1. Antiretrovirals III: Pharmacokinetics and Drug Interactions
HAIVN
Harvard Medical School AIDS Initiative in Vietnam
M2-06-ARV3-Pharmacokinetics-EN
HAIVN Module 2, Revised February 2010

2. Learning Objectives
At the end of this presentation, participants will be able to:
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.
Learning Objectives 2

3. 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 3

4. Pharmacokinetics – Definition
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”
Definition of Pharmacokinetics 4

5. Drug Absorption Definition - the movement of a drug from its site of
administration (stomach, vein, skin) into the bloodstream
Absorption is the movement of the drug into the blood. 5

6. 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)
Taking some medications (itraconazole, ketoconazole) with acidic drinks such as carbonated soft-drinks will also increase absorption. 6

7. 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.
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. 7

8. Factors Affecting Drug Distribution
Cardiac output and blood flow to organs and tissues
Drug permeability and accumulation in tissues
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
In general, drugs that have high protein binding have longer half-lives. Clinical relevance of changes in protein levels and protein binding is uncertain. 8

9. Drug Metabolism Definition –
The process of transforming active drugs into inactive metabolites that can be more readily excreted from the body.
Metabolites can be active (have desired effects) or be inactive (have no medicinal effects). 9

10. 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.
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. 10

11. Drug Effects on CYP450
The activity of the CYP450 enzymes can be affected by many medications.
Drugs that affect CYP450 are categorized as either inducers or inhibitors.
CYP450 enzymes metabolize many drugs but the enzyme activity itself can also be affected by drugs 11

12. CYP450 Inducers Inducers lead to Important enzyme inducers include:
increased activity of CYP450
faster breakdown and clearance of other drugs
decreased concentrations of other drugs
Important enzyme inducers include:
Rifampin
NVP
EFV
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

13. CYP450 Inhibitors Inhibitors lead to
decreased activity of CYP450
slower breakdown and clearance of other drugs
increased and prolonged concentrations of other drugs
Important enzyme inhibitors include:
Ritonavir
Ketoconazole
Itraconazole
The most important inhibitor to know is ritonavir. Generally ritonavir leads to increased concentrations of many medications and thus increased risk of toxicity.

14. CYP450 Substrates
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:
NVP
EFV
LPV/r (Aluvia)
Rifampin
Methadone
Ketoconazole
Itraconazole
Clarithromycin & Erythromycin
Simvastatin & Lovastatin
Birth control pills
Many drugs are both inducers or inhibitors and also substrates of CYP450 themselves.

15. 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.
Induction or inhibition of CYP450 can have advantages and disadvantages 15

16. 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.
All drugs must eventually be eliminated from the body. The kidney and the liver are the primary organs for drug excretion. 16

17. Factors Affecting Drug Excretion
Renal insufficiency and/or failure
Alkalinization or acidification of urine
Liver failure
For example, increasing the pH of the urine from 6 to 8 will increase aspirin excretion by 4-6 times. 17

18. Key Drug Interactions with and within ARVs
Now we will review some important drug-drug interactions. Many of these are mediated through induction or inhibition of the CYP450 system.

19. Rifampin and HIV medications
By inducing the Cytochrome P450 enzyme, Rifampin decreases blood levels of: PI
NNRTI (NVP, EFV)
Methadone
Antifungal Drugs
Rifampin has interactions with many other drugs because it is a very strong inducer of the CP450 enzymes. 19

20. Rifampin and ARV blood levels
SQV
IDV
NFV
LPV
NVP
EFV
Rifampin 
84%
89%
82%
75%
37%
25%
PI should not be used with Rifampin because the blood levels will be too low and ineffective.
Do not use PI with Rifampin
Finch et al. Arch Intern Med 2002;162:985-92 20

21. Rifampin and Nevirapine
RIF decreases NVP levels by 37%
Clinical significance of this interaction is debated.
Some studies demonstrate reduced virological outcomes with the use of NVP-containing ART and RIF-containing TB therapy while others have not.
Possible higher risk of hepatotoxicity with NVP and TB therapy is also a concern.
While the clinical efficacy of NVP when used concurrent with RIF is debated, many believe it can be used at standard doses in this setting. However, the increased risk of hepatotoxicity must also be considered.
1) Manosuthi et al. Clinical Infectious Diseases 2009; 48:1752–9 A Randomized Trial Comparing Plasma Drug Concentrations and Efficacies between 2
Nonnucleoside Reverse-Transcriptase Inhibitor–Based Regimens in HIV-Infected Patients Receiving Rifampicin: The N2R Study
2) Manosuthi et al. CID 2006;43:253-5 showed equivalent virologic outcomes between D4T/3TC/NVP vs. D4T/3TC/NVP + RIF containing TB therapy.
3) Boulle A et al. JAMA Aug 6;300(5):530-9 showed inferior virologic outcomes with NVP + TB Rx vs NVP w/o TB Rx

22. Rifampin and Efavirenz
RIF decreases EFV levels by 25%
This decrease is not felt to have a significant effect on clinical outcomes.
MOH guidelines recommend EFV at standard dosing (600 mg/day) when used with RIF.
Some experts recommend increasing the dose of EFV to 800 mg/day in patients who weigh more than 60 kg, but others suggest that no dosage adjustment is necessary

23. Rifampin and NNRTIs: Conclusions
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.
Conclusion: it is OK to use NVP in a patient taking Rifampin. 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 (MOH guidelines). 23

24. Rifampin and Lopinavir/Ritonavir
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 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
As mentioned, the 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. Patients should be monitored very closely for liver toxicity and may have significant GI side effects on this regimen.

25. Antifungals + ARVs: Fluconazole (FLUC)
FLUC + NVP = ↑ NPV levels
possible increase in hepatotoxicity
monitor closely
Anti-fungal agents, particularly Itraconazole and Ketoconazole, are prone to interactions. One important interaction to remember is FLUC-NVP as it is a commonly prescribed combination.
Fluconazole increases NVP levels (Cmin and AUC) by double. In some studies (but not all) NVP toxicity was dose-related with higher risk of liver toxicity at higher levels. Patients on this combination should be monitored carefully for signs/symptoms of liver toxicity.

26. Antifungals + ARVs: Itraconazole (ITRA)
ITRA + NVP: ↓ ITRA levels
(↓ AUC by 61%)
Monitor closely; consider ↑ ITRA dose
ITRA + EFV: ↓ ITRA levels
(↓ AUC by 39%)
ITRA + LPV/r (Aluvia) = ↑ ITRA levels
Limit ITRA to 200 mg/day
Interactions between AVRs 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.
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.
Ketoconazole has similar interactions as Itraconazole (decreased levels with NVP/EFV and increased with Aluvia)

27. Methadone + ARVs ARV Effect Comment EFV
Decreased methadone levels up to 60%
Can precipitate withdrawal symptoms.
May require increase in methadone dose.
NVP
Decreased methadone levels up to 50%
LPV/r
AZT
Increased AZT levels by up to 40%
Monitor for AZT side effects (e.g. anemia).
ddI
Decreased ddI levels by up to 50%
Use with caution. Buffered formulation (ddI-EC) is preferred.
Methadone levels are decreased with coadministration with EFV, NVP, and LPV/r. Methadone dosing may need to be increased to avoid withdrawal symptoms.

28. Hormonal Contraceptives + ARVs
Effect on hormonal contraceptive
Comment
EFV
↑ ethinyl estradiol
Use alternative or additional methods.
NVP
↓ ethinyl estradiol 20%
LPV/r
↓ ethinyl estradiol 42%
ART affects levels of oral hormonal contraception. Patients should be advised to use additional methods especially when on EFV (risk of teratogenicity)

29. Interactions among NRTIs
DDI + D4T – Avoid combination.
Increased toxicities
D4T + AZT – Avoid combination.
Antagonistic effect; require same enzymes for intracellular phosphorylation
TDF + DDI – Avoid combination.
Increased DDI toxicity
Loss of CD4 responses after time
Suboptimal antiviral response in regimens with EFV
Interactions between NRTI drugs. 29

30. Recognizing and Avoiding Drug Interactions
Review patient’s full medication list at every visit
Recognize drugs most commonly associated with interactions (i.e., protease inhibitors, ketoconazole, rifampin, etc)
Recognize medications with overlapping toxicities
Be aware of dietary restrictions with certain medications
Select agents with fewer drug interactions if clinically appropriate
Simplify drug regimens whenever possible
Make sure to review medications prescribed at other clinics (i.e TB), private pharmacies, home remedies, etc.
Recognize medications with overlapping toxicities (INH-D4T, DDI-D4T, AZT-ribavirin, etc)
Be aware of dietary restrictions with certain medications (DDI-empty stomach, EFV-empty stomach)

31. MOH Guidelines for the Diagnosis and Treatment of HIV/AIDS
Look it Up! When prescribing a new drug to a patient, always look it up to make sure there aren’t any drug interactions.
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.
References:
MOH Guidelines for the Diagnosis and Treatment of HIV/AIDS

32. 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. 32

33. Key Points Do not use PIs with Rifampin.
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.
Methadone levels are decreased by ART and withdrawal may be precipitated.
Avoid certain NRTI combinations (DDI+D4T, AZT+D4T, DDI+TDF)

34. Thank you!
Questions?