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  • nice presentation but i didn't found any slide describing combination regimens HAART . i think we must include for UG student as well .
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  • 24 ARVs
  • Other ARVs, when given in combination should be dose adjusted. Didanosine should be dose reduced when given with tenofovir as tenofovir increase didanosine concentrations. Recall, efavirenz and nevirapine are potent P450 inducers; therefore, decrease concentrations of drug metabolized by P450. When tenofovir, efavirenz, or nevirapine are given with atazanavir, ritonavir should be coadministered since these three ARVs reduce atazanavir concentrations. When efavirenz or nevirapine are given with fosamprenavir, ritonavir should be coadministered and when efavirenz/nevirapine are given with lopinavir/ritonavir an extra tablet twice a daily should be given.
  • There are several contraindications that should be emphasized. Simvastatin and lovastatin should not be given with PIs due to the increase in concentrations of both these statins with PIs leading to increased risk of side effects. Antiarrthymics, midazolam, triazolam, and ergot derivatives are also increased with PIs and delavirdine. St. Johns Wort and garlic induce P450 so should not be used with any NNRTIs or PIs metabolized by P450s. Rifampin is a potent P450 inducer and should not be given in general with PIs and caution should be used when given with efavirenz and nevirapine. Fluticasone or an alpha blocker alfuzosin should not be given with ritonavir and if possible avoided with other PIs that are P450 inhibitors. The other medications listed should be used with caution when combining with ARVs due to their inhibition effects (azoles, clairthromycin) or the fact that they are inducers of P450s or decrease concentrations of ARVs (OCs, phenytoin, carbamazepine, phenobarbital). Also with drugs that are metabolized by P450s such as methadone, PDE5 inhibitors, atorvastatin, and SSRIs beta blockers caution when using ARVs that are P450 inhibitors should be monitored. All herbal products should be avoided that have known, suspected, or unknown drug interactions due to the need for adequate ARV concentrations for optimal efficacy. Finally, when combining PIs dosing should always be verified as dose adjustments are often necessary.
  • Good candidate: interpatient variability; relationship between drug conc and efficacy or drug conc and toxicity When to do TDM: drug-drug or drug-food interactions; changes in pathophysiologic states; pregnancy; treatment experienced pts with reduced susceptibility; alternative dosing; concentration dependent toxicity; lack of expected virologic response
  • There is a heterogenous response to ART among patients Like other drugs with narrow therapeutic windows there is a fine line between therapeutic failure due to toxicity, failure due to suboptimal concentrations and therapeutic success This figure depicts PK/PD relationships. It is important to note that a single dose of drug does not always correspond to the same drug concentration in the plasma. This is true for ARVs. Also, variability in drug concentreations in the plasma correlates with variability of drug concentrations at the effect site
  • Antiretrovirals

    1. 1. Anti retroviral Pharmacology dr shabeel pn
    2. 2. Antiretroviral Classes <ul><li>NRTIs (Nucleoside OR Nucleotide Reverse Transcriptase Inhibitors, aka “Nukes”) </li></ul><ul><li>NNRTIs (Non-Nucleoside Reverse Transcriptase Inhibitors, aka “Non-Nukes”) </li></ul><ul><li>PIs (Protease Inhibitors) </li></ul><ul><li>Fusion Inhibitors </li></ul><ul><li>Chemokine Receptor </li></ul><ul><li>Antagonists </li></ul><ul><li>Integrase Inhibitors </li></ul>
    3. 3. Mechanism of Action of ARVs Illustration by David Klemm Fusion Inhibitor & Chemokine Receptor Antagonist NNRTI NRTI Protease Inhibitor Integrase Inhibitor
    4. 4. Antiretroviral Drug Approval: 1987 - 2007 AZT ddI ddC d4T 3TC SQV RTV IDV NVP NFV DLV EFV ABC APV LPV/r TDF T-20 TPV DRV Maraviroc Raltegravir ATV FTC FPV
    5. 5. Liver Metabolism 25% Adapted from Br J Clin Pharmacol 1998:46:101-110 Pgp small bowel gut lumen sinusoid portal vein hepatic vein 100% 3A4 CYP 100% 100% 100% 50% 50% 50% 25%
    6. 6. NRTIs Mechanism of Action <ul><li>Nucleoside analogs (like AZT below) </li></ul><ul><ul><li>Analog of thymidine, cytosine, adenine, or guanine </li></ul></ul><ul><ul><li>Triphosphorylated inside lymphocytes to active compound </li></ul></ul><ul><ul><li>Incorporate into the growing HIV viral DNA strand by reverse transcriptase </li></ul></ul><ul><li>Nucleotide analog </li></ul><ul><ul><li>Currently only tenofovir (TDF) </li></ul></ul><ul><ul><li>Does NOT need to be tri-phosphorylated only di-phosphorylated to active compound </li></ul></ul><ul><li>After incorporation of </li></ul><ul><li>the NRTI, viral DNA </li></ul><ul><li>synthesis will be </li></ul><ul><li>terminated. </li></ul>
    7. 7. NRTI Class Toxicities <ul><li>Lactic Acidosis </li></ul><ul><ul><li>Damage to mitochondria in cells </li></ul></ul><ul><ul><li>Elevated lactate, low pH/bicarbonate, N/V, shortness of breath, if untreated can lead to death </li></ul></ul><ul><li>Hepatomegaly with Steatosis </li></ul><ul><ul><li>Build up of fat droplets </li></ul></ul><ul><ul><li>inside liver cells </li></ul></ul><ul><ul><li>Enlarged liver </li></ul></ul>
    8. 8. NRTIs *dose reduce for renal dysfunction <ul><li>Note: Lactic acidosis can occur with any NRTIs </li></ul>Pancreatitis, peripheral neuropathy, LA/HS Well tolerated Well tolerated Fatigue, malaise, HA myalgia, anemia, GI Common Side Effects Renal Renal Renal Renal Metabolism/ Elimination 125,200,250, 400mg cap, pwdr for soln 400mg EC qd (  60kg) 250mg EC qd (<60kg)* Didanosine (ddI) Videx 200mg cap 200mg qd* Emtricitabine (FTC) Emtriva 150, 300mg tab, oral soln 150mg bid* or 300mg qd Lamivudine (3TC) Epivir 300mg tab, 100mg cap, iv, oral soln 300mg bid* Zidovudine (ZDV/AZT) Retrovir Dosage forms Standard Dose* Drug
    9. 9. NRTIs *dose reduce for renal dysfunction Few SEs, renal toxicity hypersensitivity Peripheral neuropathy, Pancreatitis, LA/HS, Lipoatrophy, facial wasting Common Side Effects Renal Hepatic by alcohol dehydrogenase and glucuronyl transferase Renal Metabolism/ Elimination 300mg tabs, oral soln 300mg bid, 600mg qd Abacavir (ABC) Ziagen 300mg tabs 300mg qd* Tenofovir (TDF) Viread 15,20,30,40 mg cap,oral soln 40mg bid (  60kg) 30mg bid (<60kg) * Stavudine (d4T) Zerit IR Dosage forms Standard Dose* Drug
    10. 10. NRTI Combinations *dose reduce for renal dysfunction 600/300mg tabs 1 Tablet qd* Abacavir/Lamivudine Epzicom 300/200mg tabs 1 Tablet qd* Tenofovir/Emtricitabine Truvada 300/150/300mg tabs 1 Tablet bid* Abacavir/Lamivudine/Zidovudine (TZV) Trizivir 300/200/600 mg tabs 1 Tablet qd* Tenofovir/Emtricitabine/Efavirenz Atripla 150/300mg tabs 1 Tablet bid * Lamivudine/ Zidovudine (COM) Combivir Dosage forms Standard Dose* Drug
    11. 11. Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) <ul><li>These agents directly bind to reverse transcriptase to inhibit transcription </li></ul><ul><li>NNRTIs do not </li></ul><ul><li>require </li></ul><ul><li>phosphorylation </li></ul><ul><li>to be active </li></ul>RT X
    12. 12. NNRTIs *Pregnancy Class D Vivid dreams, drowsiness or insomnia, rash (SJ), hyperlipidemia Rash (SJ), hepatotoxicity Rash Common AEs CYP3A, 2B6 inducer; 2B6, 3A4 substrate 50, 100, 200mg cap, 600mg tab 600 mg qhs Efavirenz* (EFV) Sustiva CYP3A inducer, auto inducer; 3A4, 2B6 substrate 200mg tabs, Oral susp 200 mg qd x 14 d then 200 mg bid Nevirapine (NVP) Viramune Potent CYP3A inhibitor; 3A4 substrate 100mg tab, 200mg cap 400 mg tid Delavirdine (DLV) Rescriptor Metabolism Dosage forms Standard Dose Drug
    13. 13. Protease Inhibitors (PIs): Mechanism of Action <ul><li>Protease enzyme cleaves HIV precursor proteins (gag/pol polyproteins) into active proteins that are needed to assemble a new, mature HIV virus. </li></ul><ul><li>PIs bind to protease preventing the cleavage and inhibiting the assembly of new HIV viruses </li></ul>PI HIV-1 Protease X HIV
    14. 14. Lipids, Insulin Resistance (Lypodystrophy) <ul><li>Hypercolesterolemia </li></ul><ul><ul><li>Usually hypertriglyceridemia, can have increased LDL and decreased HDL </li></ul></ul><ul><ul><li>Treat with Fibric acid derivatives and certain HMGCoA reductase inhibitors </li></ul></ul><ul><li>Insulin Resistance </li></ul><ul><ul><li>Treat with diet/exercise, metformin, TZDs, insulin, sulfonylureas </li></ul></ul>
    15. 15. Lipodystrophy Illustrations “ Buffalo hump” “ Protease paunch” “ Facial wasting”
    16. 16. Use of Ritonavir as a P450 Inhibitor with PIs
    17. 17. Protease Inhibitors (1) Take with Food (2) Must be refrigerated ** All PIs except atazanavir can increase lipids and cause insulin resistance Dyspepsia, Nausea, vomiting, diarrhea, flatulence 3A, Pgp substrate; 3A inhibitor; 2C9, 2C19 inducer 200/50 mg tabs, 80/20mg/5mL soln 400/100 bid Lopinavir/ ritonavir (Kaletra) (1,2) 3A, Pgp substrate; weak 3A inhibitor 2C19 (M8  3A) substrate; weak 3A inhibitor 3A, Pgp substrate; weak 3A inhibitor Metabolism Nephrolithiasis  Drink 7-8 glasses of water per day; hyperbilirubinemia 100, 200, 333, 400mg caps 800/ rtv 100 bid, 800mg tid Indinavir (Crixivan) (1-when taken with rtv) Diarrhea 250mg, 625mg tabs, 50mg/g oral pwdr 1250 bid, 750mg tid Nelfinavir (Viracept) (1) GI intolerance 200mg caps, 500mg tabs 1000/ rtv 100 bid or 1600/ rtv 100 qd Saquinavir (Invirase) (1) Common AEs** Dosage Forms Standard Dose
    18. 18. Protease Inhibitors (1) Take with Food (2) Must be refrigerated ** All PIs except atazanavir can increase lipids and cause insulin resistance Diarrhea, nausea, HA, nasopharyngitis 3A4 substrate; 3A4 inhibitors 300mg tabs 600/100 RTV mg bid Darunavir (Prezista) (1) Hyperbilirubinemia, PR prolongation 3A substrate; 3A and UGT1A1 inhibitor 100, 150, 200mg caps 400qd or 300/ rtv 100qd Atazanavir (Reyataz) (1) Hepatotoxicity, Increased bleeding caution with sulfur allergy 3A4, Pgp substrate; 3A4, inducer/ inhibitor??; Pgp inducer 250mg caps 500/200 RTV mg bid Tipranavir (Aptivus) (1,2) Nausea, vomiting, diarrhea, GI upset 2D6, 3A4, Pgp substrate; 3A4, Pgp inhibitor 100mg caps; 80mg/mL Used as a PK booster 100-200mg Ritonavir (Norvir) (1,2) 3A4, Pgp substrate; 3A4 inducer/ Inhibitor Metabolism Rash, GI intolerance, caution with sulfur allergy 700mg tabs (Agenerase-APV liq available) 1400mg bid; 700/100 RTV mg bid; 1400/200 RTV mg qd Fosamprenavir (Lexiva) (1) Common AEs** Dosage Forms Standard Dose
    19. 19. Dose adjustments to consider <ul><li>Renally-eliminated </li></ul><ul><li>NRTIs (except Abacavir) </li></ul><ul><li>Adjust for CrCl <50 ml/min or dialysis </li></ul><ul><li>Didanosine </li></ul><ul><li>Emtricitabine </li></ul><ul><li>Lamivudine </li></ul><ul><li>Stavudine </li></ul><ul><li>Tenofovir </li></ul><ul><li>Zidovudine </li></ul><ul><li>Reference: Drug product info and DHHS guidelines (see tables) </li></ul><ul><li>Hepatic Metabolism </li></ul><ul><li> NNRTIs </li></ul><ul><li> PIs </li></ul><ul><li>Adjust for certain inducers, substrates, or inhibitors of P450 system </li></ul><ul><li>Adjust for insufficiency </li></ul><ul><li>Indinavir </li></ul><ul><li>Fosamprenavir </li></ul><ul><li>Atazanavir </li></ul><ul><li>Avoid </li></ul><ul><li>Amprenavir oral soln </li></ul><ul><li>Foasmprenavir (+/- ritonavir) </li></ul><ul><li>Tipranavir </li></ul>
    20. 20. New ARV Targets Against HIV
    21. 21. Fusion Inhibitor <ul><li>Fuzeon (Enfuvirtide, T-20) </li></ul>See Kilby and Eron, NEJM 2003;348:2228-38
    22. 22. Fuzeon : Enfuvirtide (T-20) <ul><li>FDA-approved fusion inhibitor; 36 AA peptide </li></ul><ul><ul><li>Requires 106 steps to manufacture </li></ul></ul><ul><li>Dose: 90 mg sq bid </li></ul><ul><li>side effects: </li></ul><ul><ul><li>injection site rxn, hypersensitivity (rare) </li></ul></ul><ul><li>resistance: changes in gp41 (cell surface protein) </li></ul>
    23. 23. HIV Tropism
    24. 24. Chemokine Receptor Antagonists <ul><li>Marviroc (Selzentry ® ) </li></ul><ul><li>CCR5 or CXCR4 receptors on cell surface </li></ul><ul><li>Virus will bind to one of the 2 receptors </li></ul><ul><ul><li>Some patients’ virus will bind to either receptor </li></ul></ul><ul><li>Marviroc blocks viral entry at CCR5 </li></ul><ul><li>Dosed 300mg BID </li></ul><ul><ul><li>150mg BID with P450 inhibitors </li></ul></ul><ul><ul><li>600mg BID with P450 inducers </li></ul></ul>
    25. 25. Integrase Inhibitors <ul><li>Raltegravir (Isentress™) </li></ul><ul><li>Dosed 400mg BID (1 tab BID) </li></ul><ul><li>No induction or inhibition on CYP450 enzymes or Pgp </li></ul><ul><li>Metabolized by UGT1A1 (glucuronidation) </li></ul><ul><ul><li>Only affected by drugs that inhibit or induce UGTs (ie, rifampin) </li></ul></ul>
    26. 26. Drug Interactions
    27. 27. Antiretroviral Metabolism, Induction, and Inhibition Other enzymes 3A4 3A4, Pgp Tipranavir 3A4 3A4, Pgp Darunavir 3A4, Pgp Maraviroc 3A4, UGT, 1A2 3A4, Pgp Atazanavir 2C9, 2C19, 1A2 3A4 3A4, Pgp Lopinavir/ritonavir 3A4 (in vivo) 3A4 (in vitro) 3A4, Pgp Fosamprenavir 3A4 (in vivo) 3A4 (in vitro) 3A4, Pgp Amprenavir 3A4 2C19 (M8  3A4) Nelfinavir 3A4 3A4, Pgp Saquinavir 2D6 (at high doses only) 3A4, 2D6, Pgp 2D6, 3A4, Pgp Ritonavir 3A4 3A4, 2B6 Nevirapine 3A4, 2B6 3A4 2B6, 3A4 Efavirenz Induces Inhibits Substrate Drug
    28. 28. Cytochrome P450: Non-Antiretrovirals rifamycins, CBZ, phenytoin SSRIs, azoles, fluvastatin, omeprazole, topiramate Omeprazole, phenytoin 2C19 rifamycins, phenytoin, carbamazepine, St. John’s wort, aprepitant, garlic Cimetidine, Macrolides, FQs, SSRIs, CCB, azoles, aprepitant Macrolides,cyclosporine, CCB, statins, azoles, PDE5 inhibitors, aprepitant, midazolam, triazolam 3A4 rifamycins, phenytoin, CBZ, St. John’s wort Haldol, SSRIs, cimetidine, amiodarone Opiates, nortriptyline, amitriptyline, tramadol, trazodone, paroxetine, metoprolol, propranolol, carvedilol 2D6 Inducer Inhibitor Substrate Phenytoin, CBZ, rifammycins, aprepitant Amiodarone, SSRIs, azoles, amiodarone S-warfarin, sulfonylureas, phenytoin, carvedilol 2C9 rifamycins, phenytoin, CBZ, smoking, St. John’s wort FQs, azoles, macrolides, Amitriptyline, clozapine, caffeine, clozapine, imipramine, R-warfarin, theophylline, proprnaolol 1A2
    29. 29. Protease Inhibitors and Acid Suppression <ul><li>Do Not combine Atazanavir and Proton Pump Inhibitors </li></ul><ul><ul><li>May Combine ATV and Famotidine but dose adjustments are REQUIRED </li></ul></ul><ul><li>May use Indinavir with PPIs but ONLY if coadministered with RTV </li></ul><ul><li>May use Fosamprenavir with Esomeprazole </li></ul><ul><ul><li>Separate FPV from H2 blockers if used concomitantly </li></ul></ul>
    30. 30. Dose Adjustments Between ARVs Use RTV with FPV Fosamprenavir Efavirenz (Nevirapine) Increase LPV/RTV to 3 tabs BID Lopinavir/ritonavir Efavirenz (Nevirapine) Use RTV 100mg QD with ATV + EFV Atazanavir Efavirenz (Nevirapine) Use RTV 100mg QD with ATV + TDF Atazanavir Tenofovir Dose ddI as 250mg QD with TDF 300mg QD Didanosine Tenofovir Recommendation Drug B Drug A
    31. 31. Important Drug Interactions <ul><li>Do NOT use Simvastatin, Lovastatin, Antiarrthymics, Midazolam, Triazolam, Ergot derivatives, Rifamin, St. Johns Wort, or Garlic with most PIs or DLV </li></ul><ul><li>Do NOT combine Rifampin with PIs </li></ul><ul><ul><li>LPV/RTV may be dose increased and combined with Rifampin </li></ul></ul><ul><ul><li>Conflicting data with EFV and NVP </li></ul></ul><ul><li>Use other P450 inducers with CAUTION when combining with PIs and NNRTIs </li></ul><ul><li>Do NOT use Fluticasone or Alfuzosin with Ritonavir </li></ul><ul><li>Caution with Azoles, Clarithromycin, Oral Contraceptives, Phenytoin, Carbamazepine, Phenobarbital, Methadone, PDE5 inhibitors, Atorvastatin, Beta blockers, when combined with PIs </li></ul><ul><li>Avoid Herbal Products with Known or Suspected Interactions </li></ul><ul><li>When combining Protease Inhibitors, Often Dose Adjustments are Necessary </li></ul>
    32. 32. Importance of Adherence
    33. 33. Therapeutic Drug Monitoring <ul><li>Not widely used in the US </li></ul><ul><li>Recommended in certain situations for PIs and NNRTIs </li></ul><ul><li>What makes a drug a good candidate for TDM? </li></ul><ul><li>When should TDM be performed for antiretrovirals? </li></ul>
    34. 34. Why TDM in HIV therapy? Adapted from Acosta EP, et al AIDS Res Human Retro 2002