Transcript Antipsychotics in the Pipeline

Drug Interactions
Cara L. Alfaro, Pharm.D.
Clinical Reviewer
Division of Neuropharmacological Drug Products
Food 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 Interactions
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
True incidence difficult to determine
Data for drug-related hospital admissions do not
separate out drug interactions, focus on ADRs
Lack of availability of comprehensive and easy to
access databases
Difficulty in assessing OTC and herbal drug therapy
use
Difficulty in determining contribution of drug
interaction in morbidity of medically complicated
patients
Drug Interactions

Pharmacodynamic
 Related to the drug’s effects in the body


Receptor site occupancy
Pharmacokinetic
 Related to the body’s effects on the drug

Absorption, distribution, metabolism, elimination,
Pharmacodynamic Interactions
Pharmacodynamic Drug Interactions

Additive, synergistic, or antagonistic
effects from co-administration of two or
more drugs
 Synergistic actions of antibiotics
 Overlapping toxicities - ethanol &
benzodiazepines
 Antagonistic effects - anticholinergic
medications (oxybutinin or amitriptyline w/
acetylcholinesterase inhibitors)
Pharmacokinetic Drug Interactions

Alteration in absorption
 Protein binding effects
 Alteration in elimination
 Changes in drug metabolism
Pharmacokinetic
Absorption Interactions
Alterations in Absorption

Administration with food
 For many drugs, decrease rate of absorption
but not extent
 Indinavir - rapidly absorbed in fasted state,
AUC and Cmax decreased by ~80% with high
calorie/fat/protein meal
 Saquinavir - administration with high fat meal
increases AUC by ~570% for this low F drug
(4%)

Patient issues??
Alterations in Absorption

Chelation
 Irreversible binding of drugs in the GI tract
 Tetracyclines, quinolone antibiotics - ferrous sulfate
(Fe+2), antacids (Al+3, Ca+2, Mg+2), dairy products
(Ca+2)

Usually separating administration of chelating
drugs by 2+ hours decreases interaction effect
 Dose tetracycline 1 hour before or 2 hours after dairy
products
Thyroxine and Ferrous Sulfate
Variability of interaction

100
Serum TSH (mU/L)
TSH on stable thyroxine
dose before and after 12
weeks co-ingestion with
300 mg FeSO4
 TSH 1.6 ± 0.4 before
 TSH 5.4 ± 2.8 after
 9/14 had clinical
symptoms of
hypothyroidism
 Thyroxine + FeSO4
invitro - complexation
 Mgmt??
10
1
0.1
0
12
Study Week
Campbell NRC et al. Ann Intern Med 1992;/117:1010-1013
Alterations in Absorption

Alteration in GI motility
 Increased motility - cisapride (R.I.P.), metoclopramide
 Decreased motility - narcotics

Altering GI tract pH
 Increase in GI pH (antacids, omeprazole, cimetidine)
may decrease absorption of drugs which require
acidic pH for optimal absorption such as
ketoconazole and itraconazole
Ketoconazole Cp (mcg/ml)
Ketoconazole Interactions
pH-dependent absorption
8
7
6
5
4
3
2
1
0
Keto
K + Sucral
K + Ranit
0
0.5
1.5
2.5
4
6
Hours
Piscitelli S et al. Antimicrob Agents Chemother 1991;35:1765-1771
12
Pharmacokinetic
Protein Binding Displacement
Interactions
Protein Binding Interactions
“…the overall clinical importance of plasma protein
binding displacement interactions continues to be
overstated…”
“Despite the theoretical and experimental data to the
contrary, the concept that plasma protein binding
displacement is a common cause of clinically significant
interactions may still be widely taught in some medical
schools, often appears in textbooks and is accepted by
many in the medical community and by drug
regulators.”
Sansom LN & Evans AM. Drug Safety 1995;12:227-233.
Rolan PE. Br J Clin Pharmacol 1994;37:125-128.
Protein Binding Interactions

Competition between drugs for protein or tissue
binding sites
 Increase in free (unbound) concentration may lead to
enhanced pharmacological effect
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Many interactions previously thought to be PB
interactions, were found to be primarily
metabolism interactions
 Warfarin - sulfamethoxazole (partially metabolism
interaction)

PB interactions are not usually clinically
significant
Protein Binding Interactions
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Restrictively cleared drugs
 Small fraction of drug extracted during single
passage through the eliminating organ
 CL is directly proportional to fu
 Increase in fu leads to proportional increase in CL and
decrease in Css
 No change in Clu, Cssu will return to predisplacement
value after transient increase

phenytoin and valproic acid; decrease in phenytoin Css and
Cu unchanged
Principles of Clinical Pharmacology, pg 64
Protein Binding Interactions

Nonrestrictively cleared drugs
 Eliminating organ removing most of the drug
being presented to it, including the fraction
bound to plasma proteins
 Increase in fu will not lead to a proportional
increase in CL
Protein Binding Interactions

Drugs for which pure plasma protein binding
displacement interactions will lead to sustained
changes in Cssu
 Extensively bound to plasma proteins
 Nonrestrictively cleared
 Administered by non-oral route


alfentanil, buprenorphine, lidocaine, verapamil
Very few orally administered drugs exhibiting
properties of extensive plasma protein binding,
high hepatic first-pass extraction and narrow
therapeutic index
Pharmacokinetic
Metabolism Interactions
Drug Metabolism Interactions

Drug metabolism inhibited or enhanced by
coadministration of other drugs
 CYP 450 system has been the most extensively
studied
 CYP3A4, CYP2D6, CYP1A2, CYP2B6, CYP2C9,
CYP2C19 and others

Phase 2 metabolic interactions
(glucuronidation, etc.) occur, research in this
area is increasing
CYP 450 Substrates

Metabolism by a single isozyme (predominantly)
 Few examples of clinically used drugs

Desipramine/CYP2D6
 Examples of drugs used primarily in research on
drug interaction potential
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Debrisoquin, sparteine, dextromethorphan, mephenytoin
Metabolism by multiple isozymes
 Most drugs metabolized by more than one isozyme

Imipramine: CYP2D6, CYP1A2, CYP3A4, CYP2C19
 If co-administered with CYP450 inhibitor, some
isozymes may “pick up slack” for inhibited isozyme
Proportion of Drugs Metabolized by
CYP450 Isozymes
CYP2D6
19%
CYP3A4
36%
CYP2C19
CYP2C9
CYP1A2
CYP2E1
CYP2B6 CYP2A6
CYP 450 Inhibitors

Drugs can inhibit a specific CYP even though
they are not metabolized by that isozyme
 Quinidine - most potent CYP2D6 inhibitor but
metabolized primarily by CYP3A4

Drugs which are metabolized by a specific CYP
may not potently inhibit that CYP
 Venlafaxine is metabolized by CYP3A4 but is not a
potent inhibitor of CYP3A4

Determining whether a drug is a substrate or an
inhibitor (or inducer) of a specific CYP are
different questions
Examples of CYP 450
Substrates, Inhibitors, & Inducers
Substrates* Inhibitors
Inducers
CYP3A4
Alprazolam
Lovastatin
Quetiapine
Clarithromycin
Ritonavir
Ketoconazole
Rifampin
Carbamazepine
CYP2D6
Risperidone
Desipramine
Donepezil
Quinidine
Fluoxetine
Paroxetine
None identified
CYP1A2
Clozapine
Theophylline
Caffeine
Fluvoxamine
Cimetidine
Smoking
Omeprazole
Cruciferous veg
*Primary metabolic pathway
CYP 450 Inducers

The “usual suspects”
 Rifampin
 Rifabutin
 Carbamazepine
 Phenobarbital
 Phenytoin
CYP 450 Enzyme Induction

Gradual onset and offset
 Onset - accumulation of inducing agent
and increase in enzyme production
 Offset - elimination of inducing agent and
decay of enzymes
 Results in reduction of plasma
concentration of substrate drugs
CYP 450 Inhibitors

The “usual suspects”
 Cimetidine
 Erythromycin
 Ketoconazole
 Ritonavir
 Fluoxetine, paroxetine (CYP2D6)
 Nefazodone (CYP3A4)
CYP 450 Enzyme Inhibition

Usually by competitive binding to enzyme site
 Onset and offset dependent on the half-life and
time to steady-state of the inhibitor
 Fluoxetine & CYP2D6

Time to maximum interaction effect dependent
on time required for substrate drug to reach
new steady-state
Fluoxetine, Sertraline & Desipramine Interaction
4000
Desipramine AUC
3500
3000
2500
2000
Sertraline
Fluoxetine
1500
1000
500
0
DMI
DMI + SSRI
3 wks
DMI
3 week SSRI washout
Preskorn SH et al. J Clin Psychopharmacol 1994;14:90-98
Review of NDAs
# NMEs increased 2-fold
# DDI studies increased 4.6 fold
600
500
400
# NMEs
# DDIs
300
200
100
0
87 - 91
92 - 97
Marroum PJ et al. Clin Pharmacol Ther 2000;68:280-5
Drug Interaction Studies by
Medical Division 1992-1997
Anti-infectives
13%
Antivirals
15%
Endocrine
13%
< 10%
Pulmonary
Analgesics
GI
Oncology
Reproductive
Cardio-renal
17%
Neuropharmacol
24%
NDAs - Drug Interactions
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Most common single agent drug interactions
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Cimetidine
Digoxin
Antacids
Warfarin
Propranolol
Theophylline
Approaches to drug interaction studies > 1995
focused on mechanism based interactions
 Effects of drugs on specific CYP isozymes
 Predicting drug interactions
Investigating Drug Interaction
Potential of NMEs

cDNA expressed isozymes
 Drug probes (in vivo) - drugs with fairly specific
metabolic pathways
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Dextromethorphan, debrisoquin - CYP2D6
Midazolam - CYP3A4
Caffeine - CYP1A2
Bupropion - CYP2B6
Tolbutamide - CYP2C9
Dextromethorphan
CYP2D6
dextrorphan
Drug Labeling
“An in vitro enzyme inhibition study utilizing
human liver microsomes showed that
ziprasidone had little inhibitory effect on
CYP1A2, CYP2C9, CYP2C19, CYP2D6, and
CYP3A4, and thus would not likely interfere with
the metabolism of drugs primarily metabolized
by these enzymes.
In vivo studies have revealed no effect of
ziprasidone on the pharmacokinetics of
dextromethorphan…”
Drug Withdrawals
Drug Interactions & QT Prolongation
Risk Benefit Analysis
Labeling changes - impact??
Terfenadine
Fexofenadine
(Seldane®)
(Allegra®)
Cisapride
(Propulsid®)
Astemizole
(Hismanal®)
+ Norcisapride?
Norastemizole?
Terfenadine & Ketoconazole Interaction

700
600
500
QTc (ms)
Terf Cp at usual
doses = undetectable
 QT prolongation
correlated to terf Cp
(R2 = 0.6, p = 0.001)
~45 ng/ml = 70 to 110
ms increase in QTc
400
300
200
100
0
Baseline
Terf
Terf +
Keto
Drug Interaction Liability
Risk vs. Benefit Analysis
(Competitive Marketplace Decision too)
Therapeutic
Area
Terfenadine
Astemizole
Mibefradil
(Posicor®)
Ritonavir
(Norvir®)
Fluoxetine
(Prozac®)
Antihistamines
Liability
DDI - QT prolongation
Antihypertensive
CYP3A4 Inhibition - DDIs
(Calcium Channel Blocker) Competitive in class?
HIV Protease Inhibitor
Antidepressant
CYP3A4, CYP2D6
Inhibition - DDIs
CYP2D6 Inhibition - DDIs
Attempted R-fluoxetine
Pharmaceutical Industry
Competitive in Market
CYP1A2 Inhibition
Fluvoxamine & Clozapine Drug Interaction
N = 16, clozapine dose 202 ± 36 mg/day
600
*
Cp (ng/ml)
500
400
§
300
Clozapine
DM-clozapine
200
100
0
Baseline
*p<0.0001 vs. baseline
§p<0.05 vs. baseline
+ Fluvoxamine 50mg
x 14 days
Wetzel H et al. J Clin Psychopharmacol 1998;18:2-9
CYP2D6 Inhibition
Correlation to Paroxetine Cp
log Post Paroxetine DM/DP
1
0
EM
-1
PM
Outlier, 2D6*2 gene duplication
-2
2
R = 0.718 p = 0.008
-3
0.6
0.8
1.0
1.2
1.4
1.6
1.8
log Paroxetine Cp (ng/ml)
Alfaro CL et al. J Clin Pharmacol 2000;40:58-66
Herb - Drug Interactions
Herb-Drug Interactions Limitations

Since not regulated by FDA, safety & efficacy not
required
 Little information available regarding drug interactions

Extrapolation of data to available products difficult
 Independent lab tests many products
(http://www.consumerlabs.com/)
 6/13 SAMe preparations did not pass testing

no detectable SAMe noted in one product
 8/17 valerian preparations did not pass testing


4 - no detectable levels of valerenic acid
4 - 1/2 the amount claimed on the label
St. John’s wort: CYP3A4 Induction Effects
Indinavir
Indinavir + SJW

18
Indinavir Cp (µg/ml)
16
14
12
10
8
6
4
2
0
0
0.5
1
2
3
4
5
Time
Piscitelli SC et al. Lancet 2000;355:547-8
8 normal volunteers
 Indinavir AUC
determined before and
after 14 days SJW 300
mg TID
 Indinavir AUC
decreased by 57 ± 19%
in presence of SJW
Garlic - Saquinavir Interaction

3500
3000
AUC (h*ng/mL)
N = 10 healthy subjects
 Saquinavir 1200 mg TID x
3d - AUC
 Garlic caplets BID x ~3
weeks
 Repeat saquinavir AUC
 Discontinue garlic x 10
days
 Repeat saquinavir AUC
2500
2000
1500
1000
500
0
Saq
Piscitelli S et al. Clin Infect Dis 2002;34:234-238
Saq +
Garlic
Saq
Grapefruit Juice Interactions

Flavinoids in grapefruit juice can inhibit
gastrointestinal CYP3A4 and first pass
metabolism
 Can increase concentrations of various CYP3A4
substrates - esp. those with low F
 Saquinavir AUC increases 50 - 200%
 Benzodiazepines
 Calcium channel blockers

Wide variability - amount of GF juice, timing of
intake and drug dosing, interpatient variability
in CYP3A4 gut activity
Felodipine AUC (nmol*h/L)
Grapefruit Juice & Felodipine
180
160
140
120
100
80
60
40
20
0
*
*
*
*
Control
0
1
4
10
24
Hours After GF Before F Admin
*Sign. Diff from Control
Lundahl J et al. Eur J Clin Pharmacol 1995;49:61-67
Beneficial Drug Interactions

Saquinavir & ritonavir
 Saquinavir poorly absorbed, TID dosing, high pill
burden
 Combination with ritonavir results in 20-fold increase
in Css
 Allows for BID dosing and decreased dose from 1800
mg TID to 400 mg BID

Cyclosporin and ketoconazole
 Clozapine and fluvoxamine??
Recognizing Drug Interactions

High index of suspicion
 Patient’s demonstrating exaggerated toxicity
or drug effects


Patient could also be poor metabolizer of
dependent isozyme
Genotyping may aid in future, but would not pick
up “phenocopy” effects
 Patient’s demonstrating treatment failure or
loss of drug effect

Induction vs. absorption interactions
Evaluation of Drug Interactions

What is the time-course of the interaction
 Immediately or over a period of time


Clozapine and rifampin
Is it a drug class effect
 Cimetidine vs. ranitidine; ketoconazole vs.
fluconazole

Is the interaction clinically significant
 Therapeutic index of drugs, toxicity?, loss of
efficacy?

How should the interaction be managed?
Drug Interaction Resources
Correction to Dr. Flockhart’s website:
http://medicine.iupui.edu/flockhart