Transcript Session 7 - Teaching Slides

Antiretrovirals III:
Pharmacokinetics and Drug
Interactions
HAIVN
Harvard Medical School AIDS Initiative
in Vietnam
Learning Objectives
At the end of this presentation, participants will
be able to:
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Name the 4 components of pharmacokinetics.
Describe the importance of the liver’s P450
system in drug metabolism.
Name one P450 drug inducer and two P450 drug
inhibitors.
Describe the affect Rifampin has on NVP and
EFV blood levels.
Describe the affect Rifampin has on Protease
Inhibitor (PI) blood levels.
Name 2 different NRTI pairs that should not be
prescribed because of drug interactions.
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Outline of Talk

Review of Pharmacokinetics and factors
affecting drug absorption, distribution,
metabolism, and excretion

Review significance of the cytochrome
P450 enzyme system

Highlight important drug interactions in
HIV care
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Pharmacokinetics –
Definition

The study of how drugs enter, interact
with, and leave the body, including:
Absorption
 Distribution
 Metabolism
 Excretion

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Or, “what the body does to the drug”
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Drug Absorption
Definition the movement of a drug from its site of
administration (stomach, vein, skin)
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, Ketoconazole, Indinivir,
Atazanavir)
–
–
–

AIDS patients have low gastric acid production
avoid antacids
other drugs are absorbed better in a higher pH
environment (DDI)
Presence or absence of other medications
–
DDI decreases the absorption of itraconazole,
ketoconazole, indinivir (separate administration by
at least 1 hour)
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Drug Distribution
Definition –
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
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Cardiac output and blood flow to organs and tissues

Drug permeability and accumulation in tissues
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Protein binding
– Most HIV drugs bind to alpha-1 acid glycoprotein or
albumin
– Protein binding varies among ARVs
–
–
–
–
NRTIs (except ABC): < 25%
ABC, NVP, IDV: 50-60%
EFV, other PIs: >98%
Protein levels may vary between and within patients
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Drug Metabolism
Definition –

The process of transforming active
drugs into inactive metabolites that can
be more readily excreted from the body.
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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 and is
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

The activity of the CYP450 enzymes can be
affected by many medications.
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Drugs that affect CYP450 are categorized as
either inducers or inhibitors.
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CYP450 Inducers
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Inducers lead to
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increased activity of CYP450
faster breakdown and clearance of other drugs
decreased concentrations of other drugs
Important enzyme inducers include:
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Rifampin
NVP
EFV
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CYP450 Inhibitors
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Inhibitors lead to
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decreased activity of CYP450
slower breakdown and clearance of other
drugs
increased and prolonged concentrations of
other drugs
Important enzyme inhibitors include:
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Ritonavir
Ketoconazole
Itraconazole
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CYP450 Substrates
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Drugs that are metabolized by CYP450 (substrates)
may be affected by the presence of an inducer or an
inhibitor.
Common drugs metabolized by CYP450 include:
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NVP
EFV
LPV/r (Aluvia)
Rifampin
Methadone
Ketoconazole
Itraconazole
Clarithromycin & Erythromycin
Simvastatin & Lovastatin
Birth control pills
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Drug effects on CYP450

Advantages : The use of the protease
inhibitor (PI), Ritonavir (inhibitor) can be used
with a second PI to slow down the 2nd PI’s
breakdown and clearance. This leads to
higher, prolonged blood levels and, decreases
the required amount of the 2nd PI.

Disadvantages : The use of Rifampin
(inducer) with many ARVs leads to faster
breakdown and clearance of these drugs, with
unacceptably low blood levels.
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Drug Excretion
Definition 
Drugs are eliminated from the body either
unchanged or as metabolites.
–
–
Kidney - most important organ for drug
excretion
Liver-Intestines - substances excreted in
the feces are principally unabsorbed orally
ingested drugs or drug metabolites excreted
either in the bile or secreted directly into the
intestinal tract.
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Factors Affecting Drug
Excretion

Renal insufficiency and/or failure

Alkalinization or acidification of urine

Liver failure
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Key Drug Interactions with
and within ARVs
Rifampin and HIV medications
By inducing the Cytochrome P450 enzyme,
Rifampin decreases blood levels of:
 PI
 NNRTI
(NVP, EFV)
 Methadone
 Antifungal
Drugs
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Rifampin and ARV blood
levels
SQV IDV
Rifampin
NFV
LPV
NVP
EFV

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84%
89%
82%
75%
37%
25%
Do not use PI with Rifampin
Finch et al. Arch Intern Med 2002;162:985-92
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Rifampin and Nevirapine
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RIF decreases NVP levels by 37%
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Clinical significance of this interaction is
debated.
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Some studies demonstrate reduced
virological outcomes with the use of NVPcontaining ART and RIF-containing TB
therapy while others have not.
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Possible higher risk of hepatotoxicity with
NVP and TB therapy is also a concern.
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Rifampin and Efavirenz
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RIF decreases EFV levels by 25%
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This decrease is not felt to have a
significant effect on clinical outcomes.
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MOH guidelines recommend EFV at
standard dosing (600 mg/day) when
used with RIF.
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Rifampin and NNRTIs:
Conclusions
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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, contra-indicated
(1st trimester pregnancy), or not tolerated
NVP can be used at standard doses.
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Rifampin and
Lopinavir/Ritonavir

RIF decreases LPV levels by > 75%
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Combination should be avoided if possible.
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Patients who require RIF-based TB therapy
and PI-based ART can be treated with
“superboosted” LPV/r.
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LPV dose = RTV dose
LPV 400mg/RTV 400mg twice daily
Aluvia 2 tabs + Ritonavir 3 tabs twice a day
Available by referral to provincial-level OPC
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Antifungals + ARVs:
Fluconazole (FLUC)

FLUC + NVP = ↑ NPV levels
 possible
increase in hepatotoxicity
 monitor closely
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Antifungals + ARVs:
Itraconazole (ITRA)

ITRA + NVP: ↓ ITRA levels
(↓ AUC by 61%)
 Monitor closely; consider ↑ ITRA dose
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ITRA + EFV: ↓ ITRA levels
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(↓ AUC by 39%)
Monitor closely; consider ↑ ITRA dose
ITRA + LPV/r (Aluvia) = ↑ ITRA levels
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Limit ITRA to 200 mg/day
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Methadone + ARVs
ARV
Effect
Comment
EFV
Decreased methadone
levels up to 60%
Can precipitate
withdrawal symptoms.
NVP
Decreased methadone
May require increase in
levels up to 50%
methadone dose.
Decreased methadone
levels up to 50%
Monitor for AZT side
Increased AZT levels
effects (e.g. anemia).
by up to 40%
Use with caution.
Decreased ddI levels
Buffered formulation
by up to 50%
(ddI-EC) is preferred.
LPV/r
AZT
ddI
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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
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DDI + D4T – Avoid combination.
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D4T + AZT – Avoid combination.
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Increased toxicities
Antagonistic effect; require same enzymes for
intracellular phosphorylation
TDF + DDI – Avoid combination.
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Increased DDI toxicity
Loss of CD4 responses after time
Suboptimal antiviral response in regimens with
EFV
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Recognizing and Avoiding Drug
Interactions
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Review patient’s full medication list at every visit
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Recognize drugs most commonly associated with
interactions (i.e., protease inhibitors, ketoconazole,
rifampin, etc)
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Recognize medications with overlapping toxicities
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Be aware of dietary restrictions with certain
medications
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Select agents with fewer drug interactions if clinically
appropriate
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Simplify drug regimens whenever possible
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
Key Points

The 4 components of pharmacokinetics are:
Absorption, Distribution, Metabolism and
Excretion.

The liver’s P450 enzymes are the main
components of most drugs metabolized. Drug
metabolism is crucial in order for the inactive
metabolites to be excreted.

An inducer of the P450 system is Rifampin. Two
inhibitors of the P450 system are Ketoconazole
and Ritonavir.
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Key Points

Do not use PIs with Rifampin.
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In patients on TB therapy, EFV is the preferred
NNRTI. NVP can be given if EFV cannot be used.

Antifungal drugs have many potential interactions.
Check before prescribing.
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Methadone levels are decreased by ART and
withdrawal may be precipitated.

Avoid certain NRTI combinations (DDI+D4T,
AZT+D4T, DDI+TDF)
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Thank you!
Questions?
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