This document discusses pharmacokinetics and important drug interactions for treating HIV. It describes the four components of pharmacokinetics - absorption, distribution, metabolism and excretion - and explains how the liver's cytochrome P450 system plays a key role in drug metabolism. It provides examples of cytochrome P450 inducers and inhibitors and how they can affect substrate drugs. Specifically, it notes that the antibiotic rifampin is a strong inducer that significantly decreases levels of protease inhibitors, NNRTIs, methadone and antifungals by inducing cytochrome P450. Managing interactions is important for successful HIV treatment.
2. 2
Learning Objectives
By the end of this session, participants will be
able to:
ďŽ Describe 4 components of pharmacokinetics
ďŽ Explain importance of the liverâs P450
system in drug metabolism
ďŽ Explain how an inducer and an inhibitor
affect the blood level of CYP450 substrates
ďŽ Describe the most important drug-drug
interactions
3. 3
What is Pharmacokinetics?
ďŽ The study of how drugs enter,
interact with, and leave the body,
including:
⢠Absorption
⢠Distribution
⢠Metabolism
⢠Excretion
ďŽ Or, âwhat the body does to the drugâ
4. 4
Drug Absorption
ďŽ The movement of a drug from its site
of administration (stomach, vein,
skin, etc.) into the bloodstream
5. 5
Factors Affecting Drug
Absorption
ďŽ 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)
ďŽ Presence or absence of food or other
medications:
⢠Buffered ddI decreases the absorption of
itraconazole, ketoconazole, indinivir
6. 6
Drug Distribution
ďŽ Following absorption or systemic
administration into the bloodstream,
a drug distributes into interstitial and
intracellular fluids and then finally
into the body tissue
7. 7
Factors Affecting Drug
Distribution
ďŽ Cardiac output and blood flow to
organs and tissues
ďŽ Drug permeability and accumulation
in tissues
ďŽ Protein binding:
⢠Protein binding varies among ARVs
⢠Protein levels may vary between and
within patients
8. 8
What is Drug Metabolism?
ďŽ The process of transforming active
drugs into inactive metabolites that
can be more readily excreted from
the body
9. 9
Drug Excretion
ďŽ Drugs are eliminated from the body
either unchanged or as metabolites:
⢠Kidney
⢠Liver-Intestines
ďŽ Factors affecting drug excretion
include:
⢠Renal insufficiency and/or failure
⢠Alkalinization or acidification of urine
⢠Liver failure
12. 12
Cytochrome P450 Enzymes
ďŽ The cytochrome P450 (CYP) enzyme
family is the major enzyme system
involved in drug metabolism
ďŽ CYP-mediated metabolism occurs
mostly in the liver
ďŽ CYP3A is the most important enzyme
⢠responsible for the breakdown and
clearance of the largest number of drugs
including most PIs and NNRTIs
13. 13
Drug Effects on CYP450
ďŽ Activity of CYP450 enzymes can be
affected by many medications
ďŽ Drugs that affect CYP450 are
categorized as either inducers or
inhibitors
ďŽ Drugs that are metabolized by
CYP450 (substrates) may be affected
by the presence of an inducer or an
inhibitor
16. Example: How a CYP450 Inducer
affects Substrates
16
Substrates
CYP450
Rifampin LPV and other
PIs, NVP, EFV:
⢠decreased
concentrations
⢠increased
activity of
CYP450
⢠faster
breakdown and
clearance of
other drugs
Inducer
17. Example: How a CYP450 Inhibitor
affects Substrates
17
Substrates
CYP450
Ritonavir
The 2nd
PIs:
â˘increased &
prolonged
concentrations
⢠decreased
activity of CYP450
⢠slower
breakdown and
clearance of other
drugs
Inhibitor
18. 18
Drug Effects on CYP450
Advantages:
ďŽ Use of Ritonavir
(inhibitor) with
another PI leads to:
⢠higher, prolonged
blood levels
⢠decreases required
amount of 2nd PI
Disadvantages:
ďŽ The use of
Rifampin with
many ARVs leads
to leads to
unacceptably low
blood levels of
these ARVs
20. 20
Rifampin and HIV Medications
ďŽ By inducing the CYP450 enzyme,
Rifampin decreases blood levels of:
⢠PI
⢠NNRTI (NVP, EFV)
⢠Methadone
⢠Antifungal drugs
21. 21
Rifampin and ARV Blood Levels
SQV IDV NFV LPV NVP EFV
Rifampin
ď˘
84%
ď˘
89%
ď˘
82%
ď˘
75%
ď˘
37%
ď˘
25%
Finch et al. Arch Intern Med 2002;162:985-92
Do not use PIs with Rifampin
22. 22
Rifampin and NNRTIs (1)
Rifampin and NVP
ďŽ NVP levels
decreased by 20-
58%
ďŽ Clinical significance
of this is debated
ďŽ Risk of
hepatotoxicity with
NVP and TB therapy
is also a concern
Rifampin and EFV
ďŽ EFV levels
decreased by 26%
ďŽ Not felt to have a
significant effect on
clinical outcomes
ďŽ MOH guidelines
recommend EFV at
standard dosing
(600 mg/day) when
used with RIF
23. 23
Rifampin and NNRTIs (2)
ďŽ In patients on TB therapy, EFV is the
preferred NNRTI
ďŽ Patients on NVP at the time of TB
diagnosis should be changed to EFV
if possible
ďŽ If EFV is not available, not tolerated
or contraindicated, NVP can be used
at standard doses
24. 24
Rifampin and LPV/r
ďŽ RIF decreases LPV levels by > 75%
**Combination should be avoided if
possible
ďŽ Patients who require RIF-based TB
therapy and PI-based ART can be
treated with âsuperboostedâ LPV/r
⢠LPV 400 mg + RTV 400 mg twice daily
⢠Available by referral to provincial-level
OPC
25. 25
Case Study: Hung
ďŽ 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)
ďŽ Should his ART regimen be altered?
ďŽ If so, how and why?
27. 27
Methadone + ARVs
ARV Effect Comment
EFV
â methadone
levels
(by 52%)
ď§ Can precipitate withdrawal
symptoms
ď§ May require increase in
methadone doseNVP
â methadone
levels
(by 41%)
LPV/r
â methadone
levels
(by 26 to 53%)
⢠Opioid withdrawal unlikely but
may occur
⢠Usually no adjustment in
methadone required
AZT
â AZT levels
(by 29-43%)
ď§ Monitor for AZT side effects
(e.g. anemia)
â ddI levels ď§ Use with caution
Source: US Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and
Adolescents, January 10, 2011.
28. 28
Hormonal Contraceptives + ARVs
ARV
Effect on hormonal
contraceptive
Comment
EFV â ethinyl estradiol
Use alternative or
additional methods
NVP â ethinyl estradiol 20%
LPV/r â ethinyl estradiol 42%
29. 29
Interactions among NRTIs
NRTI Pair
Results of
Interaction
Recommen-
dation
DDI + D4T â˘Increased toxicities
Avoid
combination
D4T + AZT
â˘Antagonistic effect
(require same enzymes for
intracellular
phosphorylation)
TDF + DDI
⢠Increased DDI toxicity
⢠Loss of CD4 responses
after time
⢠Suboptimal antiviral
response in regimens
with EFV
30. 30
How Can You Recognize and
Avoid Drug Interactions?
ďŽ Review patientâs full medication list at every
visit
ďŽ Recognize:
⢠drugs most commonly associated with
interactions (PIs, itraconazole, rifampin, etc.)
⢠medications with overlapping toxicities
⢠dietary restrictions with certain medications
ďŽ Select agents with fewer drug interactions if
clinically appropriate
ďŽ Simplify drug regimens whenever possible
31. 31
Look it Up!
When prescribing a new drug to a patient,
always look it up to make sure there arenât any
drug interactions
References:
MOH Guidelines for the Diagnosis and Treatment of HIV/AIDS
www.HIV-druginteractions.org
www.AIDSinfo.nih.gov
32. 32
Key Points
ďŽ 4 components of pharmacokinetics
⢠All can affect success of drug therapy
ďŽ Drug interactions are common when
treating PLHIV
⢠Many related to effects of the P450 liver
enzymes
⢠Important to recognize and avoid drug
interactions
M2-07-Pharmacokinetics and Drug Interactions-EN
HAIVN Module 2, Revised April 2012
Note that this slide is animated. Do not click through the answers on the slide until AFTER asking participants the question in the title.
ASK participants âWhat is pharmacokinetics?â
ALLOW time for them to answer, then click to show the answer.
ASK participants âWhat factors might affect drug distribution?â
ALLOW time for them to answer, then move to the next slide.
GIVE more examples of drugs absorbed better in an acidic environment:
Itraconazole
Ketoconazole
Indinivir
Atazanavir
EXPLAIN that when prescribing drugs which are absorbed better in acidic environment, patients should be counseled to:
avoid antacids
consider taking the medication with acidic drinks such as carbonated soft-drinks
EXPLAIN that ddI is better absorbed in a low acid environment. This is why it is formulated with a built in antacid (buffered) or protective coating (enteric coated).
The buffered formulation can decrease the absorption of other drugs because of the built-in antacid.
So when prescribing itraconazole, ketoconazole or indinavir with buffered ddI, the drug should be taken at least 1 hour apart.
EXPLAIN that distribution is the movement of the drug from the blood throughout the body. The action of most drugs is in the cells, not the blood, so distribution is how the drug gets from the blood to the site of action. For most ARV, the site of action is in the cells infected by HIV, such as the CD4 cells and others.
EXPLAIN that in general, drugs that have high protein binding have longer half-lives. However, the clinical relevance of changes in protein levels and protein binding is uncertain.
Note that this slide is animated. Do not click through the answers on the slide until AFTER asking participants the question in the title.
ASK participants âWhat is drug metabolism?â
ALLOW time for them to answer, and then click to show the answer on the screen.
EXPLAIN that metabolites can be active (have desired effects) or be inactive (have no medicinal effects).
EXPLAIN that we will discuss drub metabolism in more detail later in the session
EXPLAIN that all drugs must eventually be eliminated from the body. The kidney and the liver are the primary organs for drug excretion.
For metabolism through the liver and intestine: drugs can be excreted in the bile, or secreted directly into the intestinal tract
GIVE an example of how alkalinization of the urine affects drug excretion: increasing the pH of the urine from 6 to 8 will increase aspirin excretion by 4-6 times.
GIVE brief summary of what happens when a drug enters the body in general.
EXPLAIN that the Cytochrome P450 enzymes are one of the primary pathways for metabolizing drugs and toxins in the body. Many drugs used in HIV infection, including ARV, TB, and anti-fungal drugs, are metabolized this way.
EXPLAIN that CYP450 enzymes metabolize many drugs but the enzyme activity itself can also be affected by drugs.
STRESS that the most important inducer to know if Rifampin. We will see examples shortly of how it leads to serious drug interactions. Generally rifampin leads to decreased concentrations of other drugs and thus decreased effectiveness of those drugs.
EXPLAIN that many drugs are both inducers or inhibitors and also substrates of CYP450 themselves.
EXPLAIN this diagram:
An inducer, for example rifampin, affects CYP450 enzymes, leading to:
increased activity of CYP450 enzymes
faster breakdown and clearance of other drugs
decreased concentrations of other drugs
EXPLAIN that the most important inducer to know if Rifampin. Generally rifampin leads to decreased concentrations of other drugs and thus decreased effectiveness of those drugs
EXPLAIN this diagram:
An inhibitor, for example ritonavir, affects CYP450 enzymes, leading to:
decreased activity of CYP450 enzymes
slower breakdown and clearance of other drugs
increased and prolonged concentrations of other drugs
EXPLAIN that the most important inhibitor to know is ritonavir. Generally ritonavir leads to increased concentrations of many medications and thus increased risk of toxicity.
STRESS that induction or inhibition of CYP450 can have both advantages and disadvantages.
INTRODUCE that now you will review some important drug-drug interactions. Many of these are mediated through induction or inhibition of the CYP450 system.
EXPLAIN that Rifampin has interactions with many other drugs because it is a very strong inducer of the CP450 enzymes.
STRESS that PIs should not be used with Rifampin because the blood levels will be too low and ineffective.
EXPLAIN that some studies have demonstrate reduced virological outcomes with the use of NVP-containing ART and RIF-containing TB therapy while others have not.
EXPLAIN that some experts recommend increasing the dose of EFV to 800 mg/day in patients who weigh more than 60 kg, but most suggest that no dosage adjustment is necessary
GIVE an example of contraindication of EFV: patient is in the 1st trimester of pregnancy
CONCLUDE that it is OK to use NVP in a patient taking Rifampin
EXPLAIN that the Vietnam MOH HIV/AIDS guidelines recommend using EFV in patients who are also taking Rifampin, but allow using NVP if EFV is not available or if the patient can not take EFV. If using NVP with RIF, monitor closely for clinical symptoms of hepatitis and check liver enzyme level every 2 weeks
EXPLAIN that LPV/r is Lopinavir/Ritonavir .
REMIND that combination of RIF and a PI should be avoided whenever possible. However, in some cases these drugs must be used together. For example, a patient on second-line ART (TDF/3TC/LPV-r) who develops active TB. In this situation, the patient can be referred to the provincial level for superboosted LPV/r therapy. Superboosting LPV involves providing additional ritonavir to counteract the decreased LPV levels caused by RIF. The dose is LPV 400 mg / RTV 400 mg BID.
GIVE an example of how to get the superboosted dose: Aluvia 2 tabs + Ritonavir 3 tabs twice a day
STRESS that patients should be monitored very closely for liver toxicity and may have significant GI side effects on this regimen.
HAVE a participant read the case study and question presented on this slide.
ALLOW time for participants to discuss this question.
EXPLAIN that Hungâs ART regimen should be changed.
NVP should be changed to EFV
This is due to the interaction between Rifampin and NVP where-by Rifampin lowers NVP blood levels
It is also due to the higher risk of liver toxicity when using NVP and TB therapy together
If the patient cannot tolerate EFV, it is then acceptable to switch back to NVP
EMPHASIZE that interactions between ARVs and itraconazole are very important in Vietnam because of the incidence of penicillium marneffei infection.
Patients on Itraconazole for treatment of PM should be monitored closely for non-response and/or recurrence when NNRTI-based ART is given concomitantly.
Consideration should be given to increasing the dose of Itraconazole (especially during the maintenance phase; 200 mg/day to 400 mg/day) in this scenario.
EXPLAIN that similar concerns exist with the use of Itraconazole and Rifampin-based TB therapy.
Rifampin significantly decreases Itraconazole levels (decreased AUC by 80-90%) as well.
The combination should be avoided if possible.
MENTION that Ketoconazole has similar interactions as Itraconazole (decreased levels with NVP/EFV and increased with Aluvia)
BACKGROUND:
ITRA: Itraconazole
REF:
- Pharmacokinetic study of the interaction between itraconazole and nevirapine. Eur J Clin Pharmacol (2007) 63:451â456
- US DHHS Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. March 27, 2012
EXPLAIN that Methadone levels are decreased with co-administration with EFV, NVP, and LPV/r. Methadone dosing may need to be increased to avoid withdrawal symptoms.
EXPLAIN that ART affects levels of oral hormonal contraception. Patients should be advised to use additional methods especially when on EFV (risk of teratogenicity).
Note that this slide is animated. Do not click through the answers on the slide until AFTER asking participants the question in the title.
ASK participants âHow can you recognize and avoid drug interactions?â
ALLOW time for them to answer, and then click to show the answer.
REMIND participants to review medications prescribed at other clinics (i.e. TB), private pharmacies, home remedies, etc.
GIVE example of medications with overlapping toxicities:
INH-D4T
DDI-D4T
AZT-ribavirin
GIVE example of dietary restrictions with certain medications:
DDI-empty stomach
EFV-empty stomach
EMPHASIZE that there are many drugs used to treat HIV patients and the number of potential interactions is too many to remember them all. If you are not sure about drug interactions between ARV and other drugs, then you can look it up.
REFER participants to Handout M2S7.1: Important Drug Interactions so that they can see further detail on drug interactions.