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Ganciclovir

Actions and Uses

      Ganciclovir (Cytovene®) is a synthetic analogue of 2'-deoxy-guanosine that must first be phosphorylated to a deoxyguanosine triphosphate (dGTP) analog, a substrate which competitively inhibits the incorporation of dGTP by viral DNA polymerase resulting in the termination of viral DNA elongation.
      It is 10 - 50 times more potent against cytomegalovirus (CMV) than acyclovir, but the two drugs have similar (in vitro) potency against herpes species (HSV-1, HSV-2, & HZV). It is also effective in the treatment of Epstein-Barr Virus (EBV), which is implicated in the development of post-transplant lymphoproliferative disease (PTLD)
      The ganciclovir phophorylation process is initiated by a kinase encoded by the UL97 gene and completed by cellular kinases. Drug resistance may be related to the selection of mutant strains with altered UL97 gene kinase or an altered DNA polymerase with low affinity for the phosphorylated ganciclovir.

      Here's a review of CMV

 

Pharmacokinetics

    • Absorption of oral form is very limited - ~5% fasting, ~8% with food, and ~30% with a fatty meal.
    • Achieves a CSF concentration ~50% of the plasma level.
    • ~90% of plasma ganciclovir is eliminated unchanged in the urine.
    • Ganciclovir is eliminated by tubular secretion and glomerular filtration (< 5% is bound to plasma proteins).
    • Half-life (2 - 6 hrs) dependens on renal function (> 24 hrs in end-stage renal disease).

 

Contraindications and Warnings

    • Contraindicated when the
        • ANC <500 / mm3
        • platelet count < 25,000 / mm3
        • patient has a known hypersensitivity to ganciclovir or acyclovir
    • Ganciclovir therapy may have to be discontinued due to neutropenia and/or thrombocytopenia.
    • Use with caution in children due to potential for long-term carcinogenic and adverse reproductive effects.
    • Due to its mutagenic potential, contraceptive precautions for female and male pts. need to be followed during and for at least 90 days after therapy.
    • When administer IV, make sure the vein has good blood flow.
    • Should be handled as a cytotoxic agent during preparation and administration.
    • Give after dialysis (50% removed by HD).

 

Available As

    • Lyophilized powder for IV injection (500 mg reconstituted with 10 mL of steril water for injection to give 50 mg/mL; dose must be further diluted with NS or D5W to a final concentration <10 mg/mL and infused over one hr.)
    • 250-mg and 500-mg capsules
    • The capsule contents may be formulated into an oral suspension (details)
    • Slow release formulation for intravitreal insertion (for CMV retinitis)

 

Dose and Administration

    • Dose must be adjusted according to the patient's renal function (see table)
    • IV dose is based on body wt (for both adults and children).
    • For the treatment of active CMV disease, there is usually and induction period of 2 or 3 wks followed immediately by a maintenence period of several wks. For a patient with adequate renal function, the induction dosage is 5 mg/kg iv q 12 hrs, whereas the maintenance dose is usually 5 mg/kg iv q 24 hrs.
    • The total duration of therapy depends on clinical outcome.
    • Give dose after HD or PD (50% of drug is removed by HD)
    • Give 2 mg/kg iv q24h during continuous renal replacement therapy (CVVH, CAVHD)
    • A loading dose my be required for patients with renal impairment.
    • CMV prophylaxis in transplant patients (adults and kids weighing ³ 50 kg): 1 g po tid (taken with food to improve absorption). Adjust in renal patients (see table).
    • Pediatric oral dosage: 20 mg/kg/dose (maximum=1 gram per dose) x tid.
      For children with renal impairment estimate the CLcr in mL/min/m2 using an appropriate method (details) and follow the dosing guidelines shown in the table below. These are based in part on data by Filler et al in Ped Nephrology '98; 12(1): 6 - 9.

      GFR
      (mL/min/m2)      		 Dose
      (mg/kg/dose)      		Freq
      >7520tid
      51 - 7515tid
      26 - 5015bid
      £257.5bid

    • Duration of prophylactic therapy depends on patient's risk. In most cases prophylaxis is necessary only during the first 3 - 4 months following transplantation.

 

Main Side Effects

    • Hematologic:neutropenia (> 20% of pts), thrombocytopenia (20%), anemia.
    • CNS: headache (>10%), confusion and seizures (5%), fever (~5%).
    • Liver: Elevated liver function indeces (~2%).
    • Miscellaneous: rash (~5%), sepsis

 

Drug Interactions

    • Probenecid Þ òrenal tubular secretion of ganciclovir Þ ñ ganciclovir's t½
    • The combination of imipenem and ganciclovir Þ ñ risk for seizures
    • The combination of ziduvidine and ganciclovir Þ ñ bone marrow toxicity (neutropenia)

 

References

    1. Noble S, Faulds D. Ganciclovir. An update of its use in the prevention of cytomegalovirus infection and disease in transplant recipients. Drugs. 1998;56(1):115-46
    2. Spector SA. Oral ganciclovir. Adv Exp Med Biol. 1999;458:121-7
    3. Couchoud C. Cytomegalovirus prophylaxis with antiviral agents for solid organ transplantation. Cochrane Database Syst Rev. 2000;(2):CD001320.
    4. Anaizi NH. Prevention and treatment of cytomegalovirus (CMV) in solid organ transplantation

A related topic: Valganciclovir
 

 
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