Pharmacology of Antiviral Agents Keith W. Crawford, R.Ph., Ph.D. Department of Pharmacology Howard University College of Medicine
HIV Life Cycle
Pharmacologic strategies that block viral entry and fusion Enfuvirtide (Fuzeon) - a peptide that binds gp41 and blocks interaction with chemokine receptors - administered SC 90mg BID - most commonly used in salvage therapy
Chemokine receptor antagonists (investigational)
CD4+ monoclonal antibody (investigational)
Nucleoside reverse transcriptase Inhibitors (NRTI’s) require metabolic activation
DNA synthesis uses nucleoTIDES. Nucleotides are triphosphates.
NucleoSIDES must be phosphorylated sequentially by host enzymes to generate active nucleotides analogues.
The drug tenofovir is a nucleoTIDE analog and does not require activation.
Mechanism of action of Nucleoside Reverse transcriptase Inhibitors (NRTI’s)
NRTI’s compete with the incorporation of nucleotides in DNA synthesis
These drugs lack the hydroxyl group necessary to form a phosphodiester linkage for DNA chain growth. Hence, the incorporation of these drugs into a growing DNA chain results in chain termination.
Common toxicities of NRTI’s may involve the drug inhibition of γpolymerase and mitochondrial toxicity Lactic acidosis Peripheral neuropathy Myopathy Lipoatrophy
Approved NRTI drugs
Zidovudine (AZT)
Lamivudine (3TC)
Didanosine (ddI)
Emtricitabine (FTC)
Zalcitabine (ddC)
Abacavir
Tenofovir – This drug is actually a nucleoTIDE analog; it does not require activation
Stavudine (d4T)
Combination NRTI products
Combivir (zidovudine/lamivudine)
Epsicom (abacavir/lamivudine)
Truvada (tenofovir/emtricitabine)
Trizivir (abacavir/zidovudine/lamivudine)
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI’s)
Inhibit Reverse Transcriptase non-competitively at a site distinct from where NRTI’s act
Some of these agents are among the most potent anti-retrovirals (e.g. efavirenz)
Good CNS penetration
Acquisition of a single high-level resistance mutation confers cross resistance throughout the class
Major Toxicities of NNRTI’s
Rash – may be mild with efavirenz or nevirapine; nevirapine can cause a serious rash that can be lifethreatening Hepatotoxity – Nevirapine can cause life-threatening liver disease particular in patients with relatively good immune function (Do not use in men with CD4+> 400, women >250). CNS side-effects – efavirenz vcan cause dizziness, disorientation, vivid dreams and other distubing effects. Effect usually diminish with time, administering the drug before going to bed minimizes the effects.
Approved NNRTI’s
Efavirenz
Nevirapine
Delavridine
Atripla (combination of efavirenz, tenofovir and emtricibine; one pill once a day)
Protease Inhibitors (PIs)
Among the most potent inhibitors of HIV replication (>1 log decrease in HIV RNA)
Reach high concentrations in the lymphoid tissues
Poor penetration into the CNS (except indinavir and atazanavir)
These agents are often combined, utilizing the competition for metabolism to pharmacokinetically enhance plasma drug levels. Low-doses of the PI ritonavir (sub-therapeutic) pharmacokinetically enhance plasma levels of other PI’s (e.g. the PI lopinavir is co-formulated with low-dose ritonavir in the product KaletraR).
Effects of Anti-retrovirals on Drug metabolism
Protease inhibitors are primarily metabolized by CYP3A4, but other pathways are also important. Ritonavir is the most potent CYP450 inhibitor in clinical use. Atazanavir also inhibits CYP’s while amprenavir/fosamprenavir are inducers.
NNRTI’s efavirenz and nevirapine are CYP450 inducers. They can accelarate the metabolism of many drugs.
Enzyme Inhibition and Induction Drug
Enzyme Inhibition
Enzyme Induction
Atazanavir
++
—
Delavirdine
++
—
Efavirenz
+
+++
Fosamprenavir
+
++
Indinavir
++
—
Lopinavir/ritonavir[1]
++++
++
Tipranavir/ritonavir[1]
++++
+++
Nelfinavir
++
+
Nevirapine
—
++
++++
++
—
—
Ritonavir Saquinavir[2]
Approved Protease Inhibitors
Saquinavir Ritonavir Indinavir Nelfinavir Amprenavir
Fosamprenavir (a prodrug of Amprenavir) Atazanavir Tipranavir Darunavir
Some Metabolic Toxicities of Protease Inhibitors
HAART and the Risk of Myocardial Infarction: Updated Data From D:A:D Exposure to elements of HAART ► ► ►
► ► ►
NNRTI: 6.3 years (3.8-8.3) PI: 3.0 (0.5-5.4) NNRTI: 0.9 (0-3.2)
Peak RR of MI in 2001; falling since Adjustment for lipids largely explains decline in MI PI exposure associated with similar increased risk as HAART exposure NNRTI exposure not associated with increased risk of MI Adjustment for NRTI exposure did not change risk Suggests that increased risk previously reported with HAART largely driven by PIs El-Sadr W, et al. CROI 2006. Abstract 144.
RR of MI by ART Exposure 1.8 1.6 1.4 RR of MI
►
1.2 1.0 0.8
ART
PI*
NNRTI†
0.6 0.4 0.2 0 *Adjusted for NNRTI exposure. †Adjusted for PI exposure.
Metabolic Effects of PIs RTV LPV IDV NFV APV/FPV TPV SQV ATV
Lipids
Glucose
↑ TC/TG ↑ TC/TG ↑ TC/TG ↑ LDL/TG, ↓ HDL ↑ TC/TG ↑ TC/TG no Δ no Δ
↑ insulin resistance ↑ insulin resistance ↑ insulin resistance no Δ insulin sensitivity no Δ insulin sensitivity ? no Δ insulin sensitivity no Δ insulin sensitivity
Evaluating response to Highly Active Anti-Retroviral Therapy (HAART)
Rationale for combining anti-retrovirals (HAART)
Greater reduction in plasma viral load/ increased CD4+ lymphocytes
More durable suppression
Reduction in the time to develop resistance
Pharmacokinetic/dynamic synergy
Guidelines for starting Antiretrovirals
AIDS-defining illness (e.g. PCP); symptomatic at any CD4+ cell count, Treatment recommended
Assymptomatic, CD4+ cells < 200, Treatment recommended
Asymptomatic, CD4+ cells = 201-350 Offer treatment Asymptomatic, CD4+ cells > 350 but HIV RNA >100,000 copies, Offer treatment CD4+ cell >350, HIV RNA < 100,000 copies, Defer treatment
Nucleoside Analogue Anti-virals (Non-HIV)
Like to NRTI’s, these agents also require metabolism to active triphosphates.
Phosphorylations are usually initiated by viral kinases, followed by host cell kinases. Viruses can mutate their enzymes to decrease drug activation leading to drug resistance
The activated drugs compete with nucleotides in DNA synthesis and produce chain termination when inserted
Acyclovir
– an analogue of 2’-deoxguanosine
Active against HSV, VZV, prophylaxis of CMV
HSV-encoded thymidine kinase forms acyclovir monophosphate, subsequent phosphorylations utilize host enzyme
Acyclovir triphosphate is 30-50 fold more potent inhibiting HSV DNA polymerase than human α-DNA polymerase
Valacyclovir- l-valyl ester of acyclovir, a prodrug metabolized to yield acyclovir concentrations 3-5X higher than acyclovir preparations
Gancyclovir/Valgancyclovir
Gancyclovir- activity against CMV, HSV I and II, EBV, VSV, HH8
CMV-encoded phosphotransferase activates ganciclovir to ganciclovir monophosphate
Valgancyclovir-the valine ester prodrug of gancyclovir produces significantly higher blood levels of gancyclovir
Toxicities – Hematologic: Granulocytopenia, thrombocytopenia, anemia, CNS disturbances
Cidofovir
Does not require viral enzymes to activate it. Host enzymes metabolize the drug to cidofovir diphosphate, the active form
Active against CMV, acyclovir-resistant HSV, VSV, topical gel for HPV
Nephotoxicity: administer with probenecid; neutropenia; increased intra-ocular pressure may occur
Pyrrophosphate analogue - Foscarnet
-
-
Active against CMV, VZV, acyclovir-resistant HSV, EBV, HBV Foscarnet binds viral DNA polymerase at the pyrophosphate binding site, preventing the cleavage of pyrophosphate from nucleoside triphosphates, thus blocking primer-template extensions Toxicities decreased creatinine clearance and acute renal failure occur in about 1/3 of patients Electrolyte abnormalities (hypocalcemia, hypo/hyperphosphatemia, hypomagnesemia, hypokalemia.
- Also, fever, GI disturbances, headaches occur rather frequently
Ribavirin
Activity against RSV, HCV, Infuenza A&B, Hantavirus
A guanosine analogue activated in virally-infected cells
Believed to inhibit early steps in viral gene transcription by interfering with capping and elongation of mRNA. Ribavirin introduces mutations to viral mRNA leading to non-functional proteins.
Toxicities - anemia
Neuraminidase Inhibitors (Zanamavir, Oseltamavir)
Activity against influenza A and B virus; active against avian influenza
Neuraminidase is a surface glycoprotein of infuenza A and B. It cleaves terminal sialic acid residues from glycoconjugate which: Allows virion release from infected cells Prevents aggregation of virions Reduces inactivation of virus by respiratory tract mucus
-
Inhibitors of M2 protein
M2 is an integral membrane protein that functions as an ion channel. Uncoating of the virus and nuclear transport of viral genetic material require and acidic environment maintained by M2
Amantadine and Rimantadine inhibit M2 function in influenza A virus
These drugs have central dopaminergic activity and Amandatine is used in treating Parkinson’s Disease
Treatments for HBV
Lamivudine and Tenofovir have activity against HBV and are also anti-retroviral agents. Because many patients are HBV/HIV co-infected, and these drugs have low toxicity, they are extremely useful agents
Adefovir
Entecavir – a recently approved nucleoside analogue with potent activity against drug-resistant HBV
Alpha interferon
Clinical Care Options Hepatitis - Life Cycle of Hepatitis C Virus
Interferons
Cytokines with potent broad-spectrum anti-viral activities (HTLV-II, HH8, HPV, HBV, HCV, HIV)
Interferons induce the synthesis of a host of proteins that can block viral transcription and translation
2’-5’Oligo-adenylate synthase/RNaseL –degrades dsRNA, inhibit viral protein synthesis
Interferon inducible kinase phosphorylates eIF-2 which inhibits translation initiation, block viral protein synthesis
Pegylated Interferons
Coupling a polyethylene glycol (PEG) moiety to interferon remarkably enhances the pharmacokinetic chararcteristics and efficacy of the drug. Dosing frequency is reduced due to the extended half-life. Therapeutic effects are improved over regular alpha-interferon Pegylated interferons with high-dose ribavirin produce the best responses to HCV Pegasys, PegIntron