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Ganciclovir and valganciclovir: An overview

Ganciclovir and valganciclovir: An overview
Literature review current through: Jan 2024.
This topic last updated: Apr 15, 2022.

INTRODUCTION — Ganciclovir was the first antiviral agent approved for the treatment of cytomegalovirus (CMV) infection. It is widely used for the treatment of CMV infections among patients with impaired cell-mediated immunity, particularly persons with poorly controlled and advanced human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), and recipients of solid organ and bone marrow transplantation, who are at high risk for invasive CMV disease. Valganciclovir, an oral prodrug that is rapidly converted to ganciclovir, also plays a major role in the treatment and prevention of CMV infections in immunocompromised hosts.

An overview of the basic pharmacology, pharmacokinetics, and toxicities of ganciclovir and valganciclovir will be discussed here. Treatment of specific clinical syndromes can be found in the appropriate topics. (See "Treatment of AIDS-related cytomegalovirus retinitis" and "AIDS-related cytomegalovirus gastrointestinal disease" and "Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients" and "Prevention of cytomegalovirus infection in lung transplant recipients" and "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes".)

MECHANISM OF ACTION — Ganciclovir (9-[(1,3,-dihydroxy-2-propoxy)methyl] guanine, or DHPG) is an acyclic analog of the nucleoside guanosine. The drug is converted intracellularly to ganciclovir 5'-monophosphate by a viral kinase, which is encoded by the cytomegalovirus (CMV) gene UL97 during infection. Subsequently, cellular kinases catalyze the formation of ganciclovir diphosphate and ganciclovir triphosphate, which is present in 10-fold greater concentrations in CMV or herpes simplex virus (HSV)-infected cells than uninfected cells.

Ganciclovir triphosphate is a competitive inhibitor of deoxyguanosine triphosphate incorporation into deoxyribonucleic acid (DNA) and preferentially inhibits viral DNA polymerases more than cellular DNA polymerases. In addition, ganciclovir triphosphate serves as a poor substrate for chain elongation, thereby disrupting viral DNA synthesis by a second route [1-3].

SPECTRUM OF ACTIVITY — Ganciclovir and valganciclovir are used primarily in treating cytomegalovirus (CMV) infections. In vitro synergy with foscarnet has been observed against CMV [3] (see "Foscarnet: An overview"). Ganciclovir is also used to treat human herpes virus 6 encephalitis, which occurs primarily in severely immunocompromised individuals [4].

Ganciclovir also inhibits the replication of other herpesviruses in vitro, including herpes simplex virus types 1 and 2 (HSV-1, HSV-2), Epstein-Barr virus (EBV), varicella-zoster virus (VZV), and herpes simian B virus at clinically achievable concentrations [1-3]. Ganciclovir is considered the drug of choice for symptomatic herpes simian B virus disease, including central nervous system infections [5]. However, other antiviral agents, such as acyclovir, famciclovir, or valacyclovir are usually preferred over ganciclovir for treatment of HSV infections. (See "Treatment of genital herpes simplex virus infection".)

There are scant data on the use of ganciclovir or valganciclovir for the treatment of severe EBV infection [6,7]. (See "Human herpesvirus 6 infection in hematopoietic cell transplant recipients", section on 'Treatment' and "Treatment and prevention of post-transplant lymphoproliferative disorders", section on 'Treatment'.)

MECHANISMS OF RESISTANCE — Ganciclovir resistance can occur in patients receiving prolonged therapy with either intravenous (IV) ganciclovir or oral valganciclovir. One study of 76 AIDS patients with cytomegalovirus (CMV) retinitis treated initially with ganciclovir reported resistance in 11 percent of patients at six months of treatment and 28 percent at nine months [8].

Mutations in the UL97-encoded CMV phosphotransferase have been associated with resistance [9], as have alterations in UL54-encoded viral DNA polymerase [10]. It has been postulated that UL97 mutations arise first and confer moderate resistance to ganciclovir but not to other CMV antivirals, such as cidofovir or foscarnet. With continued therapy, DNA polymerase mutations may subsequently appear, leading to high-level resistance to ganciclovir with cross-resistance to cidofovir and, sometimes, resistance to foscarnet [11-13].

BASIC PHARMACOKINETICS — Ganciclovir is excreted, unmodified, in the urine with a plasma half-life of two to four hours; the intracellular half-life of ganciclovir triphosphate is considerably longer, about 16.5 hours. Clearance is directly correlated to glomerular filtration rate; therefore, dosage adjustment is required in patients with impaired renal function [1-3]. Ganciclovir is also available as an oral capsule, but this formulation has poor bioavailability and is no longer marketed in the United States. For both oral valganciclovir and IV ganciclovir, hemodialysis decreases the serum concentration by about 50 percent [14-16]. (See 'Dose modification' below.)

Valganciclovir, an L-valyl ester of ganciclovir, is well absorbed after oral administration and rapidly hydrolyzed to ganciclovir in the intestinal wall and liver [17,18]. The absolute bioavailability of ganciclovir from valganciclovir tablets (taken with food) is approximately 60 percent [15]. Systemic exposure of a 900 mg dose of valganciclovir in adults is similar to that attained by a single dose of 5 mg/kg of intravenous ganciclovir [17,19-21]. Given this favorable oral bioavailability, oral valganciclovir has supplanted oral ganciclovir capsules.

ROUTES OF ADMINISTRATION — Ganciclovir is given as an intravenous formulation rather than orally because of its poor bioavailability (ie, 6 percent) that is only modestly increased by food [2,3]. Oral ganciclovir is no longer available in the United States. Intravenous ganciclovir is usually used for induction treatment of severe cytomegalovirus (CMV) disease in immunocompromised individuals. (See "Treatment of AIDS-related cytomegalovirus retinitis", section on 'Systemic therapy' and "Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients", section on 'Treatment' and "Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients", section on 'Antiviral therapy'.)

Ganciclovir can also be given intraocularly for the treatment of CMV retinitis. Although a sustained-release ganciclovir intraocular implant was previously available for the treatment of CMV retinitis, it is no longer being produced. Intraocular injections, in conjunction with systemic therapy, are currently recommended for the treatment of immediate sight threatening retinitis [22]. (See "Treatment of AIDS-related cytomegalovirus retinitis", section on 'Intravitreal therapy'.)

The development of oral valganciclovir was a major advance in the treatment and prevention of CMV disease in both HIV and non-HIV infected patients. Valganciclovir provides systemic concentrations of active drug similar to what is achieved with IV ganciclovir, and has the advantage of avoiding the complications associated with chronic IV or intraocular therapies [17,23]. (See "Prevention of infections in hematopoietic cell transplant recipients", section on 'Antiviral prophylaxis or pre-emptive therapy' and "Treatment of AIDS-related cytomegalovirus retinitis", section on 'Systemic therapy'.)

DOSING — The usual dose of ganciclovir for induction therapy is 5 mg/kg every 12 hours, followed by 5 mg/kg as a single daily infusion for maintenance therapy. The duration of induction therapy depends on the host and the severity of disease and is typically 14 to 21 days.

In patients able to take and absorb oral medications, valganciclovir is a reasonable alternative to intravenous (IV) ganciclovir for both induction and maintenance therapy [24]. The dosing of valganciclovir, in adult patients with normal renal function, is 900 mg twice daily during induction therapy followed by 900 mg once daily during maintenance therapy. (See "Treatment of AIDS-related cytomegalovirus retinitis", section on 'Systemic therapy' and "Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients", section on 'Antiviral therapy'.)

Dose modification — We administer valganciclovir to patients with renal dysfunction; however, the dose must be modified. Empiric dose adjustments for valganciclovir can be based upon measured or estimated creatinine clearance [22,25]:

≥60 mL/min: Usual dose (ie, 900 mg every 12 hours for induction; 900 mg once daily for maintenance)

40 to 59 mL/min: 450 mg every 12 hours for induction; 450 mg once daily for maintenance

25 to 39 mL/min: 450 mg once daily for induction; 450 mg every 48 hours for maintenance

10 to 24 mL/min: 450 mg every 48 hours for induction; 450 mg twice per week for maintenance

<10 mL/min but not on dialysis: Use IV ganciclovir or consider 200 mg oral suspension three times per week for induction; 100 mg oral suspension three times per week for maintenance

Hemodialysis: 200 mg oral suspension three times per week after dialysis for induction; 100 mg oral suspension three times per week after dialysis for maintenance

Dose modification of IV ganciclovir in patients with renal dysfunction is reviewed separately. (See "Ganciclovir (systemic): Drug information".)

The dosing of intraocular ganciclovir for the treatment of immediate sight threatening CMV retinitis is discussed elsewhere. (See "Treatment of AIDS-related cytomegalovirus retinitis", section on 'Intravitreal therapy'.)

TOXICITY

Bone marrow suppression — Ganciclovir and valganciclovir are both associated with bone marrow suppression, particularly leukopenia [26]. The frequency and severity of these hematologic abnormalities varies widely in different patient populations.

Many potential recipients of these drugs, particularly patients with hematologic malignancies or advanced HIV/AIDS, also have other factors contributing to myelosuppression [27]. In fact, disseminated cytomegalovirus (CMV) per se characteristically suppresses bone marrow production, but antiviral therapy usually results in improvement of hematologic parameters. However, ganciclovir and valganciclovir should be used with caution in patients with pre-existing cytopenias; neither drug should be used when the absolute neutrophil count is under 500 cells/microL or when the platelet count is under 25,000/microL [15,16].

Hematopoietic growth factors (eg, granulocyte-colony stimulating factor, G-CSF or granulocyte macrophage colony-stimulating factor, GM-CSF) are widely used to counter the effects of myelosuppressive drugs, such as chemotherapeutic agents, and can be given to manage neutropenia in patients receiving ganciclovir or valganciclovir [3,28-33]. Hematopoietic growth factors are particularly useful when ongoing anti-CMV treatment is necessary and the disadvantage of switching to foscarnet is judged to outweigh the risks of myelosuppression. These growth factors are well tolerated and have been shown to facilitate ganciclovir and valganciclovir dosing [34-36]. Growth factors also reduce the risk of bacterial infections, which may be secondary to improved neutrophil chemotaxis and phagocytosis [32,37,38].

Renal insufficiency — In some placebo-controlled trials, intravenous ganciclovir has been associated with an increased frequency of elevated serum creatinine; concomitant administration of other medications with well-known nephrotoxicity, such as cyclosporine, has been a frequent confounder [39]. The mechanism of nephrotoxicity is unknown, and the risk associated with ganciclovir per se appears to be low. Nevertheless, frequent monitoring of renal function is necessary, at least as much to ensure proper dosing as to look for nephrotoxicity.

DRUG INTERACTIONS — There are many potential drug interactions and overlapping toxicities between ganciclovir and other agents, particularly cytoreductive chemotherapeutics and immunosuppressive drugs commonly administered to transplant patients [40]. In such cases, increased frequency of laboratory monitoring is advisable and alternative treatment may be necessary.

Nephrotoxicity induced by other drugs (for example, cyclosporine and amphotericin B) reduces the clearance of ganciclovir and thereby increases the risk of myelosuppression. Trimethoprim-sulfamethoxazole, especially at high doses such as those used to treat Pneumocystis pneumonia and nocardiosis, can be both myelosuppressive and nephrotoxic, and therefore co-administration of ganciclovir can be problematic. Co-administration of ganciclovir and imipenem may increase the risk of seizures beyond that of imipenem alone [39].

PATIENT MONITORING — Given the risk of bone marrow suppression, patients receiving ganciclovir or valganciclovir should have a complete blood count (CBC) with a differential at least twice a week during induction therapy.

In addition, renal function testing such as serum blood urea nitrogen (BUN) and creatinine should be checked at least weekly during induction therapy, since a decline in renal function may require adjusting the dose of ganciclovir [41]. The risk of direct nephrotoxicity is low, but patients receiving ganciclovir are often at increased risk for kidney injury related to comorbidities and nephrotoxic medications [40]. More frequent monitoring should be considered in patients at particularly high risk for nephrotoxicity, such as those receiving cyclosporine, tacrolimus, aminoglycosides, or amphotericin B (including liposomal preparations).

During maintenance therapy, the frequency of laboratory monitoring can be reduced and should be individualized. At a minimum, serum creatinine and a complete blood count with differential should be checked at least once a month.

USE IN PREGNANCY — Information on use of ganciclovir and valganciclovir during pregnancy is limited to a few case reports of fetal or maternal cytomegalovirus infection, primarily after 20 weeks of gestation [42]. Although fetal toxicity was not observed in these reports, a wide range of embryotoxic potency has been observed in rat embryos [43], raising concerns of human teratogenicity.

Given the mutagenic potential of these drugs observed in animal studies, persons of reproductive potential should undergo pregnancy testing before treatment with ganciclovir or valganciclovir and should be counseled to use effective contraception during treatment and for at least 30 days thereafter. In addition, men who have sex with women of reproductive potential should be advised to practice barrier contraception during and for at least 90 days following treatment [15,16].

SUMMARY AND RECOMMENDATIONS

Ganciclovir, a nucleoside analog, disrupts viral DNA synthesis through selective incorporation of ganciclovir triphosphate, which terminates DNA chain elongation. (See 'Mechanism of action' above.)

Ganciclovir has been primarily used for treatment of cytomegalovirus (CMV) infections, although it does have in vitro activity against other herpesviruses, such as human herpes virus 6. (See 'Spectrum of activity' above.)

Ganciclovir resistance, which is associated with mutations in CMV phosphotransferase and DNA polymerase, is seen mainly among immunocompromised patients receiving prolonged therapy. (See 'Mechanism of action' above.)

Ganciclovir is excreted, unmodified, in the urine with a plasma half-life of two to four hours. Dosage adjustment is required in patients with impaired renal function. (See 'Basic pharmacokinetics' above and 'Dose modification' above.)

Ganciclovir is available intravenously and orally, although the bioavailability of oral ganciclovir is poor. Oral ganciclovir has been essentially replaced by oral valganciclovir, a well-absorbed prodrug that is rapidly converted to ganciclovir. Oral valganciclovir (900 mg) can achieve similar systemic exposure as a standard dose of intravenous ganciclovir (5 mg/kg). (See 'Routes of administration' above.)

Intraocular injections of ganciclovir plus systemic ganciclovir are indicated for the treatment of immediate sight threatening CMV retinitis. Ganciclovir implants are no longer produced. (See 'Routes of administration' above.)

Ganciclovir and valganciclovir are associated with bone marrow suppression, particularly leukopenia, which can usually be managed with hematopoietic growth factors. (See 'Toxicity' above.)

During ganciclovir or valganciclovir therapy, patients should be monitored for hematologic and renal toxicity. Prior to administration, drug-drug interactions should also be reviewed by the clinician. (See 'Patient monitoring' above and 'Drug interactions' above.)

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