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Synopsis: Ganciclovir is a nucleoside analogue with antiviral activity in vitro against members of the herpes group and some other DNA viruses. It has demonstrated efficacy against human cytomegalovirus infections and should be considered a first-line therapy in the treatment of life- or sight-threatening cytomegalovirus infection in immunocompromised patients. Clinical efficacy varies with the underlying aetiology of immunocompromise and the site of disease, and prompt diagnosis and early treatment initiation appear to improve the response. In patients with cytomegalovirus pneumonia, particularly bone marrow transplant recipients, concomitant administration of cytomegalovirus immune globulin may significantly improve clinical outcome. Maintenance therapy to prevent recurrence is usually required by bone marrow transplant recipients until the recovery of adequate immune function, whereas AIDS patients may require indefinite ganciclovir maintenance therapy to prevent disease progression, as ganciclovir (like other antivirals) does not eradicate latent viral infection. Haematological effects occur relatively frequently during ganciclovir administration but are usually reversible. Ganciclovir has not been directly compared with other antiviral drugs because of the absence until recently of other effective treatments. However, comparative studies with foscarnet, particularly in cytomegalovirus retinitis, will be of considerable interest.

Thus, ganciclovir represents a major advance in the therapy of severe cytomegalovirus infections in immunocompromised patients. Comparative studies, and investigation of ways of reducing toxicity (intravitreal administration; concomitant use of stimulants of haematopoiesis; use in conjunction with other antivirals with differing mechansisms of action), may further expand its eventual role.

Antiviral Activity: Ganciclovir exhibits in vitro activity against human cytomegalovirus and herpes simplex virus types 1 and 2, and to a lesser degree, Epstein-Barr virus, varicella zoster virus, human herpesvirus 6 and human adenoviruses. Although results vary depending on the viral strain and methodological considerations, in general ganciclovir is considerably more potent than aciclovir (acyclovir) against cytomegalovirus and tends to be more potent against herpes simplex viruses. Studies of its activity against other viruses and comparisons with other antiviral agents are limited, but ganciclovir is more active than many other nucleoside analogues against cytomegalovirus, and appears to inhibit the productive cycle but not the latent phase of Epstein-Barr virus in a manner similar to aciclovir. Synergism of ganciclovir with interferons against human cytomegalovirus and with foscarnet and interferons against herpes simplex viruses has been demonstrated in various in vitro assays. The mechanism of action of ganciclovir involves highly selective inhibition of viral DNA replication as a result of enhanced uptake by infected cells, phosphorylation by viral thymidine kinase and/or cellular kinase enzymes, and substrate specificity for viral rather than cellular DNA polymerases.

Although an in vivo animal model of human cytomegalovirus infection has not been developed, studies of cytomegalovirus infections in animals have demonstrated the antiviral efficacy of ganciclovir and indicate greater potency than aciclovir in pulmonary infections. The beneficial effects of concomitant ganciclovir and cytomegalovirus antiserum have also been demonstrated in encephalitis and disseminated infection in animal studies. Models of pulmonary cytomegalovirus infection indicate that ganciclovir reduces viral titres but not interstitial pneumonitis. Limited data from animal studies suggest prophylactic ganciclovir may prevent cytomegalovirus infection. Ganciclovir was also effective in in vivo models of various herpes simplex virus type 1 and 2 infections. However, like aciclovir, ganciclovir was unable to eradicate established latent herpesvirus infection.

Mutations in the viral DNA polymerase gene and/or the viral genes involved in ganciclovir monophosphorylation appear to mediate the development of ganciclovir resistance in cytomegalovirus and herpes simplex virus infections, and may also confer crossresistance to other antiviral agents. The incidence and clinical significance of viral resistance to ganciclovir remains to be fully determined.

Pharmacokinetics: Following intravenous administration, peak ganciclovir concentrations in plasma vary in a linear fashion over the therapeutic dose range. With an 8-hourly dosage regimen, steady-state plasma concentrations of about 9 to 45 [mu]mol/L are observed over a dose range of 1 to 5 mg/kg and are similar to those seen after equivalent single doses. Furthermore, no evidence of ganciclovir accumulation has been observed in patients with normal renal function. Intravitreal ganciclovir administration produces high concentrations in intravitreal fluid, apparently with minimal systemic absorption. The low bioavailability of oral ganciclovir may preclude the use of this administration route.

Ganciclovir concentrations in CSF were 31 to 67% of plasma concentrations reported following intravenous administration, while subretinal fluid concentrations several hours after an infusion of ganciclovir 5 mg/kg were similar to or exceeded plasma concentrations. Ganciclovir is only minimally bound to plasma proteins (1 to 2%). The volume of distribution at steady-state is about 33 to 45L. In patients with normal renal function almost 100% of an intravenous ganciclovir dose is excreted in the urine with an elimination half-life of 2 to 4 hours. Ganciclovir clearance decreases linearly with decreasing creatinine clearance, with elimination half-life increasing to 30 to 40 hours in severe renal dysfunction; however, plasma ganciclovir concentrations are significantly reduced by haemodialysis. The half-life of ganciclovir in vitreous fluid following intravitreal administration is about 13 hours.

Therapeutic Use: Ganciclovir has been almost exclusively evaluated in immunocompromised patients with cytomegalovirus infections, including retinitis, pneumonia, gastrointestinal, hepatic, CNS and disseminated infections. Many patients have been treated under 'compassionate plea' protocols, mainly because patients requiring ganciclovir therapy usually have life-or sight-threatening cytomegalovirus disease. Placebo-controlled and comparative studies are reportedly underway. Ganciclovir has generally proved effective, although the degree of response varies according to disease site and the underlying aetiology of immunocompromise, and efficacy is not well established in some indications (CNS infections). Patients with cytomegalovirus pneumonia, particularly bone marrow transplant recipients, may develop fatal interstitial pneumonitis despite apparent virological cure, and concomitant cytomegalovirus immune globulin administration appears to considerably increase the likelihood of a favourable therapeutic outcome in these patients. Prompt diagnosis and early institution of ganciclovir therapy also appear to improve the response to therapy. Maintenance ganciclovir therapy is usually required by patients with acquired immune deficiency syndrome (AIDS) and bone marrow transplant recipients to prevent cytomegalovirus disease relapse since, as with other antiviral drugs, ganciclovir does not eradicate latent viral infections. However, ganciclovir therapy may usually be withdrawn in the latter group of patients as immune function recovers. Ganciclovir has been successfully used in a small number of children and in the elderly. Intravitreal ganciclovir therapy appears effective in those AIDS patients with cytomegalovirus retinitis in whom intravenous ganciclovir is likely to cause unacceptable toxicity (for example, patients receiving zidovudine). However, it is not a substitute for systemic therapy as it is not effective against the disseminated cytomegaloviral disease which is usually found in association with cytomegalovirus retinitis.

Adverse Effects: Adverse effects requiring interruption or withdrawal of ganciclovir therapy occur in about 32% of patients, although subsequent reintroduction of ganciclovir or use of a reduced dosage regimen is often successful. Haematological changes are the most commonly observed unwanted effects, particularly neutropenia (about 40% of patients) and thrombocytopenia (about 20%), although these are usually reversible. Patients with AIDS may be particularly susceptible to developing neutropenia during ganciclovir therapy. Concomitant administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) may serve to moderate the depressive effects of ganciclovir on granulocyte production. Inhibition of spermatogenesis and fertility has been observed in animal models at ganciclovir doses lower than those recommended in humans, but this effect has not been observed clinically. A variety of other adverse effects have been reported, although their association with ganciclovir is often unclear as the underlying cause of immunocompromise and concomitant medications and infections may be involved.

Drug Interactions: Ganciclovir and zidovudine have overlapping toxicity profiles, and in general the use of ganciclovir concurrently with drugs that inhibit the replication of rapidly dividing cell populations or alter renal function should be approached with caution. In addition, seizures may be associated with the concomitant use of ganciclovir and imipenem/cilastatin.

Dosage and Administration: Currently, ganciclovir is recommended for use only in immunocompromised patients with life- or sight-threatening cytomegalovirus disease. In patients with normal renal function ganciclovir should be administered as a 1-hour intravenous infusion at a dosage of 2.5 mg/kg 8-hourly or 5 mg/kg 12-hourly for 14 to 21 days. Maintenance therapy to prevent recurrences is usually required in patients with AIDS or in bone marrow transplant recipients. A maintenance regimen of 5 mg/kg/day, or 6 mg/kg/day 5 days/week is recommended, with patients experiencing progressive cytomegalovirus disease during maintenance being retreated with the induction regimen. Ganciclovir dosage should be reduced in patients with impaired renal function (table X, section 7).

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