Pharmacology of Anti-Hepatitis Drugs Lecture Notes PDF

PHARMACOLOGY OF ANTI-HEPATITIS DRUGS VAIDEHI THANAWALA 15 NOVEMBER 2022 Goal: To define the mechanisms of action of the currently available/used anti-hepatitis drugs ¡ Objectives: ¡ Understand and distinguish between the viral strains and replication methods ¡ Understand the MOA of available dr...

PHARMACOLOGY OF ANTI-HEPATITIS DRUGS VAIDEHI THANAWALA 15 NOVEMBER 2022 Goal: To define the mechanisms of action of the currently available/used anti-hepatitis drugs ¡ Objectives: ¡ Understand and distinguish between the viral strains and replication methods ¡ Understand the MOA of available drugs for hepatitis B and C ¡ Identify relevant ADME, related to the pharmacology ¡ Identify main and relevant adverse reactions 2 TYPES OF HEPATITIS VIRUSES Type Virus Structure Notes A RNA, picornavirus Non-enveloped, linear Oro-fecal transmission, acute infection only, no antiviral therapies, vaccine available B DNA, hepadnavirus Enveloped, circular (partial double stranded DNA) Percutaneous or mucosal contact transmission Viral polymerase lacks proofreading = mutations = resistance Acute and chronic hepatitis Neonatal exposure (90% chance of chronic), adult (5% chance of chronic) – high risk of HCC and other hepatic sequelae Vaccine available, limited curative treatments C RNA, flavivirus Enveloped, linear Viral RNA polymerase lacks proofreading = frequent mutations in genome. IV drug abuse or blood transfusion (not recent) Acute and chronic hepatitis, curative therapies available D RNA Enveloped, circular “satellite” or ”defective” virus lacks gene for envelope proteins, uses HBsAg (HBV) envelope proteins. Co-infection with HBV needed, worse prognosis than HBV alone. Limited Treatment options/efficacy- pegIFN-α, Hepcludex/Bulevertide qd sc chronic (approved by EMEA; FDA pending) E RNA, hepevirus Non-enveloped, linear (Rare) Oro-fecal transmission, acute infection mainly, no antiviral therapies, no vaccine, high mortality rate in pregnancy 3 HEPATITIS B VIRUS (HBV) ¡ Virus has a partially stranded DNA, has its own polymerase and synthesizes reverse transcriptase ¡ HBsAg (surface), HBcAg (core) and HBeAg are antigens useful for diagnosis ¡ Transmission ¡ Vertical – Mother to child ¡ Horizontal - IVDU or blood transfusions Dane particle (HBV) ¡ HBV has a high replication rate, polymerase lacks proofreading --> mutations and resistance ¡ Mutations in RT or polymerase domain = resistance to NRTI ¡ Only 10% patients achieve a functional cure ¡ Functional cure = HBV DNA < LLOQ and HBsAg seroclearance ≥ 24 weeks 4 LIFE CYCLE OF HEPATITIS B VIRUS ¡ Binds to Na+/taurocholate cotransporter (NTCP), enters hepatocyte and is uncoated ¡ Partial double stranded DNA is repaired in the nucleus to form cccDNA ¡ In addition, it also integrates into host DNA ¡ mRNA transcribed and translated into viral proteins including reverse transcriptase ¡ RT synthesizes uses pgRNA as template ¡ Viral proteins assembled and envelope formed in ER ¡ New viral particles formed and released 5 THERAPIES FOR HEPATITIS B VIRAL INFECTION Notes Interferon-alfa and PEGinterferon-alfa 2a Potent cytokines. Recombinant IFN used for therapy. Naturally produced in response to viral infection MOA: • Antiviral and antiproliferative • Activate Jak-STAT pathway • stimulates the cytotoxic activity of lymphocytes, NK cells, and macrophages • upregulates expression of class I MHC antigens and other surface markers SIDE EFFECTS: Patients often end up discontinuing due to the side effects Flu-like syndrome, CNS effects (fatigue, depression), Ophthalmic disorders (retinopathy), ↑LFTs , GI upset (N/V weight loss) Boxed warnings: Neuropsychiatric disturbances, cytopenias, ischemic complications, autoimmune disorders Entecavir NRTI (covered in detail in anti-retroviral lectures) Nausea, Body fat redistribution (lipodystrophy), hepatomegaly Adefovir Not as commonly used Tenofovir (TDF and TAF) Covered in detail in anti-retroviral lectures NRTI/NA Interferon Drug 6 IN THE PIPELINE ¡ Current therapeutics (NRTIs) result in control of HBV DNA but limited functional cure (NRTI or PEG-IFN) ¡ Newer compounds in development, focus on achieving a functional cure, proposed to be better than anti-virals ¡ In the pipeline are compounds that are siRNAs, capsid assembly modulators, monoclonal antibodies, antisense oligonucleotides (ASOs), therapeutic vaccines among others 7 LIFE CYCLE OF HEPATITIS C VIRUS (HCV) ¡ Replicates entirely in the cytoplasm ¡ Positive single stranded RNA codes for ¡ Three structural proteins Core, E1 and E2 ¡ Ion channel p7 ¡ Six nonstructural proteins NS2, NS3, NS4A, NS4B, NS5A, and NS5B ¡ High heterogeneity – obstacle for treatment/vaccine ¡ Curable = sustained virologic response (SVR) = no measurable HCV RNA in blood following cessation of therapy ¡ Patients usually classified by 6 genotypes 8 CLASSES OF THERAPIES FOR HCV INFECTION Nonspecific • IFN alpha • p-IFN alpha • • • • NS5A inhibitors “..asvir” NS5B inhibitors “..buvir” Velpatasvir Elbasvir Ledipasvir Pibrentasvir • Sofosbuvir NS3/4 protease inhibitors “..previr” • Voxilaprevir • Glecaprevir • Grazoprevir Resistance to HCV therapies and DDIs are important considerations for the treatment of HDV 9 RESISTANCE TO HCV TREATMENTS ¡ Polymerase lacks proofreading = continuous generation of a large variety of variants ¡ New or existing resistant associated variants (RAVs) ¡ Treatments success dependent on ¡ RAVs (type and number of mutations)/the drug’s barrier to resistance ¡ Level of drug exposure ¡ Replicative capacity/fitness of the RAV ¡ Nucleotide NS5B polymerase inhibitors have a high barrier to resistance (3 or more RAVs needed) ¡ Non-nucleotide NS5B polymerase inhibitors, NS5A inhibitors and NS3 protease inhibitors have low barriers to resistance 10 ANTI-HCV DRUGS (DIRECT ACTING ANTIVIRALS- DAA) ALL DAAs have a black box warning: Risk of HBV reactivation in patients coinfected with HCV and HBV Target Drug Notes Nonspecific IFN-alfa and pIFN-alfa (not DAA) Were historically used with (pegasys) or without ribavirin (copegasys). Not very effective in lowering SVR. Side effects see HBV NS5A inhibitors (Fatigue and headaches) Velpatasvir Baseline RAVs do not affect SVR (with sofosbuvir). All genotypes susceptible pH dependent absorption- avoid H2 antags, antacids and PPIs Susceptible to CYP3A4 mediated interactions (ketoconazole) Substrate for Pgp (digoxin) and weak inhibitor of BCRP and OATP1B1/1B3 (pravastatin, rovustatin, rifampin) Elbasvir Combn with grazoprevir Substrate for CYP3A4 and Pgp and an inhibitor of BCRP and Pgp Risk of increased LFTs Ledipasvir RAV found in baseline treatment naïve subjects but does not affect SVR, treatmentexperience subjs RAV does affect SVR. pH dependent absorption- avoid H2 antags, antacids and PPIs Used for genotypes 1,4,5,6 (with sofosbuvir), co-infection with HIV Substrate for Pgp and BCRP Pibrentasvir Substrate and inhibitor of P-gp and BCRP; inhibitor of OATP1B1/3 11 ANTI-HCV DRUGS (DIRECT ACTING ANTIVIRALS- DAA) Target Drug Notes NS5B inhibitor Sofosbuvir Prodrug for a uridine analog, defective dNTP substrate for the polymerase and as a chain terminator High barrier to resistance Active against all genotypes Low potential for drug interactions, substrate for Pgp and BCRP (avoid with inducers: rifampin, phenytoin, carbamazepine) NS3/4A Protease inhibitors Voxilaprevir Combination with sofosbuvir and velpatasavir. All genotypes Inhibitor of BCRP Metabolized by CYP3A4, taken with food Glecaprevir Combination with pibrentasvir. All genotypes Inhibitor of P-gp, BCRP, OATP1B1/3, substrate of P-gp and OATP1B1/3 Metabolized by CYP3A4, taken with food Grazoprevir Combination with elbasvir Inhibitor of BCRP, substrate for CYP3A4, Pgp, and OATP1B1(efavirenz) Higher barrier to resistance compared to other NS3 inhibitors LFT elevations 12 ENZYMATIC INTERACTIONS Drug CYP3A4 BCRP P-gp OATP1B1/3 Velpatasvir Substrate Weak inhibitor Substrate Weak inhibitor Elbasvir Substrate Inhibitor Substrate Inhibitor Ledipasvir - Substrate Substrate - Pibrentasvir Inducer Substrate/inhibitor Substrate/inhibitor Inhibitor Sofosbvir - Substrate Substrate - Voxilaprevir Substrate Inhibitor - - Glecaprevir Substrate Inhibitor Substrate/inhibitor Substrate/inhibitor Grazoprevir Substrate Inhibitor Substrate Substrate CYP3A4: Cytochrome P enzyme – drug metabolism BCRP: Breast cancer resistance protein – Efflux transporter P-gp: P glycoprotein – Efflux transporter protein expressed in multiple cell types OATP1B1/3: Organic anion-transporting polypeptides – transporters on hepatocytes 13 UNDERSTANDING IMPACT OF ENZYMATIC INTERACTIONS ¡ CYP3A4 is a metabolizing enzyme ¡ Drug A is a CYA3A4 inhibitor and Drug B is a CYP3A4 substrate ¡ Drug A will inhibit the metabolism of another Drug B resulting in increased conc of Drug B in blood – may result toxicity ¡ Same applies to transporters such as OATP1/2, BCRP and P-gp 14 DRUG-DRUG INTERACTIONS DAA Drug Interaction Consequence All DAAs Antiepileptics CYP3A4, 2B6, 2C8 induction Decreased conc of DAA Anti-mycobacterials CYP3A4, 2B6, 2C8 induction St. John’s Wort CYP3A4 induction Cholesterol-lowering agents (statins) CYP3A4 inhibition Increased conc of statin HIV antiretrovirals CYP3A4 inhibition/ induction Dependent on DAA Amiodarone Not fully established Bradycardia Increased gastric pH Decreased absorption of DAA Sofosbvir ledipasvir, velpatasvir Al and Mg antacids H2-Receptor antagonists PPIs Decreased conc of DAA Decreased conc of DAA 15