6, p = 0.001)

~45 ng/ml = 70 to 110 ~45 ng/ml = 70 to 110 ms increase in QTcms increase in QTc

0

100

200

300

400

500

600

700

QT

c (m

s)

BaselineBaseline TerfTerf Terf +Terf +KetoKeto

Drug Interaction LiabilityDrug Interaction LiabilityRisk vs. Benefit AnalysisRisk vs. Benefit Analysis

(Competitive Marketplace Decision too)(Competitive Marketplace Decision too)

MibefradilMibefradil(Posicor®)(Posicor®)

TerfenadineTerfenadineAstemizoleAstemizole

RitonavirRitonavir(Norvir®)(Norvir®)

FluoxetineFluoxetine(Prozac®)(Prozac®)

TherapeuticTherapeuticAreaArea

AntihistaminesAntihistamines

LiabilityLiability

DDI - QT prolongationDDI - QT prolongation

AntihypertensiveAntihypertensive(Calcium Channel Blocker)(Calcium Channel Blocker)

CYP3A4 Inhibition - DDIsCYP3A4 Inhibition - DDIsCompetitive in class?Competitive in class?

HIV Protease InhibitorHIV Protease Inhibitor CYP3A4, CYP2D6CYP3A4, CYP2D6Inhibition - DDIsInhibition - DDIs

AntidepressantAntidepressant CYP2D6 Inhibition - DDIsCYP2D6 Inhibition - DDIsAttempted R-fluoxetineAttempted R-fluoxetine

DDI - QT prolongationDDI - QT prolongation

CYP3A4CYP3A4 Inhibition - DDIsCompetitive in class?

Pharmaceutical IndustryPharmaceutical IndustryCompetitive in MarketCompetitive in Market

CYP1A2 InhibitionCYP1A2 InhibitionFluvoxamine & Clozapine Drug InteractionFluvoxamine & Clozapine Drug Interaction

0

100

200

300

400

500

600

Baseline + Fluvoxamine 50mg

Cp

(n

g/m

l)

Clozapine

DM-clozapine

Wetzel H et al. J Clin Psychopharmacol 1998;18:2-9Wetzel H et al. J Clin Psychopharmacol 1998;18:2-9

x 14 days*p<0.0001 vs. baseline§p<0.05 vs. baseline

*

§

N = 16, clozapine dose 202 ± 36 mg/day

CYP2D6 InhibitionCYP2D6 InhibitionCorrelation to Paroxetine CpCorrelation to Paroxetine Cp

1.81.61.41.21.00.80.6-3

-2

-1

0

1

log Paroxetine Cp (ng/ml)

log

Post

Paro

xeti

ne D

M/D

P

R = 0.718 p = 0.0082

Alfaro CL et al. J Clin Pharmacol 2000;40:58-66Alfaro CL et al. J Clin Pharmacol 2000;40:58-66

EM

PM

Outlier, 2D6*2 gene duplication

Herb - Drug InteractionsHerb - Drug Interactions

Since not regulated by FDA, safety & efficacy not requiredSince not regulated by FDA, safety & efficacy not required Little information available regarding drug interactionsLittle information available regarding drug interactions

Extrapolation of data to available products difficultExtrapolation of data to available products difficult

Independent lab tests many products (Independent lab tests many products (http://http://www.consumerlabs.comwww.consumerlabs.com//))

6/13 SAMe preparations did not pass testing6/13 SAMe preparations did not pass testing no detectable SAMe noted in one productno detectable SAMe noted in one product

8/17 valerian preparations did not pass testing8/17 valerian preparations did not pass testing 4 - no detectable levels of valerenic acid4 - no detectable levels of valerenic acid 4 - 1/2 the amount claimed on the label4 - 1/2 the amount claimed on the label

Herb-Drug Interactions LimitationsHerb-Drug Interactions Limitations

St. John’s wort: CYP3A4 Induction EffectsSt. John’s wort: CYP3A4 Induction Effects

0

2

4

6

8

10

12

14

16

18

0 0.5 1 2 3 4 5

Time

Ind

inav

ir C

p (

µg

/ml)

Indinavir Indinavir + SJW

Piscitelli SC et al. Lancet 2000;355:547-8

8 normal volunteers8 normal volunteers Indinavir AUC Indinavir AUC

determined before and determined before and after 14 days SJW 300 after 14 days SJW 300 mg TIDmg TID

Indinavir AUC Indinavir AUC decreased by 57 ± 19% decreased by 57 ± 19% in presence of SJWin presence of SJW

Garlic - Saquinavir InteractionGarlic - Saquinavir Interaction

N = 10 healthy subjectsN = 10 healthy subjects Saquinavir 1200 mg TID x Saquinavir 1200 mg TID x

3d - AUC3d - AUC Garlic caplets BID x ~3 Garlic caplets BID x ~3

weeksweeks Repeat saquinavir AUCRepeat saquinavir AUC Discontinue garlic x 10 Discontinue garlic x 10

daysdays Repeat saquinavir AUCRepeat saquinavir AUC 0

500

1000

1500

2000

2500

3000

3500

AU

C (

h*n

g/m

L)

Saq SaqSaq +Garlic

Piscitelli S et al. Clin Infect Dis 2002;34:234-238Piscitelli S et al. Clin Infect Dis 2002;34:234-238

Grapefruit Juice InteractionsGrapefruit Juice Interactions Flavinoids in grapefruit juice can inhibit Flavinoids in grapefruit juice can inhibit

gastrointestinal CYP3A4 and first pass metabolismgastrointestinal CYP3A4 and first pass metabolism Can increase concentrations of various CYP3A4 Can increase concentrations of various CYP3A4

substrates - esp. those with low Fsubstrates - esp. those with low F Saquinavir AUC increases 50 - 200%Saquinavir AUC increases 50 - 200% BenzodiazepinesBenzodiazepines Calcium channel blockersCalcium channel blockers

Wide variability - amount of GF juice, timing of Wide variability - amount of GF juice, timing of intake and drug dosing, interpatient variability in intake and drug dosing, interpatient variability in CYP3A4 gut activityCYP3A4 gut activity

Grapefruit Juice & FelodipineGrapefruit Juice & Felodipine

Lundahl J et al. Eur J Clin Pharmacol 1995;49:61-67Lundahl J et al. Eur J Clin Pharmacol 1995;49:61-67

0

20

40

60

80

100

120

140

160

180

Hours After GF Before F Admin

Fel

od

ipin

e A

UC

(n

mo

l*h

/L)

Control 0 101 244

* * **

*Sign. Diff from Control*Sign. Diff from Control

Beneficial Drug InteractionsBeneficial Drug Interactions

Saquinavir & ritonavirSaquinavir & ritonavir Saquinavir poorly absorbed, TID dosing, high pill Saquinavir poorly absorbed, TID dosing, high pill

burdenburden Combination with ritonavir results in 20-fold increase Combination with ritonavir results in 20-fold increase

in Cssin Css Allows for BID dosing and decreased dose from 1800 Allows for BID dosing and decreased dose from 1800

mg TID to 400 mg BIDmg TID to 400 mg BID Cyclosporin and ketoconazoleCyclosporin and ketoconazole Clozapine and fluvoxamine??Clozapine and fluvoxamine??

Recognizing Drug InteractionsRecognizing Drug Interactions

High index of suspicionHigh index of suspicion Patient’s demonstrating exaggerated toxicity or Patient’s demonstrating exaggerated toxicity or

drug effectsdrug effects Patient could also be poor metabolizer of dependent Patient could also be poor metabolizer of dependent

isozymeisozyme Genotyping may aid in future, but would not pick up Genotyping may aid in future, but would not pick up

“phenocopy” effects“phenocopy” effects

Patient’s demonstrating treatment failure or loss Patient’s demonstrating treatment failure or loss of drug effectof drug effect Induction vs. absorption interactionsInduction vs. absorption interactions

Evaluation of Drug InteractionsEvaluation of Drug Interactions

What is the time-course of the interactionWhat is the time-course of the interaction Immediately or over a period of timeImmediately or over a period of time

Clozapine and rifampinClozapine and rifampin

Is it a drug class effectIs it a drug class effect Cimetidine vs. ranitidine; ketoconazole vs. Cimetidine vs. ranitidine; ketoconazole vs.

fluconazolefluconazole Is the interaction clinically significantIs the interaction clinically significant

Therapeutic index of drugs, toxicity?, loss of Therapeutic index of drugs, toxicity?, loss of efficacy?efficacy?

How should the interaction be managed?How should the interaction be managed?

Drug Interaction ResourcesDrug Interaction Resources

Correction to Dr. Flockhart’s website:Correction to Dr. Flockhart’s website:

http://medicine.iupui.edu/flockharthttp://medicine.iupui.edu/flockhart