1. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Viral Infections Part 1 and 2 Robert P. Rapp, Pharm. D. Professor College of Pharmacy

2. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Antiviral Agents There has been slow but steady progress in the development of antiviral chemotherapy. There are currently Drugs Approved for: –Influenza –Respiratory syncytial virus –herpes simplex virus –Varicella-zoster virus –Hepatitis –Cytomagalovirus –HIV (covered by Dr. Liter - not in this section)

3. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Antiviral Agents - Classification Agents that directly inactivate intact viruses –Ether, chloroform, UV light, podophyllin Agents that inhibit viral replication at the cellular level. –Acyclovir, ganciclovir, AZT, etc. (where all the drugs are right now) agents that augment or modify the host response to infection (immunomodulators) –Ampligen, ditiocarb, (none marketed at this time )

4. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Susceptibility Testing - Antiviral Drugs Presently not standardized Many variable factors –Assay system, viral innoculum, laboratory Rapidly developing and presently somewhat effective for: –HIV –Herpes viruses

5. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Viral Infection and Immunity We remain dependent upon our immune system for recovery from viral infections. If immunity does not recover. –Mortality is increased –Response to therapy is usually delayed. –Risk of selecting resistant viruses may be higher in such patients. Mutations within the viral genome Usually detected only by a lack of clinical response

6. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Drug efficacy Depends on achieving effective antiviral concentrations at the site of infection. –Adequate intracellular concentrations of the drug or active metabolites. –Many antiviral drugs are inactive until metabolized within cells to phosphorylated derivatives that compete with natural nucleosides for viral and sometimes host enzyme systems.

7. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Drug Efficacy(Continued) Predictive relationships between drug concentrations active in-vitro and those achieved in blood or other body fluids, and clinical response have not been established for most antiviral agents. Topical/local administration - becoming more important - examples: –Inhalation ribavirin (Virazole) –Ganciclovir intravitreal implant

8. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Antiviral Drugs of Choice CMV –Retinitis - ganciclovir I.V. or insert –Pneumonia - ganciclovir - I.V. –Others - ganciclovir - I.V. Hepatitis virus –Hepatitis C - Interferon-a-2-b - SC/IM –Hepatitis B - Interfron -a-2-b - SC/IM

9. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Antiviral Drugs of Choice(cont) Herpes simplex virus (HSV) –Genital 1st episode- acyclovir - P.O. –Genital recurrence - acyclovir - P.O. –Suppression - acyclovir - P.O. –Encephalitis - acyclovir - I.V. –Mucocutaneous disease in the immunocompromised patient - acyclovir - I.V. –Neonatal - acyclovir - I.V. –Conjunctivitis - trifluridine or vidarabine - topical

10. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Antiviral Drugs ofChoice(Cont) Influenza A virus - amantadine or rimantadine - P.O. Papillomavirus - Interferon a-2b - Interlesional. Respiratory syncytial virus - ribaviron - inhalation.

11. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Antiviral Drugs of choice(Cont) Varicella-zoster virus. –Varcella in normal children - acyclovir - P.O. –Varicella in immunocompromised - acyclovir - I.V. –Herpes-Zoster in immunocompromosed - acyclovir - P.O. –Herpes-Zoster in normal hosts - acyclovir P.O. or famciclovir P.O.

12. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Amandatine and Rimantadine Indication - prevention and treatment of influenza A. Mechanism - Inhibits viral replication by preventing uncoating of the virus after entering the cell. Approximately 70% effective as prophylaxis taken during an outbreak. However - 1st line is vaccination!!!

13. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Amantadine - adverse effects Primary adverse effects - nausea, vomiting, other GI disturbances, CNS effects. Rimantadine is even more potent on a weight basis and has less CNS effects.

14. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Amantadine Pharmacokinetics –High oral bioavailability –T 1/2 - 12-18 hours. –Excreted as parent drug in the urine with major dosing adjustment required in renal failure (CC < 10 ml/minute T 1/2 - 30 days - not cleared by hemodialysis.)

15. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Rimantadine Pharmacokinetics –Extensively metabolized and < 15% of the drug is excreted unchanged in the urine. –T 1/2 - 24-36 hours. –Dose reduction is required for severe renal and hepatic failure.

16. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Amantadine and Rimantadine Almost all the toxicities are seen in the setting of renal failure when the dose has not been adjusted. –Neurotoxic reactions - tremor, seizures, coma. –Cardiac - arrhythmias With normal dosing - nervousness, lightheadedness, insomnia, loss of appetite - all are usually mild.

17. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Acyclovir The prototype of a group of antiviral agents that is activated by viral thymidine kinases to become inhibitors of viral DNA polymerases and block viral DNA synthesis. Acyclovir uptake and intracellular phosphorylation to the monophosphate derivative is facilitated by sHSV thymidine kinase. Cellular enzymes then convert the monophosphate to acyclovir triphosphate which is present in 40-100 fold higher concentations in HSV-infected cells than in uninfected cells. The triphosphate then is incorporated into viral DNA which leads to irreversible inactivation of DNA polymerase.

18. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Acyclovir Resistance –Defined in-vitro by concentration > 3 mcg/ml –Always present in a native viral population at very low levels. (about 1%) –Several mechanisms identified most common is thymidine kinase deficiency. –Recovered uncommonly from normal hosts. –Now occurring frequently in patients with AIDS and in transplant patients. 1 in 52 first treatment courses and 2 of 22 second treatment courses.

19. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Acyclovir When resistance occurs. –Optimal management is not certain. –In patients with progressive disease - I.V. foscarnet therapy is usually effective but vidarabine is not and ganciclovir is not. –Other options High dose continuous-infusion acyclovir

20. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Acyclovir Pharmacokinetics –Oral bioavailability - 15-21% –Prodrug valaciclovir - (L-valine ester of acyclovir) - 3-5 x greater oral bioavailibility compared to acyclovir. –Protein binding - < 20% –CSF - 1/2 of plasma levels. –t1/2 - 2.5 - 3 hours. –Renal excretion - 60-91%

21. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Acyclovir Adverse effects - I.V. (most of these associated with decreased renal function - serum conc > 25 mcg/ml) –CNS - lethargy, confusion, tremor - 1-3% –Reversible renal dysfunction - 5% –Oral acyclovir - nausea, vomiting, rash, headache - infrequent. –Appears to be safe in pregnancy.

22. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Acyclovir Dosing regimens –Oral - 200 - 4000 mg/day in divided doses. –I.V. - 5-20 mg/kg - every 8 hours. Drug interactions –AZT - increased CNS toxicity –Cyclosporin - increased renal toxicity –Decreases renal clearance of other drugs.

23. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Penciclovir Similar to acyclovir in spectrum of antiviral activity. Inhibitory activity about twofold higher than for acyclovir and the triphosphate is 100 fold less active. T 1/2 intracellular - 7-20 hours - less infrequent dosing compared to acyclovir.

24. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Famciclovir The diacetyl ester prodrug of penciclovir and it lacks any antiviral activity until it is converted in-vivo.

25. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Foscarnet Inhibitory for all HSV and HIV. Inhibitory for most ganciclovir - resistant CMV and acyclovir-resistant HSV and VSZ Also acts synergistically with ganciclovir An inorganic pyrophosphate analog and unlike nucleosides, directly inhibits the virus by blocking the pyrophosphate binding site of viral polymerase.

26. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Foscarnet Resistance does occur and is associated with poor clinical response. Pharmacokinetics –Low oral bioavailabilty - < 20% - therefore usually given by the I.V. route. –Renal elimination - 80% of dose - must adjust does in renal failure. –T 1/2 - 4-8 hours, secondary prolonged T 1/2 - 88 hours - sequestration in bone.

27. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Foscarnet Toxicity –Renal toxicity - the major dose limiting side effect - ATN. Crystalluria and interstitial nephritis. Increases in creatinine occurs in 50% of patients treated. –Metabolic - hypo and hypercalcemia, hypo, and hyperphosphatemia –CNS - headache in 25% of patients, tremor, irritability, seizures in 10% of patients.

28. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Foscarnet Approved for the treatment of CMV retinitis in AIDS patients. Useful for acyclovir-resistant HSV or VZV, and ganciclovir resistant CMV retinitis in immumocompromised patients. Doses - 60 mg/kg every 8 hours, 90 mg/kg every 12 hours.

29. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Ganciclovir A oxyguanosine analog that differs somewhat from acyclovir. Spectrum –Inhibitory against all HSV. –Uniqueness - potent inhibitory against CMV replication. Compared to acyclovir, 10 - 100 fold lower inhibitory concentrations.

30. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Ganciclovir Mechanism –Intracellular ganciclovir is phosphorylated to the monophosphate derivative by thymidine kinase - then to the di and triphosphates. At least 10 fold higher ganciclovir triphosphate are present in CMV infected cells compared with uninfected cells.

31. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Ganciclovir Resistance –Occurs and is recognized by progressive disease and persistent CMV recovery despite therapy. –Pharmacokinetics Oral bioavailibility - < 10% - usually have to give doses of 1000 mg every 6 hours. Low plasma protein binding. T 1/2 - 2-4 hours. High Vd - good tissue distribution Elimination unmetabolized by kidney (> 90%)

32. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Ganciclovir Indications –Treatment of CMV retinitis in immunocompromised patients. –Prevention of CMV in transplant patients. –Intravitreal implant now approved as well - cost around $1500 per implant. –Used for all forms of CMV disease.

33. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Ganciclovir Toxicity –Myelosuppression - the major dose-limiting toxicity of ganciclovir. 40% of patients will have neutropenia (< 1000 cells /mm 3 ) and thrombocytopenia (< 50,000/mm 3 ) - usually occurs in the 2nd week of therapy and is reversible. DC when the ANC < 500. GMCSF may be helpful but expensive. –Others - headache, behavorial changes, confusion, psychosis.

34. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Interferons Potent cytokines associated with complex antiviral, immunomodulating, and antiproliferative activity. Proteins, synthesized by erkaryotic cells in response to various inducers and each type if immunologically distinct. Not directly antiviral but cause elaboration of effector proteins in exposed cells - over 24 - many of which have antiviral activity

35. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Interferons Pharmacokinetics –Effect not directly related to serum levels. –Given I.M/SC or interlesional (genital warts) Drug interactions - via cytochrome P450 Adverse effects –Acute influenza like activity. –Major - BM suppression, neurotoxicity

36. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Interferons Indications –Condyloma accuminatum –Chronic hepatitis C. –Chronic hepatitis B. (80% remissions) –Karposi’s sarcoma Dose and expense. –Most indications require high doses for long periods of time ( 10 MU 3 times a week for 4-6 months) and this is very expensive.

37. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Ribarvin A guanosine analog - inhibits the in-vitro replication of RNA and DNA viruses (specific mechanism at the cellular level is not presently known) In the US - only the aerosolized form is approved. Approved for RSV bronchiolitis and pneumonia in hospitalized children - 12- 22 hour exposure daily for 3-6 days.

38. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Ribavirin For influenza infection - 12-18 hour exposure per day for 3 days. For use in high risk patients (transplant) by inhalation or by intravenous injection of the inhaled product - may be effective and the only therapy available. Intravenous form also used for Lassa fever and other hemorrhagic fever. May be useful for Hanta virus infection

39. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Ribavirin Adverse effects –Marrow suppression –Increased bilirubin in 25% of patients. –Intravenous - acute flu like syndromes. –Pulmonary symptoms when given by inhalation Ribavirin exposure to health care workers during aerolization is a very major concern.

40. September 15, 1997Copyright Robert Rapp, University of Kentucky College of Pharmacy Vidarabine Antiviral activity against HSV, Zoster, or varicella in immunocompromised patients. Acyclovir has replaced it for most indications because of greater efficacy and safety. Many serious toxicities.