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Pharmacokinetics and Drug Interactions

HAIVNHarvard 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

Example: How a CYP450 Inducer affects Substrates

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SubstratesCYP450

Rifampin LPV and other PIs, NVP, EFV:• decreased

concentrations

• increased activity of CYP450

• faster breakdown and clearance of other drugs

Inducer

Example: How a CYP450 Inhibitor affects Substrates

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SubstratesCYP450

RitonavirThe 2nd PIs:•increased & prolonged concentrations

• decreased activity of CYP450

• slower breakdown and clearance of other drugs

Inhibitor

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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

SQV IDV NFV LPV NVP EFV

Rifampin

84%

89%

82%

75%

37%

25%

Finch et al. Arch Intern Med 2002;162:985-92

Do not use PIs with Rifampin

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Rifampin and NNRTIs (1)

Rifampin and NVP NVP levels

decreased by 20-58%

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

ITRA + NVP↓ ITRA levels (↓ AUC by 61%)

•Monitor closely•Consider ↑ ITRA dose

ITRA + EFV ↓ ITRA levels (↓ AUC by 39%)

•Monitor closely•Consider ↑ ITRA dose

ITRA + LPV/r ↑ ITRA levelsLimit ITRA to 200 mg/day

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Methadone + ARVs

ARV Effect Comment

EFV↓ methadone

levels(by 52%)

Can precipitate withdrawal symptoms

May require increase in methadone doseNVP

↓ methadone levels

(by 41%)

LPV/r

↓ methadone levels

(by 26 to 53%)

• Opioid withdrawal unlikely but may occur

• Usually no adjustment in methadone required

AZT↑ AZT levels(by 29-43%)

Monitor for AZT side effects (e.g. anemia)

ddI↓ ddI levels

(by up to 50%)

Use with caution Enteric coated (EC) formulation

preferred

Source: US Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, January 10, 2011.

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Hormonal Contraceptives + ARVs

ARVEffect on hormonal

contraceptiveComment

EFV ↑ ethinyl estradiol

Use alternative or additional methods

NVP ↓ ethinyl estradiol 20%

LPV/r ↓ ethinyl estradiol 42%

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Interactions among NRTIs

NRTI PairResults of Interaction

Recommen-dation

DDI + D4T •Increased toxicities

Avoid combination

D4T + AZT

•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

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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 anydrug interactions

References:

MOH Guidelines for the Diagnosis and Treatment of HIV/AIDSwww.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?