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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: 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. 2 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 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” 4 Drug Absorption Definition the movement of a drug from its site of administration (stomach, vein, skin) into the bloodstream 5 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) 6 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. 7 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 8 Drug Metabolism Definition – The process of transforming active drugs into inactive metabolites that can be more readily excreted from the body. 9 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. 10 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. 11 CYP450 Inducers Inducers lead to increased activity of CYP450 faster breakdown and clearance of other drugs decreased concentrations of other drugs Important enzyme inducers include: Rifampin NVP EFV 12 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 13 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 14 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. 15 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. 16 Factors Affecting Drug Excretion Renal insufficiency and/or failure Alkalinization or acidification of urine Liver failure 17 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 19 Rifampin and ARV blood levels SQV IDV Rifampin NFV LPV NVP EFV 84% 89% 82% 75% 37% 25% Do not use PI with Rifampin Finch et al. Arch Intern Med 2002;162:985-92 20 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 NVPcontaining ART and RIF-containing TB therapy while others have not. Possible higher risk of hepatotoxicity with NVP and TB therapy is also a concern. 21 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. 22 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. 23 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 24 Antifungals + ARVs: Fluconazole (FLUC) FLUC + NVP = ↑ NPV levels possible increase in hepatotoxicity monitor closely 25 Antifungals + ARVs: Itraconazole (ITRA) 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 (Aluvia) = ↑ ITRA levels Limit ITRA to 200 mg/day 26 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 27 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. 28 Interactions among NRTIs DDI + D4T – Avoid combination. D4T + AZT – Avoid combination. Increased toxicities 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 29 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 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. 32 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) 33 Thank you! Questions? 34