Transcript Session 7

Pharmacokinetics and
Drug Interactions
HAIVN
Harvard Medical School AIDS
Initiative in Vietnam
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Learning Objectives
By the end of this session, participants will be
able to:
 Describe 4 components of pharmacokinetics
 Explain importance of the liver’s P450
system in drug metabolism
 Explain how an inducer and an inhibitor
affect the blood level of CYP450 substrates
 Describe the most important drug-drug
interactions
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What is Pharmacokinetics?

The study of how drugs enter,
interact with, and leave the body,
including:
•
•
•
•

Absorption
Distribution
Metabolism
Excretion
Or, “what the body does to the drug”
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Drug Absorption

The movement of a drug from its site
of administration (stomach, vein,
skin, etc.) into the bloodstream
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Factors Affecting Drug
Absorption

Alterations in gastric pH:
• some drugs are absorbed better in an
acidic environment (itraconazole)
• other drugs are absorbed better in a
higher pH environment (ddI)

Presence or absence of food or other
medications:
• Buffered ddI decreases the absorption
of itraconazole, ketoconazole, indinivir
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Drug Distribution

Following absorption or systemic
administration into the bloodstream,
a drug distributes into interstitial and
intracellular fluids and then finally
into the body tissue
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Factors Affecting Drug
Distribution



Cardiac output and blood flow to
organs and tissues
Drug permeability and accumulation
in tissues
Protein binding:
• Protein binding varies among ARVs
• Protein levels may vary between and
within patients
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What is Drug Metabolism?

The process of transforming active
drugs into inactive metabolites that
can be more readily excreted from
the body
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Drug Excretion

Drugs are eliminated from the body
either unchanged or as metabolites:
• Kidney
• Liver-Intestines

Factors affecting drug excretion
include:
• Renal insufficiency and/or failure
• Alkalinization or acidification of urine
• Liver failure
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Summary of Pharmacokinetics
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Role of CYP450 in
Metabolism
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Cytochrome P450 Enzymes



The cytochrome P450 (CYP) enzyme
family is the major enzyme system
involved in drug metabolism
CYP-mediated metabolism occurs
mostly in the liver
CYP3A is the most important enzyme
• responsible for the breakdown and
clearance of the largest number of
drugs including most PIs and NNRTIs
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Drug Effects on CYP450



Activity of CYP450 enzymes can be
affected by many medications
Drugs that affect CYP450 are
categorized as either inducers or
inhibitors
Drugs that are metabolized by
CYP450 (substrates) may be affected
by the presence of an inducer or an
inhibitor
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Examples of CYP450 Inducers
and Inhibitors
Inducers:
• Rifampin
• NVP
• EFV
Inhibitors:
• Ritonavir
• Ketoconazole
• Itraconazole
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Examples of
Common CYP450 Substrates







ARVs: NVP, EFV, LPV/r (Aluvia)
Rifampin
Methadone
Ketoconazole & Itraconazole
Clarithromycin & Erythromycin
Simvastatin & Lovastatin
Birth control pills
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Example: How a CYP450 Inducer
affects Substrates
Inducer
Rifampin
CYP450
• increased
activity of
CYP450
• faster
breakdown and
clearance of
other drugs
Substrates
LPV and other
PIs, NVP, EFV:
• decreased
concentrations
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Example: How a CYP450 Inhibitor
affects Substrates
Inhibitor
Ritonavir
CYP450
• decreased
activity of CYP450
• slower
breakdown and
clearance of other
drugs
Substrates
The 2nd PIs:
•increased &
prolonged
concentrations
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Drug Effects on CYP450
Advantages:
 Use of Ritonavir
(inhibitor) with
another PI leads to:
• higher, prolonged
blood levels
• decreases required
amount of 2nd PI
Disadvantages:
 The use of
Rifampin with
many ARVs leads
to leads to
unacceptably low
blood levels of
these ARVs
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Key Drug Interactions
with ARVs
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Rifampin and HIV Medications

By inducing the CYP450 enzyme,
Rifampin decreases blood levels of:
•
•
•
•
PI
NNRTI (NVP, EFV)
Methadone
Antifungal drugs
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Rifampin and ARV Blood Levels
Finch et al. Arch Intern Med 2002;162:985-92
SQV IDV
Rifampin


NFV
LPV
NVP
EFV




84% 89% 82% 75% 37%
25%
Do not use PIs with Rifampin
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Rifampin and NNRTIs (1)
Rifampin and NVP
 NVP levels
decreased by 2058%
 Clinical significance
of this is debated
 Risk of
hepatotoxicity with
NVP and TB therapy
is also a concern
Rifampin and EFV
 EFV levels
decreased by 26%
 Not felt to have a
significant effect on
clinical outcomes
 MOH guidelines
recommend EFV at
standard dosing
(600 mg/day) when
used with RIF
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Rifampin and NNRTIs (2)



In patients on TB therapy, EFV is the
preferred NNRTI
Patients on NVP at the time of TB
diagnosis should be changed to EFV
if possible
If EFV is not available, not tolerated
or contraindicated, NVP can be used
at standard doses
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Rifampin and LPV/r
RIF decreases LPV levels by > 75%
**Combination should be avoided if
possible
 Patients who require RIF-based TB
therapy and PI-based ART can be
treated with “superboosted” LPV/r

• LPV 400 mg + RTV 400 mg twice daily
• Available by referral to provincial-level
OPC
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Case Study: Hung

Hung, a 26 year old HIV-positive man
presents to HIV OPC
• Has been on ART for about 3 months with
AZT, 3TC, NVP
• Baseline CD4 count was 67; Hb and ALT
normal
• Developed pulmonary TB and was recently
started on TB therapy (RHEZ)


Should his ART regimen be altered?
If so, how and why?
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Antifungals + ARVs: ITRA
Interactive pair
Result
Management
•Monitor closely
(↓ AUC by 61%) •Consider ↑ ITRA
dose
↓ ITRA levels
ITRA + NVP
ITRA + EFV
ITRA + LPV/r
•Monitor closely
↓ ITRA levels •Consider ↑ ITRA
(↓ AUC by 39%) dose
↑ ITRA levels
Limit ITRA to 200
mg/day
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Methadone + ARVs
Source: US Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and
Adolescents, January 10, 2011.
ARV
Effect
EFV
↓ methadone levels
(by 52%)
NVP
↓ methadone levels
(by 41%)
Comment


Can precipitate withdrawal
symptoms
May require increase in
methadone dose
↓ methadone levels • Opioid withdrawal unlikely but
may occur
(by
26
to
53%)
LPV/r
• Usually no adjustment in
methadone required
 Monitor for AZT side effects
↑ AZT levels
AZT
(e.g. anemia)
(by 29-43%)
 Use with caution
↓ ddI levels
 Enteric coated (EC)
ddI
(by up to 50%)
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formulation preferred
Hormonal Contraceptives + ARVs
ARV
Effect on hormonal
contraceptive
EFV
↑ ethinyl estradiol
NVP
↓ ethinyl estradiol 20%
LPV/r
↓ ethinyl estradiol 42%
Comment
Use alternative or
additional methods
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Interactions among NRTIs
NRTI Pair
DDI + D4T
D4T + AZT
TDF + DDI
Results of
Interaction
Recommendation
•Increased toxicities
•Antagonistic effect
(require same enzymes for
intracellular
phosphorylation)
• Increased DDI toxicity
• Loss of CD4 responses
after time
• Suboptimal antiviral
response in regimens
with EFV
Avoid
combination
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How Can You Recognize and
Avoid Drug Interactions?


Review patient’s full medication list at every
visit
Recognize:
• drugs most commonly associated with
interactions (PIs, itraconazole, rifampin, etc.)
• medications with overlapping toxicities
• dietary restrictions with certain medications


Select agents with fewer drug interactions if
clinically appropriate
Simplify drug regimens whenever possible
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Look it Up!
When prescribing a new drug to a patient,
always look it up to make sure there aren’t any
drug interactions
References:
MOH Guidelines for the Diagnosis and Treatment of HIV/AIDS
www.HIV-druginteractions.org
www.AIDSinfo.nih.gov
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Key Points

4 components of pharmacokinetics
• All can affect success of drug therapy

Drug interactions are common when
treating PLHIV
• Many related to effects of the P450 liver
enzymes
• Important to recognize and avoid drug
interactions
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Thank you!
Questions?
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