antiviral agents Flashcards
acyclovir MOA
Conversion to active form – acyclovir triphosphate
-Viral thymidine kinase** in herpes simplex virus (HSV) and varicella zoster virus (VZV) converts acyclovir to acyclovir monophosphate
-Human cellular kinases convert acyclovir monophosphate to acyclovir diphosphate and then to acyclovir triphosphate (active form)
MOA – inhibition of viral DNA replication
-Acyclovir-TP competitively inhibits viral DNA polymerase → inhibition of viral replication
-Acyclovir-TP is incorporated into viral DNA → premature chain termination
Mechanisms of resistance in HSV and VZV
-Absence (TK-deficient) or partial or altered production of viral thymidine kinase (most common)
-Altered viral DNA polymerase
acyclovir SOA
Herpes simplex virus (HSV) types 1 and 2
Varicella zoster virus (VZV)
Order of activity: HSV-1 > HSV-2 > VZV > EBV»_space; CMV
acyclovir PKs
Absorption
-Oral bioavailability ≈ 10-20% (not affected by food)
-Dose-dependent oral absorption (bioavailability decreases with increasing dose)
Distribution
-Widely distributed in tissues and body fluids – correlates with total body H2O
-around 50% of IV acycovir penetrates the CSF**
-9-33% protein bound (15% average)
Metabolism/Elimination
-Eliminated renally by glomerular filtration and tubular secretion (probenecid increases the half-life and AUC)
-62-91% of IV dose excreted unchanged in urine (14% after PO)
-Half-life ≈ 2.5-3.5 hours (19.5 hours in anuria) → adjust for renal dysfunction
-Removed by hemodialysis – ≈ 60% during 6 hour session (10% per hour); administer dose after dialysis
-Peritoneal dialysis – no effect on acyclovir pharmacokinetics
acyclovir and HSV
Primary genital HSV: 400 mg PO TID or 200 mg PO q4h (5x/day) for 7-10 days
Recurrent genital HSV: 400 mg PO TID for 5 days
Chronic suppression of genital HSV: 400 mg PO BID for 5 days; 800 mg PO BID for 5 days; 800 mg TID for 2 days
HSV encephalitis: 10 mg/kg IV q8h for 10 days
Mucocutaneous disease in immunocompromised host: 5 mg/kg IV q8h or 400 mg PO TID for 7 days
Neonatal HSV 45-60 mg/kg/day IV q8h for 14-21 days
acyclovir and VZV
VZV (shingles): 800 mg PO q4h (5x/day) for 7-10 days
Severe VZV in immunocompromised host: 10 mg/kg IV q8h for 7 days
Adult with chicken pox: 800 mg 4x/day for 5 days
acyclovir and prevention of HSV and CMV disease in transplant patients
HSV seropositive bone marrow transplant patients: 125-250 mg/m2 IV q8h, then 400 mg PO 5x/day (begin 6 hours before transplant; continue for 6 weeks)
CMV seropositive bone marrow transplant patients: 10 mg/kg IV q8h
acyclovir dosing
must be dose adjusted
NOT LINEAR
dosing in obesity - recommended adult dose based on IBW
acyclovir AEs
Nausea, vomiting, diarrhea, rash, and headache with oral acyclovir
Nephrotoxicity (crystalline nephropathy)
-Reversible increase serum creatinine and BUN in 5-10% of patients
-Risk factors: bolus infusion (need to administer over 1 hour), dehydration (maintain adequate hydration), preexisting renal insufficiency, high acyclovir concentrations (> 25 µg/ml)
Neurotoxicity - reversible
-Lethargy, confusion, agitation, disorientation, hallucination, seizures, coma
-Majority of cases – severe renal insufficiency
Thrombophlebitis with IV form (alkaline pH ≈ 11)
Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) –
reported in immunocompromised patients
acyclovir availability
Oral -Tablets – 400 mg, 800 mg -Capsule – 200 mg -Suspension – 200 mg per 5 mL Intravenous – 500 mg and 1 g vials (rapid or bolus IV infusion and IM/SQ injection must be avoided)
valacyclovir MOA
L-valyl ester prodrug of acyclovir – same MOA as acyclovir
valacyclovir SOA
same as acyclovir
valacyclovir PKs
Rapidly absorbed and completely converted to acyclovir by intestinal and hepatic metabolism following oral administration – peak concentrations achieved in 1-3 hours
Relative bioavailability of acyclovir is 3-5 times greater with valacyclovir (55%)
May be given without regards to meals
Removed by hemodialysis (dose after dialysis)
clinical indications
Cold sores (herpes labialis): 2 g q12h for 1 day (begin at earliest symptom onset)
Varicella zoster virus (preferred over PO acyclovir): 1 gram PO q8h for 7 days (start within 48-72 hours of rash onset)
Primary genital HSV: 1 gram PO BID for 7-10 days
Recurrent genital HSV: 500 mg PO BID for 3 days or 1 g daily for 5 days
Suppression of genital HSV: 500-1,000 mg PO once a day in immunocompetent patients (1 gram if ≥ 10 outbreaks/year); 500 mg PO BID in HIV-infected patients
Adjust for renal dysfunction
valacyclovir AEs
Same as oral acyclovir – headache, nausea, diarrhea, abdominal pain, dizziness, CNS
Thrombotic thrombocytopenic purpura/Hemolytic uremic syndrome (TTP/HUS) reported with high doses (8 grams/day) in immunocompromised patients
famciclovir structure/chem/MOA
Diacetyl ester prodrug of penciclovir (nucleoside analog similar to acyclovir)
Oral famciclovir undergoes rapid and extensive conversion to penciclovir
Penciclovir is phosphorylated by viral thymidine kinase to penciclovir monophosphate and eventually to penciclovir triphosphate by cellular enzymes → inhibits viral replication
Penciclovir triphosphate is ≈ 100-fold less potent than acyclovir triphosphate in inhibiting viral DNA polymerase (present in higher concentrations)
famciclovir SOA
HSV-1, HSV-2, and VZV
famciclovir PKs
Well absorbed orally (penciclovir F ≈ 77% when given as famciclovir) Penciclovir concentrations increase in proportion to famciclovir dose (linear) Food slows absorption, decreases Cmax by 50% – no significant effect on overall AUC of penciclovir (dose may be administered without regards to food) Extensive distribution (Vdβ 1.1 L/kg); less than 20% protein binding Plasma half-life of penciclovir ≈ 2.5 hours (intracellular half-life 7-20 hours) ≈ 90% of penciclovir is excreted unchanged in urine by tubular secretion and glomerular filtration Dose reduction is recommended in renal dysfunction No effect of mild to moderate hepatic impairment on penciclovir AUC – no dosage adjustment needed
famciclovir clinical indications
Cold sores (herpes labialis): 1.5 g single dose (at symptom onset)
Primary genital HSV: 250 mg PO TID for 7-10 days
Recurrent genital HSV: 125 mg PO BID for 5 days; 1 g PO BID for 1 day; 500 mg PO x 1, then 250 mg PO BID for 2 days
Suppression of genital HSV: 250 mg PO BID
VZV: 500 mg PO TID for 7 days (begin within 72 hours of rash onset)
HIV-infected patients (recurrent orolabial or genital herpes): 500 mg PO BID for 7 days
famciclovir AEs
Generally well tolerated
Headache, nausea, vomiting, diarrhea
Acute renal failure – in patients with underlying renal disease receiving higher than recommended dosing for renal insufficiency
famciclovir DIs
probenecid decreases renal clearance, increases serum concentrations
famciclovir availability
125 mg, 250 mg, 500 mg tablets
ganciclovir SOA
HSV-1, HSV-2
VZV
Cytomegalovirus (CMV)**
Epstein-Barr virus (EBV)
ganciclovir MOA
In cells infected with HSV or VZV, monophosphorylation by viral thymidine kinase → diphosphorylation → triphosphorylation (active form)
In CMV-infected cells, ganciclovir is mono-phosphorylated by a CMV-encoded protein kinase (UL97 gene), then to the di- and triphosphate forms by cellular kinases
GCV triphosphate inhibits viral DNA polymerase and/or incorporation into viral DNA → inhibits viral replication
Resistance – UL97 gene mutation which leads to viral kinase deficiency or altered viral DNA polymerase
ganciclovir PKs
Low oral bioavailability ≈ 5% (up to 9% with food) and protein binding (1-2%)
Concentrations following IV administration
-Aqueous humor and sub-retinal fluid – similar to plasma concentrations
-CSF – 24-70% of plasma
-Brain tissue – 40% of plasma
Plasma half-life ≈ 3.5 hours (intracellular half-life >24 hours)
> 90% eliminated unchanged by glomerular filtration and tubular secretion
Half-life increases as renal function decreases – adjust dose for renal dysfunction
Hemodialysis removes ≈ 50%
ganciclovir clincal indications
CMV retinitis
-Induction: 5 mg/kg IV q12h for 14-21 days (infuse over 1 hour)
-Maintenance (life-long): 5 mg/kg IV q24h OR 6 mg/kg IV for 5 days every week OR 1,000 mg PO TID with food
-Adjustment for renal dysfunction
-Intravitreal implants (increased risk of retinal detachment)
Other CMV infections: esophagitis, colitis, pneumonitis, neurologic disease
Prevention and treatment of CMV in bone marrow and organ transplant recipients: 5 mg/kg IV q12h for 7-14 days, then 5 mg/kg once daily (7 days/week) or 6 mg/kg once daily (6 days/week)
ganciclovir dosing
must be renally adjusted
ganciclovir AEs
Bone marrow suppression*** – generally reversible
-Incidence increases as cumulative dose increases
-Neutropenia is 40%; thrombocytopenia in 20%, anemia
-Monitor CBC/differential; stop if ANC under 500/mm3 or platelet under 25,000/mm3
-G-CSF may be useful in treating neutropenia
Phlebitis, headache, confusion, rash, fever, N/V, psychosis
ganciclovir DIs
Other cytotoxic drugs with risk of bone marrow suppression
Probenecid and acyclovir impair GCV excretion
valganciclovir structure/chem/MOA
L-valyl ester of ganciclovir – rapidly converted to ganciclovir by intestinal and hepatic esterases
Mechanism – same as ganciclovir
valganciclovir SOA
same as ganciclovir
valganciclovir PKs
Well absorbed and rapidly metabolized to ganciclovir in the intestinal wall and liver
Absolute bioavailability of ganciclovir ≈ 60% when administered as valganciclovir (with food)
Tmax – 1 to 3 hours
Valganciclovir 900 mg once daily AUC ≈ IV ganciclovir 5 mg/kg once daily AUC
Cmax increased 14% and AUC increased 30% when administered with high fat meal – administer with food
Ganciclovir half-life ≈ 4 hours when administered as valganciclovir
Major route of elimination – renal (glomerular filtration and tubular secretion)
Adjust for renal dysfunction***
HD decreases ganciclovir concentrations by 50% following valganciclovir
valganciclovir indication
Treatment of CMV retinitis in patients with AIDS
-Induction – 900 mg (450 mg x 2) twice daily with food for 21 days
-Maintenance – 900 mg (450 mg x 2) once daily with food
Prevention of CMV disease in transplant patients at high risk
-900 mg (450 mg x 2) once daily with food
-Start within 10 days of transplant to 100-200 days post-transplant, depending on organ transplanted
valganciclovir AEs
same as ganciclovir
Hematologic toxicity – severe neutropenia, thrombocytopenia, anemia, pancytopenia, bone marrow aplasia, aplastic anemia
Fertility – temporary or permanent inhibition of spermatogenesis
Potential to cause birth defects and cancers in humans
foscarnet MOA
Directly inhibits viral DNA polymerase
Does NOT require phosphorylation by thymidine kinase or other kinases**
foscarnet SOA
HSV-1, HSV-2 (including acyclovir-resistant strains)
VZV (including acyclovir-resistant strains)
CMV (including ganciclovir-resistant strains)
Foscarnet resistance due to mutation in viral DNA polymerase
foscarnet PKs
Oral bioavailability less than 20%
Low protein binding (14-17%)
CSF concentrations 13-68% of serum
Bone sequesters 10-20% of a dose
Initial half-life 4-8 hours; terminal half-life up to 88 hours (related to bone deposition)
> 80% excreted unchanged by glomerular filtration – adjust for renal dysfunction***
Hemodialysis removes ≈ 50%
foscarnet clinical indications
CMV retinitis
-Induction: 60 mg/kg IV q8h or 90 mg/kg q12h for 14-21 days (infusion rate not to exceed 1 mg/kg/minute)
-Maintenance: 90-120 mg/kg IV q24h (infusion rate not to exceed 1 mg/kg/minute)
-Combination therapy with ganciclovir is indicated for patients who relapse with monotherapy with either drug
HSV and VZV (resistant): 40 mg/kg IV q8h for 14-21 days (infuse over 1 hour)
foscarnet AEs
Nephrotoxicity*** – major dose-limiting adverse effect
-Risk factors: high doses, rapid infusion, dehydration, preexisting renal dysfunction, concomitant nephrotoxic agents
-Hydrate with 0.75-1 liter of normal saline or D5W prior to first infusion
-For subsequent infusions, hydrate with 075-1 L for doses of 90-120 mg/kg and 0.5 L for doses of 40-60 mg/kg (administer concurrently with each infusion)
Metabolic: hypocalcemia, decreased ionized calcium (may not be reflected in total serum calcium; due to chelation of divalent metal ions by foscarnet), hypo- or hyperphosphatemia, hypokalemia, hypomagnesemia
CNS: headache, tremor, irritability, seizures, paresthesias, perioral tingling, numbness
in extremities
GI: nausea, vomiting (15-30%)
Hematologic: anemia (33%), neutropenia (17%)
foscarnet DIs
nephrotoxic drugs; pentamidine
amantadine and rimantadine MOA
block uncoating of viral RNA within host cell
amantadine and rimantadine SOA
Influenza A virus (rimantadine 4-10 times for active)
Vast majority of influenza viruses are resistant to both agents (>99%) – not recommended for treatment or prophylaxis of influenza A***
amantadine and rimantadine PKs
Well absorbed orally
Amantadine
-Half-life 12-18 hours (increased twofold in elderly)
-Excreted unchanged in urine – adjust for renal dysfunction (not cleared by HD)
Rimantadine
-Extensively metabolized (less than 15% excreted unchanged in urine)
Half-life 24-36 hours
Reduce dose by 50% for severe hepatic or renal insufficiency
amantadine and rimantadine clinical indications
Treatment and prophylaxis of influenza A virus
amantadine and rimantadine AEs
CNS – more common with amantadine
GI – same number of side effects with amantadine and rimantadine
neuraminidase inhibitors - available products
Zanamivir (Relenza®) – administered by inhalation (IV investigational)
Oseltamivir (Tamiflu®) – available in 30 mg, 45 mg, and 75 mg capsules; powder for oral suspension (6 mg/ml)
Peramivir – IV formulation
neuraminidase inhibitors SOA
influenza A and influenza B (resistance has been reported and associated with mutations in viral neuraminidase or viral hemagglutinin)
neuraminidase inhibitors MOA
Role of neuraminidase (NA)
-NA is a protein on the surface of influenza virus, allows virus to break through the host cell wall; once inside the host cell, viral replication occurs
-After replication, the virus leaves the host cell and infects other cells → spread of
virus through host
-NA promotes release of virus from infected cells
NA inhibitors
-Attach to the virus inside host cell, replication occurs
-NA inhibitors prevent virus from leaving the cell → halts spread of virus
zanamivir clinical indications
Treatment of influenza infection in patients ≥ 7 years of age who have been symptomatic for no more than 2 days
Prophylaxis of influenza in patients ≥ 5 years of age
Do not administer the live attenuated influenza vaccine (intranasal) until 48 hours after cessation of zanamivir
Do not administer zanamivir until 2 weeks following administration of the live attenuated influenza vaccine
Not recommended*** in patients with underlying respiratory disease (e.g., asthma, COPD)
oseltamivir clinical indications
Treatment of influenza infection in patients ≥ 2 weeks of age who have been symptomatic for no more than 2 days (not approved for less than 1 year old)
Prophylaxis of influenza in patients ≥ 1 year of age
Do not administer the live attenuated influenza vaccine (intranasal) within 2 weeks before or 48 hours after administration of oseltamivir
Inactivated influenza vaccine can be administered at any time
neuraminidase inhibitor dosing
oseltamivir must be renally adjusted
neuraminidase inhibitor AEs
Zanamivir – bronchospasm, allergic reactions (oropharyngeal or facial edema), neuropsychiatric events (seizures, hallucinations, delirium), headache, nausea, sinusitis, nasal signs and symptoms, bronchitis, cough, dizziness
Oseltamivir – nausea, vomiting, diarrhea, abdominal pain, transient neuropsychiatric events (self injury or delirium) mainly reported among Japanese adolescents and adults.
peramivir
won’t be used
must be given IV, can only be used in uncomplicated infuenza
