Antiretroviral Pharmacology

Transkripsi

1 Antiretroviral Pharmacology Dept. Pharmacology & Therapeutic School of Medicine Universitas Sumatera Utara Different living organisms Eucaryotes Mono or polycellular Cell nucleus; DA May have cell wall Sexual and/or asexual replication Animals Plants Fungi Protocista(protozoea, algea) Procaryotes Bacteriea Monocellular, no nucleus DA single strand Cell wall, asexual replication Virus RA or DA + protein coating (not really a cell) Use other organisms ribosomesfor protein synthesis 1

2 IFEKSI VIRUS PELEKATA VIRUS DA DIDIG SEL (DIHIDRLISA LEH EZIM VIRUS) DA/RA MASUK KE DLM SEL SEDAG CAPSID TIDAK VIRUS SEBAGAI PARASIT, MEGGUAKA PRSES ASIMILASI SEL VIRI BARU ( PERBAYAKA VIRI SAMPAI PUCAK GEJALA PEYAKIT) Antiviral Drugs Amantadine and analogs euraminidase Inhibitors ucleoside analogs - Antimetabolites ther comp. that interfere with replication Comp. that interfere with translation (protein synth) Interferon / interferon inducers Specific retroviral drugs Reverse transcriptase inhibitors ucleosides (RTIs) on-nucleosides (RTIs) Protease inhibitors 2

3 Klasifikasi Antivirus berdasarkan Mekanisme Kerja Mekanisme Kerjanya Antivirus Menghalangi penetrasi γ Globulins Menghalangi uncoating Menghambat sintesis protein awal Menghambat sintesis asam nukleat Menghambat sintesis protein akhir Menghambat perakitan Menghambat rilis Menghambat penetrasi, uncoating, sintesis mra, translasi, perakitan,rilis Amantadine & Rimantadine Formivirsen 1. Analog purin & pirimidin (Acyclovir, Valacyclovir, Famciclovir, Penciclovir, Ganciclovir, Idoxurudine, Sorivudine,Trifluridine, Cidofovir, Vidarabine, Ribavirine) 2. Pyrophosphate anorganic (Foscarnet ) 3. RTI (Zidovudine, Lamivudine, Stavudine Didanosine, Zalcitabine, Abacavir) 4. RTI (evirapine, Delavirdine, Efavirenz ) Inhibitor protease (Saquinavir, Ritonavir, Indinavir, elfinavir, Amprenavir) Rifampin Inhibitor neuraminidase (Zanamivir, seltamivir) Interferon Viral zinc-finger nucleocapsid proteins Fusion inhibition Viral protease Reverse transcriptase RA RT RA DA RT DA RA RA Proteins Viral regulatory proteins DA Provirus Viral integrase 3

4 Antiretroviral Classes RTIs (ucleoside R ucleotide Reverse Transcriptase Inhibitors, aka ukes ) RTIs (on-ucleoside Reverse Transcriptase Inhibitors, aka on-ukes ) PIs (Protease Inhibitors) Fusion Inhibitors Chemokine Receptor Antagonists Integrase Inhibitors Mechanism of Action of ARVs Integrase Inhibitor Protease Inhibitor Fusion Inhibitor & Chemokine Receptor Antagonist RTI RTI Illustration by David Klemm 4

5 RTIs (ucleoside R ucleotide Reverse Transcriptase Inhibitors) ucleoside Reverse Transcriptase Inhibitors ucleoside analogs without 3 H - DA chain termination Pro-drugs - Phosphorylated by kinases in vivo Zidovudine (AZT) Retrovir Trizivir Kombi prep. H H 3 Didanosine (ddi) Videx H H in vivo P P P H 2 Stavudine Zerit H H Zalcitabine (ddc) H H 2 Abacavir (ABC) Trizivir Kombi prep. H 2 H H Lamividine (3TC) Epivir Trizivir Compivir Kombi prep. S H 2 H Higher bioavail. than ddc 5

6 RTIs (ucleoside R ucleotide Reverse Transcriptase Inhibitors) Drug Std Dose Dosage forms Side Effects Elimination Zidovudine (ZDV/AZT) Retrovir Lamivudine (3TC) Epivir Emtricitabine (FTC) Emtriva Didanosine (ddi) Videx Stavudine (d4t) Zerit IR Abacavir (ABC) Ziagen Tenofovir (TDF) Viread 300mg bid* 150mg bid* or 300mg qd 300mg tab, 100mg cap, iv, oral soln 150, 300mg tab, oral soln Fatigue, malaise, HA myalgia, anemia, GI Well tolerated Renal Renal 200mg qd* 200mg cap Well tolerated Renal 400mg EC qd ( 60kg) 250mg EC qd (<60kg)* 40mg bid ( 60kg) 30mg bid (<60kg) 300mg bid, 600mg qd 125,200,250, 400mg cap, pwdr for soln 15,20,30,40 mg cap,oral soln 300mg tabs, oral soln Pancreatitis, peripheral neuropathy, LA/HS Peripheral neuropathy, Pancreatitis, LA/HS, Lipoatrophy, facial wasting hypersensitivity 300mg qd* 300mg tabs Few SEs, renal toxicity Renal Renal Hepatic by alcohol dehydrogenase and glucuronyl transferase Renal RTIs Mechanism of Action ucleoside analogs (like AZT below) Analog of thymidine, cytosine, adenine, or guanine Triphosphorylated inside lymphocytes to active compound Incorporate into the growing HIV viral DA strand by reverse transcriptase ucleotide analog Currently only tenofovir (TDF) Does T need to be tri-phosphorylated only di-phosphorylated to active compound After incorporation of the RTI, viral DA synthesis will be terminated. 6

7 RTI Class Toxicities Lactic Acidosis Damage to mitochondria in cells Elevated lactate, low ph/bicarbonate, /V, shortness of breath, if untreated can lead to death Lactic acidosis can occur with any RTIs Hepatomegaly with Steatosis Build up of fat droplets inside liver cells Enlarged liver on-nucleoside Reverse Transcriptase Inhibitors (RTIs) 7

8 on-ucleoside Reverse Transcriptase Inhibitors (RTI) Binds directly to TR evirapin Viramune Efavirenz / Sustiva Stocrin H Me F 3 C H Cl FDA 1998 Already resistance RTIs Drug Std Dose Dosage forms Side Effects Elimination Delavirdine (DLV) Rescriptor evirapine (VP) Viramune Efavirenz* (EFV) Sustiva 400 mg tid 100mg tab, 200mg cap 200 mg qd x 14 d then 200 mg bid 200mg tabs, ral susp 600 mg qhs 50, 100, 200mg cap, 600mg tab Rash Rash (SJ), hepatotoxicity Vivid dreams, drowsiness or insomnia, rash (SJ), hyperlipidemia Potent CYP3A inhibitor; 3A4 substrate CYP3A inducer, auto inducer; 3A4, 2B6 substrate CYP3A, 2B6 inducer; 2B6, 3A4 substrate *Pregnancy Class D 8

9 RTIs Mechanism of Action These agents directly bind to reverse transcriptase to inhibit transcription RTIs do not require phosphorylation to be active RT Protease Inhibitors (PIs) 9

10 Saquinavir Fortovase H H H H H Ph H 2 H Protease Inhibitors Saquinavir (green) bound to HIV-1 Protease Indinavir Crixivan Lopinavir Kaletra H H Ph H H H Ph H Ph H H elfinavir Viracept Amprenavir Agenerase H H H H H S Ph H S H H Ph Protease Inhibitors (PIs) Drug Std Dose Dosage forms Side Effects Metabolism Atazanavir (Reyataz) (1) Fosamprenavir (Lexiva) (1) Tipranavir (Aptivus) (1,2) Darunavir (Prezista) (1) Ritonavir (orvir) (1,2) 400qd or 300/ rtv 100qd 1400mg bid; 700/100 RTV mg bid; 1400/200 RTV mg qd 500/200 RTV mg bid 600/100 RTV mg bid Used as a PK booster mg 100, 150, 200mg caps 700mg tabs (Agenerase-APV liq available) 250mg caps 300mg tabs 100mg caps; 80mg/mL (1) Take with Food; (2) Must be refrigerated ** All PIs except atazanavir can increase lipids and cause insulin resistance Hyperbilirubinemia, PR prolongation Rash, GI intolerance, caution with sulfur allergy Hepatotoxicity, Increased bleeding caution with sulfur allergy Diarrhea, nausea, nasopharyngitis ausea,vomiting, diarrhea, GI upset 3A substrate; 3A and UGT1A1 inhibitor 3A4, Pgp substrate; 3A4 inducer/ Inhibitor 3A4, Pgp substrate; 3A4, inducer/ inhibitor??; Pgp inducer 3A4 substrate; 3A4 inhibitors 2D6, 3A4, Pgp substrate; 3A4, Pgp inhibitor 10

11 Protease Inhibitors (PIs): Mechanism of Action Protease enzyme cleaves HIV precursor proteins (gag/pol polyproteins) into active proteins that are needed to assemble a new, mature HIV virus. PIs bind to protease preventing the cleavage and inhibiting the assembly of new HIV viruses X HIV Dose adjustments to consider Renally-eliminated RTIs (except Abacavir) Adjust for CrCl <50 ml/min or dialysis Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine Reference: Drug product info and DHHS guidelines (see tables) Hepatic Metabolism RTIs PIs Adjust for certain inducers, substrates, or inhibitors of P450 system Adjust for insufficiency Indinavir Fosamprenavir Atazanavir Avoid Amprenavir oral soln Foasmprenavir (+/- ritonavir) Tipranavir 11

12 Fusion Inhibitor Fuzeon (Enfuvirtide, T-20) See Kilby and Eron, EJM 2003;348: Fuzeon : Enfuvirtide (T-20) FDA-approved fusion inhibitor; 36 AA peptide Requires 106 steps to manufacture Dose: 90 mg sq bid side effects: injection site rxn, hypersensitivity (rare) resistance: changes in gp41 (cell surface protein) 12

13 Chemokine Receptor Antagonists Marviroc (Selzentry ) CCR5 or CXCR4 receptors on cell surface Virus will bind to one of the 2 receptors Some patients virus will bind to either receptor Marviroc blocks viral entry at CCR5 Dosed 300mg BID 150mg BID with P450 inhibitors 600mg BID with P450 inducers Integrase Inhibitors Raltegravir (Isentress ) Dosed 400mg BID (1 tab BID) o induction or inhibition on CYP450 enzymes or Pgp Metabolized by UGT1A1 (glucuronidation) nly affected by drugs that inhibit or induce UGTs (ie, rifampin) 13

14 Drug Interactions ARV metabolism, induction, and inhibition Drug Substrate Inhibits Induces Efavirenz 2B6, 3A4 3A4 3A4, 2B6 evirapine 3A4, 2B6 3A4 Ritonavir 2D6, 3A4, Pgp 3A4, 2D6, Pgp 2D6 (at high doses only) Saquinavir 3A4, Pgp 3A4 elfinavir 2C19 (M8 3A4) 3A4 Amprenavir 3A4, Pgp 3A4 (in vitro) 3A4 (in vivo) Fosamprenavir 3A4, Pgp 3A4 (in vitro) 3A4 (in vivo) Lopinavir/ritonavir 3A4, Pgp 3A4 2C9, 2C19, 1A2 Atazanavir 3A4, Pgp 3A4, UGT, 1A2 Tipranavir 3A4, Pgp 3A4 ther enzymes Darunavir 3A4, Pgp 3A4 Maraviroc 3A4, Pgp 14

15 Cytochrome P450: on-antiretrovirals Cyp. Substrate Inhibitor Inducer 3A4 2D6 1A2 Macrolides,cyclosporine, CCB, statins, azoles, PDE5 inhibitors, aprepitant, midazolam, triazolam nortriptyline, amitriptyline, tramadol, trazodone, opiates, paroxetine, metoprolol, propranolol, carvedilol Amitriptyline, clozapine, caffeine, clozapine, imipramine, R-warfarin, theophylline, proprnaolol Cimetidine, Macrolides, FQs, SSRIs, CCB, azoles, aprepitant Haldol, SSRIs, cimetidine, amiodarone FQs, azoles, macrolides, 2C19 meprazole, phenytoin SSRIs, azoles, fluvastatin, omeprazole, topiramate 2C9 S-warfarin, sulfonylureas, phenytoin, carvedilol Amiodarone, SSRIs, azoles, amiodarone rifamycins, phenytoin, CBZ, St. John s wort, aprepitant, garlic rifamycins, phenytoin, CBZ, St. John s wort rifamycins, phenytoin, CBZ, smoking, St. John s wort rifamycins, CBZ, phenytoin Phenytoin, CBZ, rifammycins, aprepitant Protease Inhibitors and Acid Suppression Do ot combine Atazanavir and Proton Pump Inhibitors May Combine ATV and Famotidine but dose adjustments are REQUIRED May use Indinavir with PPIs but LY if coadministered with RTV May use Fosamprenavir with Esomeprazole Separate FPV from H2 blockers if used concomitantly 15

16 Important Drug Interactions Do T use Simvastatin, Lovastatin, Antiarrthymics, Midazolam, Triazolam, Ergot derivatives, Rifamin, St. Johns Wort, or Garlic with most PIs or DLV Do T combine Rifampin with PIs LPV/RTV may be dose increased and combined with Rifampin Conflicting data with EFV and VP Use other P450 inducers with CAUTI when combining with PIs and RTIs Do T use Fluticasone or Alfuzosin with Ritonavir Caution with Azoles, Clarithromycin, ral Contraceptives, Phenytoin, Carbamazepine, Phenobarbital, Methadone, PDE5 inhibitors, Atorvastatin, Beta blockers, when combined with PIs Avoid Herbal Products with Known or Suspected Interactions When combining Protease Inhibitors, ften Dose Adjustments are ecessary PI/ RTI/ Antidepressant Drug Interactions Antidepressant Amitriptyline Fluoxetine Sertraline Potential for Interaction ritonavir, lopinavir/r, amprenavir, ritonavir, lopinavir/r, all other PIs, efavirenz ritonavir, lopinavir/r, all other Pis, efavirenz Effects Levels of amitriptyline may be increased Levels of both fluoxetine and ARVs may be increased Levels of sertraline may be increased. ARV levels not likely to change. Management Start with lower dose (50%) of amitriptyline, adjust dose when adding ritonavir. Monitor for side effects As above As above 16

17 PI Drug Interactions All PIs are metabolized all or in part by the CYP3A4 enzyme system All PIs can inhibit CYP3A4 enzymes Ritonavir most potent inhibitor Saquinavir least potent inhibitor Ritonavir can also induce CYP1A2 ARV Interactions with Recreational Drugs Effect Comments Alcohol Abacavir AUC 41% Clinical significance unknown Amphetamines Barbiturates Benzo-diazepines λ-hydroxybutyrate (GHB) Heroin RTV may amphetamine levels Potential levels of PIs and RTIs Midazolam and triazolam levels with PIs and delavirdine (levels of alprazolam and clonazepam may ) Potential GHB levels Potential enhanced heroin effect Potential amphetamine toxicity Potential virologic failure/resistance Potential benzodiazepine toxicity Potential GHB toxicity Clinical significance unknown Marijuana Minimal effect on IDV and FV Interaction with ARVs unlikely 3,4-MDMA (Ecstasy) Potential ecstasy levels Potential ecstasy toxicity 17

18 Dirgahayu negeriku Dirgahayu FK USU KEBAGGAA IDESIA UTUK DUIA ATIRETRVIRAL 18

19 ARV dibagi dalam 6 kelas: ucleoside reverse transcriptase inhibitors (RTIs) onnucleoside reverse transcriptase inhibitors (RTIs) Protease inhibitors (PIs) Integrase inhibitors (IIs) Fusion inhibitors (FIs) Chemokine receptor antagonists (CRAs) ucleotide Reverse Transcriptase Inhibitor (RTI) Difosforilasi oleh enzim seluler untuk menjadi bentuk aktif RTI toksik terhadap hati kecuali Lamivudine dan Abacavir Secara umum bekerja untuk menghentikan pembentukan rantai DA virus Monitoring kepada toksisitas oleh karena obat 19

20 Zidovudine (AZT) Bentuk aktif berupa azido-deoxythymidine monophosphate (AZT-MP) Bekerja menghalangi sintesis DA bat diserap dengan baik melalui oral, dapat menembsu sawar otak SE: toksisitas sumsum tulang, sakit kepala Resistensi jarang terjadi Bentuk aktif berupa dideoxyadenosine monophosphate Sama dengan AZT, ddl juga bekerja pada rantai DA Makan saat puasa,saat kondisi basa Dapat juga memasuki CSF, ttapi tidak seluas AZT SE: pancreastitis Didanosine (ddl) Resistensi terjadi pada terapi yang panjang 20

21 Zalcitabine (ddc) Digunakan bersama AZT Bentuk aktif berupa triphosphate Bekerja pada rantai DA Penggunaan secara oral, hindari penggunaan bersama antasida SE: Rash dan stomatitis, periferal neuropati Tidak boleh digunakan bersama pentamidine, dapat menyebabkan pankreatitis Stavudine (d4t) Bentuk aktif berupa triphosphate Bekerja menghentikan rantai DA Diabdsorbsi dengan sangat baik tanpa dipengaruhi makanan SE: periferal neuropati 21

22 Lamivudine (3TC) Dikombinasikan dengan AZT, tidak boleh digunakan dengan ddc Menyebabkan terminasi sintesis rantai DA virus 3TC dapat mengembalikan sensitiviras terhadap AZT Penggunaan secara oral Abacavir Merupakan analog dari guanosine Penggunaan secara oral SE: gangguan pencernaan, sakit kepala, dan pusing 22

23 Tenovovir Analog nukleotid Menghambat reverse trankriptase Dimakan pada saat setelah makan SE: mual, muntah, diare Emtricitabine Derivatif dari lamivudine Menghambat reverse transkriptase Dikonsumsi secara oral SE: sakit kepala, diare, mual, dan kulit merah gatal 23

24 Tn H, harus segara cuci tangan debgan air dan sabun serta melaporkan diri ke pihak rs dan segera mengeluasi pajanan. Kode pajanan 3 dan status 2 dan diperlukan profilaksis obat AZT Zidovudin (3 kali sehari 200mg ) dan dikombinasi dgn lamivudin 300mg/hari dan Idanavir 3 kali sehari 800mg per oral dan nelvinapir 3 kali sehari 800 mg per oral.tn H harus lakukan follow up 3 bulan dan 6 bulan pasca pajanan. ucleoside Reverse Transcriptase Inhibitors Abacavir (ABC, Ziagen) Didanosine (ddi, Videx) Emtricitabine (FTC, Emtriva) Lamivudine (3TC, Epivir) Stavudine (d4t, Zerit) Tenofovir (TDF, Viread) Zalcitabine (ddc, Hivid; no longer available in the United States) Zidovudine (ZDV, Retrovir; formerly azidothymidine [AZT]) Mekanisme kerja RTIs menghambat replikasi HIV melalui inhibisi secara kompetitif HIV reverse transcriptase dan terminasi rantai DA. 24

25 Therapy of HIV Infection ucleoside-analog Reverse Transcriptase Inhibitors (RTI). These drugs inhibit viral RA-dependent DA polymerase (reverse transcriptase) and are incorporated into viral DA (they are chain-terminating drugs). Zidovudine (AZT = ZDV, Retrovir) first approved in 1987 Didanosine (ddi, Videx) Zalcitabine (ddc, Hivid) Stavudine (d4t, Zerit) Lamivudine (3TC, Epivir) on-ucleoside Reverse Transcriptase Inhibitors (RTIs). In contrast to RTIs, RTIs are not incorporated into viral DA; they inhibit HIV replication directly by binding non-competitively to reverse transcriptase. evirapine (Viramune) Delavirdine (Rescriptor) Protease Inhibitors. These drugs are specific for the HIV-1 protease and competitively inhibit the enzyme, preventing the maturation of virions capable of infecting other cells. Saquinavir (Invirase) first approved in 1995 Ritonavir (orvir) Indinavir (Crixivan) elfinavir (Viracept) 25