Download Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Significant Drug Interactions with
Antiretroviral Drugs
HIV Care and ART: A Course for Pharmacists
Introductory Case: Aida
 Aida, a 25 year-old HIV+ woman, comes to your
pharmacy with prescriptions for her routine therapy of
phenytoin and cotrimoxazole
 Her recent labs indicate that her repeat TLC is 1000
and she is going to begin treatment with ART
 Today she is given prescriptions for the first line
regimen in Ethiopia: nevirapine, lamivudine and
stavudine
2
Introductory Case: Aida (cont.)

Which of the following statements is true about an
interaction between these medications?
1. There is no interaction between antiretroviral drugs and
phenytoin. They can safely be administered together
2. An interaction exists between phenytoin and nevirapine.
The dose of nevirapine must be increased to account for
increased metabolism due to phenytoin
3. An interaction exists between phenytoin and cotrimoxazole.
They should not be administered together
4. Nevirapine may decrease phenytoin levels and therefore
the dose of phenytoin may need to be increased to avoid
loss of seizure control
3
Unit Learning Objectives
 Identify primary drug interaction concepts
 Describe types and mechanisms of interactions
 Identify drug interactions commonly encountered
with antiretroviral drugs
 Describe how to manage known interactions
 Discuss pharmacokinetic enhancement and protease
inhibitor combinations
4
Basic Definitions
 Pharmacokinetic:
 Refers to what the body does
to the drug
 Associated with the length of
time the drug stays in the body
 “LADME” principle
• Liberation
• Absorption
• Distribution
• Metabolism
• Elimination
 Pharmacodynamic:
 Refers to what the drug does
to the body
 Can change the
pharmacological effect of
drugs
 Examples
• Bone marrow toxicity
caused by ganciclovir or
AZT
• Peripheral neuropathy –
ddI, d4T, DDC
• Pancreatitis – ddI,
pentamidine, alcohol
5
Mechanisms for Drug Interactions
 Pharmacokinetic Interactions
 Altered drug absorption and tissue distribution
• Chelation, pH, P-gp (efflux proteins or drug transporters)
 Altered drug metabolism
• Induction/inhibition, GT,P-gp
 Reduced renal excretion (P-gp)
 Altered intracellular activation
• Impairment of phosphorylation (D4T, ZDV)
 The outcome of these interactions could be
additive/synergistic, antagonistic/opposing or potentiation
6
Mechanisms for Drug Interactions (2)
 Pharmacodynamic interactions
 Additive or synergistic interactions
 Antagonistic or opposing interactions
7
First Pass Effect
 Recognize that metabolism can occur in the
intestines, liver or blood
 Route of orally administered drugs:
 Absorbed in the gastrointestinal tract
 Then pass through the portal venous system to the liver
where they are exposed to first pass effect, which may limit
systemic circulation
 Once in the systemic circulation, drugs interact with
receptors in target tissues
8
Refer to enlarged image at end of handout
Drug Metabolism and Elimination
 The goal of metabolism is to change the active form
of drugs
 Making them more water soluble and more readily
excreted by kidney or other organs
 Drug metabolism occurs via two types of reactions:
 Phase I
 Phase II
9
Refer to enlarged image at end of handout
Cytochrome P450 (CYP450)
 >30 isoenzymes identified in
humans
 Present in liver, small
intestines, lungs, and brain
 Primary function is to alter
toxins (drugs) to speed
excretion
 Nomenclature:
Family<subfamily<individual
gene (called isoenzyme)
 Isoenzymes:1A2, 2C9/19,
2D6, 3A4 are primarily
responsible for drug
metabolism
 Also metabolize steroid
hormones, vitamins, toxins,
prostaglandins, fatty acids
 Knowledge of substrates,
inhibitors and inducers helps
predict drug interactions
 Enzyme 3A4 (3 =family, A=
subfamily, 4= isoenzyme)
10
Cytochrome P450 Enzymes
Patient Factors
•Genetics
Outcome of
Drug
Interaction
Drug Factors
•Dose
•Diseases
•Duration
•Diet/Nutrition
•Dosing Times
•Environment
•Sequence
•Smoking
•Route
•Alcohol
Variability
•Dosage Form
Adapted from Philip D. Hansten, 1998, Science & Medicine 5(1): 16-25
11
P450 Drug Interactions
 Substrate
 Medication depends on enzymatic pathway(s) for
metabolism
 Object drug which is affected by inducer or inhibitor
 Inducer
 Speeds up metabolism
 Decreases substrate level (lack of efficacy is concern)
 Gradual onset/offset
 Inhibitor
 Slows metabolism
 Increases substrate level (toxicity is concern)
 Quick onset/offset
12
CYP P450 Drug-Drug Interactions
 Pharmacologic action of drug is altered by
coadministration of second drug
effect (eg. ritonavir + saquinavir;
ritonavir + simvastatin)
Drug B
New effect (eg. ritonavir + amitriptyline)
Drug A
 effect (eg. rifampin + protease
inhibitors, rifampin + coumadin)
No Consequences
13
Cytochrome P450 Caveats
 A potent enzyme inhibitor is
likely to inhibit the
metabolism of ANY drug that
is metabolized by that
enzyme
 Some substrates for a
particular enzyme are also
inhibitors or inducers of that
same enzyme
 Some inhibitors affect more
than one enzyme
 Magnitude of inhibition may
depend upon the dose
 An inhibitor may produce
inhibition of an isozyme at
one dose, but require a
larger dose to inhibit another
isozyme
 Most, but not all, CYP450
inhibitors are eliminated by
the liver
 Enantiomers may be
metabolized by different
enzymes
 Some ARVs have mixed
effect: EFV, LPV/RTV, RTV
14
Pharmacist Beware
 A drug interaction can occur whenever a:




New medication is started
Medication is discontinued
Dose is changed
Drug is changed
 Remember:
 Inducing interactions
• Gradual onset/offset
 Inhibiting interactions
• Quick onset/offset
15
Red Flags for Potential Interactions
 PIs or NNRTIs and






Statins
Ergot alkaloids
Azole antifungals
Antihistamines
Anticonvulsants
Anti-tuberculars
(rifamycins)
 Warfarin
 Benzodiazepines
 Alternative medicine
 Cardiac medicine
• Amiodarone, quinidine
 Oral contraceptives
• Containing estradiol
 Macrolide antibiotics
 Methadone
16
CYP 3A4: Substrates







Alpra-, tria-, mida- zolam
Calcium channel blockers
Carbamazepine
Corticosteroids
Digoxin
Cyclosporine
Methadone
17
CYP 3A4: Substrates (2)







Protease inhibitors
Statins
Amitriptyline
Quinidine
Terfenadine
Pimozide
Many, many more
18
CYP 3A4: Inhibitors








Erythro-, > clarithromycin
Delavirdine
Efavirenz
Fluoxetine
Fluvoxamine
Grapefruit juice
Keto-, itra- > fluconazole
PIs: ritonavir >>> amprenavir, atazanavir, indinavir,
nelfinavir > saquinavir
19
CYP 3A4: Inducers
 Inducers
 Carbamazepine, phenytoin, phenobarbital
 Rifampin, rifabutin, St. John’s wort, garlic
 Efavirenz, nevirapine
20
Introductory Case: Aida (cont.)
1. There is no interaction between ART and phenytoin.
They can safely be administered together
FALSE
The interaction between phenytoin and nevirapine
is unknown. Both drugs are cytochrome P450 3A4
inducers and therefore an interaction can be
anticipated
21
Introductory Case: Aida (cont.)
2. An interaction exists between phenytoin and
nevirapine. The dose of nevirapine must be
increased to account for increased metabolism due
to phenytoin
FALSE
 Phenytoin may decrease the levels of nevirapine,
however, the interaction is unknown
 Levels of nevirapine should not be increased empirically
 If there are no other options for anti-seizure medications
for this patient, and this combination must be used, the
patient should be monitored for loss of virologic control 22
CYP 2C9/19
 Substrates







Diazepam
NSAIDs
Phenobarbital
Phenytoin
Tolbutamide
S-warfarin
Sertaline
 Inhibitors








Ritonavir
Delavirdine
Efavirenz
Cimetidine
Fluoxetine
Fluvoxamine
Omeprazole
TMP/SMX
 Inducers
 Rifampin
 Carbamazepine
 Phenobarbital
23
Refer to enlarged image at end of handout
Introductory Case: Aida (cont.)
3. Part 1: An interaction exists between phenytoin and
Cotrimoxazole
TRUE
3. Part 2: They should not be administered together
FALSE
 Cotrimoxazole is an inhibitor of CYP 2C9 and phenytoin
is a substrate of the same enzyme. The levels of
phenytoin may be increased when Cotrimoxazole is
started (after a few weeks)
 This patient has been taking both medications together
and is stable on therapy. She can continue to receive
these medications together
24
CYP 2D6: Substrates





Amphetamines
Codeine-to-morphine
Encainide, flecainide
Haloperidol
Hydrocodone-tomorphine





Metoprolol, propranolol
Phenothiazines
Risperidone
SSRIs
TCAs (amitriptyline)
25
Refer to enlarged image at end of handout
CYP 2D6: Inhibitors







Ritonavir
Cimetidine
Fluoxetine
Haloperidol
Paroxetine
Quinidine
Methadone
26
PI/ NNRTI/ Antidepressant
Drug Interactions
Antidepressant
Potential for
Interaction
Effects
Management
Amitriptyline
ritonavir,
lopinavir/r,
amprenavir,
Levels of
Start with lower dose
amitriptyline may be (50%) of amitriptyline,
increased
adjust dose when addIng
ritonavir. Monitor for side
effects
Fluoxetine
ritonavir,
Levels of both
lopinavir/r, all other fluoxetine and
PIs, efavirenz
ARVs may be
increased
As above
Sertraline
ritonavir,
Levels of sertraline
lopinavir/r, all other may be increased.
Pis, efavirenz
ARV levels
not likely to change.
As above
27
ARV Interactions with Pain Medication:
Methadone Interactions
 Primarily metabolized by 3A4
 Likelihood for interactions with PIs/NNRTIs is high
 Numerous studies/case reports
 Difficult to determine effect due to long half-life of
methadone and differential effects on inactive S(+)
enantiomer versus active R(-) enantiomer
 Watch for signs of opiate withdrawal
 Methadone may increase zidovudine levels – watch for
increased nausea/vomiting
28
Metabolic Characteristics of ARVs
Source: Antoniuo T. and A.L. Tseng. Annals of Pharmacotherapy 2002:36:1598-61
29
PI: Safer Choices
 Anxiety/insomnia
 Use Diphenhydramine, Temazepam or Oxazepam
 MAI prophylaxis/treatment
 Use Azithromycin
 Antidepressants
 Start low and go slow!
 Amitriptyline: 2D6 and 32A4 substrate
 Fluoxetine and Fluvoxamine: broad CYP450 inhibition
(serotonin syndrome)
 Sertraline: minimal 3A4 inhibition, may be sig.>150 mg/day
30
PI: Safer Choices (2)
 Anticonvulsants
 Use sodium valproate, gabapentin or lamotrigene, if
possible. If use with phenytoin, phenobarbitol, or
carbamazepine, need to monitor antiseizure activity
 Migraine therapy
 Use paracetamol, sumatriptan, or narcotic analgesics
 Antihistamines
 Use loratadine or cetirizine or diphenhydramine
 Rifampicin (only use with adjusted doses of EFZ)
 Rifabutin, if possible
 Requires dose reduction with all PIs and dose increase
with efavirenz
31
Introductory Case: Aida (cont.)
4. Nevirapine may decrease phenytoin levels and
therefore the dose of phenytoin may need to be
increased to avoid loss of seizure control
TRUE


The patient would need to be monitored closely for loss of seizure
control and then the dose would need to be adjusted accordingly by the
physician
The best option would be to gradually switch the patient from phenytoin
to another drug for seizure control, one that does not interact with ART.
Options may include sodium valproate or gabapentin
32
Ritonavir: Do NOT Co-administer
 Antiarrhythmics
 Amiodarone, quinidine




Antihistamines – terfenadine,* astemizole*
Ergot derivatives* (ergotamine)
Herbal Preparations
HMG-CoA Reductase Inhibitors – lovastatin*,
simvastatin*
 Neuroleptic – Pimozide* (Orap)
 Benzodiazepines – midazolam,* triazolam*
 GI – cisapride*
* These drugs must also never be co-administered with any PIs
33
NNRTIs: Do NOT Co-administer
 Ergot derivatives (ergotamine)
 Benzodiazepine: midazolam, triazolam
 Rifampicin (Nevirapine) – unless there is NO
alternative
 Terfenadine (Efavirenz)
 Herbal – St. Johns wort
34
PI and NNRTI Drug Interactions:
Nevirapine (NVP)
 NVP (standard dose) +
 Indinavir (increase IDV to 1000 mg q8h or consider
IDV/RTV)
 Ritonavir (dose RTV standard)
 Saquinavir (use with RTV)
 Nelfinavir (NFV dose standard)
 Amprenavir, fos-Amprenavir (no data)
 Lopinavir/r (use 4 caps bid or 3 tablets bid)
 Atazanavir (no data, most clinicians would use with
ritonavir)
35
PI and NNRTI Drug Interactions:
Efavirenz (EFV)
 EFV (standard dose) +
 Indinavir (increase IDV to 1000 mg q8 or consider
IDV/RTV)
 Ritonavir (dose standard)
 Saquinavir (SQV not recommended as sole PI when used
with EFV- use with RTV)
 Nelfinavir (dose standard)
 Amprenavir (add RTV 200 mg to standard APV of consider
using APV/RTV 450/200 mg
 Fos-Amprenavir (use 1400 mg APV with 300 mg RTV once
daily or 700 mg APV with 100 mg RTV bid
 Atazanavir (use ATV 300 mg with RTV 100 mg qd
 Lopinavir/r (use 4 caps of LPV/r bid or 3 tablets bid)
36
Nucleoside Interaction:
Didanosine and Tenofovir
 ddI alone must be taken on an empty stomach
 TDF can be taken without regard to meals
 The Cmax and AUC of didanosine (buffered
formulation or enteric coated) increased when given
with tenofovir. Increases in didanosine concentrations
could increase risk of adverse events, including
pancreatitis and peripheral neuropathy
 Staggered or simultaneous administration of ddI EC
250mg with TDF, with or without a meal, results in
similar drug exposures to ddI EC 400mg alone
37
Dosing Options for Tenofovir (TDF)
and Didanosine (ddI) Buffered or EC
> 60 kg
< 60 kg
FASTED
(given together) or
STAGGERED ddI
EC given 2 hours
before
FED
(given
simultaneously
with a light meal=
373 kcal, 20%fat)
ddI 250 mg
ddI 250 mg
TDF 300 mg
TDF 300 mg
ddI 200-250 mg
TDF 300mg
ddI 200-250 mg
TDF 300mg
38
Antiretroviral/Food Interactions
Take with food:
 Lopinavir (capsules or
solution):  50-130%
 Saquinavir: 7 fold 
(fatty meal)
 Nelfinavir: 2-3 fold 
 Ritonavir: 15% 
 Itraconazole caps
 Atazanavir 70 % 
 Ganciclovir  up to 5%
 atovaquone 24% 
Avoid food:
 Amprenavir:  23% with
high fat meal (regular food
OK)
 Indinavir: 77%  with high
fat meal (light snack OK)
 ddI: 47%  with meal
 Efavirenz:  79% high fat
meal increases toxicity
 Rifampin: food may  levels
 Itraconazole liquid
 Isoniazid
39
Avoid Antacids
 PIs




Indinavir
(fos)amprenavir
Amprenavir
Atazanavir
 Ketoconazole





Fluoroquinolones
Isoniazid
Dapsone
Zalcitabine
Delavirdine
40
Alternative Medicine
 Some alternative medicine or herbal therapies have
been shown to interact with ART
 Pharmacists and providers must be aware of the
potential interaction should their patient wish to take
alternative medicine
 The interactions may increase or decrease ART
levels leading to either an increase in toxicity or loss
of efficacy
41
Intoxicants
 Drug interactions involving recreational drugs are of
particular concern
 Limited Data







Amphetamine
Ketamine
Marijuana [Tetrahydrocanabinol (THC)]
Alcohol
LSD
Cocaine
Chat
42
Pharmacokinetic Enhancement
Pharmacokinetic Enhancement
 Ritonavir used to
“boost” Cmin and
increase t½ of other
protease inhibitors
 Allows extended dosing
intervals
 Decreases pill burden
 Reduces adverse effects
 May allow salvage in
patients with resistance
and reduced
susceptibility
 Ritonavir (cont)
 Overcomes enzyme
induction caused by other
drugs
 Increase drug exposure
 Remove meal
requirements
 Activity primarily via
inhibition of CYP450 3A4
 May also inhibit MDRPGP efflux pumps
44
Pharmacokinetics Principles
Concentration (ug/mL)
10
Cmax
maximum concentration
correlates with some short-term
side effects, e.g. nausea
8
6
AUC
area under the curve
overall drug exposure
4
2
0
45
2
4
6
8
10
12
Pharmacokinetics Principles (2)
Concentration (ug/mL)
10
Cmin
minimum, or trough concentration
occurs at the end of the dosing interval
correlates with anti-HIV effect for all PIs
8
6
4
2
0
2
4
6
8
10
12
46
Pharmacokinetic Rationale for Dual
Protease Inhibitor Therapy
 When a single PI is used, its peaks may reach well
above the desired concentration for effectiveness
and this may lead to drug toxicity.
 When PIs are used together, you are able to achieve
lower peak levels
 Reduces the chance of side effects
 Achieves higher trough levels, increasing potency and
reducing the chance of viral replication.
47
An Example of Ritonavir Boosting:
Indinavir/Ritonavir BID PK Study
10,000
IDV/RTV q12h:
800/200 High-fat Meal
Indinavir
Plasma
Concentration
(nM)
800/100 High-fat Meal
1,000
400/400 High-fat Meal
IDV q8h:
800 mg Fasted
100
0
2
4
6
8
Time Postdose (hours)
10
12
48
Image used with permission from Saah et al. Antimicrobial Agents and Chemotherapy 2001; 45(10): 2710-15
Indinavir Concentration (µg/mL)
Steady State IDV Plasma Profile after IDV
+ RTV 400 mg Q12H with Food
100
IC90
IDV + RTV 400/400 mg q12h (regular 35%-fat meal)
IDV 800 mg q8h (Fasting)
10
1
0.1
0.01
0
4
8
12
Time (h)
16
20
24
49
Source: Hsu A. et al., 12th Int'l AIDS Conf., Geneva, 1998, Abstract #22361
Dual Protease Inhibitors
 Saquinavir + ritonavir
 SQV 400mg/RTV 400mg BID
 SQV 1000mg/RTV 100mg BID
 SQV 1600mg/RTV 100mg QD
 Indinavir + ritonavir
 IDV 400mg/RTV 400mg BID
 IDV 800mg/RTV 100-200mg
BID
 Amprenavir + ritonavir
 APV 600mg/RTV 100mg BID
 APV 1200mg/RTV 200mg QD
 Lopinavir + ritonavir
 3 Co-formulated capsules BID
or 2 tablets BID
 Atazanavir + ritonavir
 ATV 300mg/RTV 100mg QD
 Fosamprenavir +
ritonavir
 F-APV 700mg/RTV 100mg
BID
 F-APV 1400mg/RTV 200mg
QD
50
The Role of a Pharmacist in
Drug Interactions
 Pharmacists must be knowledgeable about
potential drug-drug, drug-food interactions
 Pharmacists should question a patient about
their current medications whenever filling a
prescription that is new for them
 Patients should be educated that drug
interactions can also occur if they stop or
receive a change in dose of their medications
 Pharmacists should ask patients about their use
of herbal preparations as they can interact with
ARV therapy
51
Drug Interaction Case Studies
Case 1
Case Study: Endalk
 Endalk is 45 year-old HIV+ male presenting for
routine follow-up. He has been on HAART for two
years
 CD4 count: 480 cells/mm3 HIV RNA < 50 copies/mL.
 He comes into your pharmacy after seeing a
physician for his migraines. He is glad to try a new
medication as his headaches have been a problem
for years. He is so distraught about them that he
has begun to take an herbal product to help with his
mood
54
Case Study: Endalk (2)
 You ask him his current medication regimen, which
is:




Nevirapine 200 mg bid
Lamivudine 150mg bid
Zidovudine 300 mg bid
An herbal medicine when he feels “down”
 New medications prescribed today: Ergotamine +
caffeine
55
Case Study: Endalk (3)
1. Which of the following combinations represents a
potential drug-drug interaction?
A.
B.
C.
D.
Nevirapine and herbal medicine
Zidovudine and ergotamine
Ergotamine and nevirapine
Caffeine and zidovudine
56
Case Study: Endalk (4)
 Herbal medicines
 Concomitant use with herbal medicine can decrease
serum levels of NNRTIs.
• e.g. St. John's Wort can increase the oral clearance of
nevirapine (viramune) by 35%
 Sub-therapeutic concentrations are associated with
therapeutic failure, development of viral resistance, and
development of drug class resistance
• e.g. St. John's Wort induces intestinal and hepatic
cytochrome P450 3A4 (CYP3A4) and intestinal Pglycoprotein/MDR-1, a drug transporter
 Avoid use with any NNRTI or PI
57
Case Study: Endalk (5)
2. What would you recommend to Endalk for his
depression?
3. What would you recommend to him for his
migraines?
58
Case 2
Case Study: Sara
 Sara is a 41 year-old female with esophageal
candida and has just completed a 10 day course of
fluconazole. She has lost weight because symptoms
of thrush made it difficult to swallow. She weighs 62
kg. She is to begin ARV therapy today. She comes to
your pharmacy to fill her prescriptions.
60
Case Study: Sara (2)

She presents you with the following:
 Zidovudine 300 mg bid
 Stavudine 40 mg bid
 Nevirapine 200 mg once daily for the first 2 weeks, then
increase to 200 mg bid
 Cotrimoxazole DS, 1 tablet daily
1. Is this an appropriate regimen for her? Can you identify
any possible drug interactions?
61
Case Study: Sara (3)
2. How would you communicate the change that you
recommended to the physician who wrote the
prescription?
3. What would you say to the physician?
62
Case 3
Case Study: Lake
 Lake, a 50 year-old male who has been HIV+ for 5
years and is stable on therapy, presents to the clinic
to get more medication to treat his thrush
 He has been taking his brother’s medication, which
seemed to help at first and then stopped working. He
would like to get some more to clear the white
plaques on his tongue
64
Case Study: Lake (2)
Oral Thrush
65
Case Study: Lake (3)
 His current ARV regimen is:
 Nevirapine 200 mg bid
 Stavudine 40 mg bid
 Lamivudine 150 mg bid
 He has one pill of his brother’s medication left. The
physician brings it to your pharmacy to determine
what medication it is
 You identify the tablet as ketoconazole 200 mg
66
Case Study: Lake (4)
1. Is this an appropriate medication to use with his
current ARV regimen?
2. What are some counseling points for this patient?
67
Case 4
Case Study: Micahel
 Micahel is a 50 year-old male patient who has just
completed 9 months of TB therapy (regimen was
rifampicin and isoniazid along with pyridoxine) 3
weeks ago. He has also been on ARVs (EFV 800
mg qhs, 3TC 150 mg bid and ZDV 300 mg bid)
during this time. He presents with a bloody nose and
bruises on his arm
 Other current medications include:
 Coumadin for atrial fibrillation
 Atenolol for blood pressure
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Case Study: Micahel (2)


What do you suspect has happened?
How should this patient have been counseled
before the TB medication was discontinued?
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Case Study: Micahel (3)

If it is necessary to use enzyme inducers and drugs
that are substrates of those enzymes. Monitor for
altered response if the inducer is initiated,
discontinued, or changed in dosage
3. What other drug interactions should be addressed
today?
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Key Points
 Pharmacokinetic interactions refer to what the body
does to the drug
 Pharmacodynamic interactions refer to what the drug
does to body
 A drug interaction can occur whenever a medication
is started or discontinued or whenever a dose is
changed.
 Pharmacists play a critical role in detecting drug
interactions before they happen
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Key Points (2)
 Pharmacists must be knowledgeable about potential
drug-drug and drug-food interactions
 Pharmacists should question a patient about their
current medications whenever filling a new
prescription, changing dose, or discontinuing a
medication
 Patients should be educated that drug interactions
can also occur if they stop or change a medication or
dose
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Key Points (3)
 Pharmacists should ask patients about their use of
herbal preparations as they can interact with ARV
therapy
 Pharmacokinetic enhancement combines agents
from different classes or various agents from similar
classes to:




Improve ARV pharmacokinetics
Improve adherence
Minimize side effects
Enhance antiviral activity
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