Ganciclovir (BW 759) is an acyclic deoxyguanosine analog chemically similar to acyclovir but more effective against CMV. The median Ganciclovir concentration required to suppress viral replication by 50% is 2.15 μM, compared to 72 μM for acyclovir [4]. Ganciclovir's major mechanism of action against CMV is suppression of viral DNA replication via ganciclovir-5'-triphosphate (ganciclovir-TP). This inhibition involves the specific and strong inhibition of viral DNA polymerase. Ganciclovir is predominantly converted to its triphosphate form by three cellular enzymes: a deoxyguanosine kinase produced by CMV-infected cells, guanylate kinase, and phosphoglycerate kinase[5].

Ganciclovir (BW 759) (50 mg/kg; intraperitoneal; twice daily for five injections) can diffuse into the brain and the perilymphatic area of the inner ear and dramatically reduces white blood cells, red blood cells, and platelets in newborn mice[3]. Morbidity and wasting syndrome caused by the murine cytomegalovirus (MCMV) are postponed by ganciclovir (1–80 mg/kg; ih; daily for 5 days)[6].

Animal/Disease Models: Non-inbred Oncins France 1 (OF1) mice and albino rats non-immunized for MCMV[3]
Doses: 50 mg/kg
Route of Administration: intraperitoneal (ip)injection, twice a day for five injections (mice) or 3 days (adult rats) (pharmacokinetic/PK Study)
Experimental Results: In adult rats, the intracochlear diffusion of Ganciclovir was shown to achieve the same concentration as in blood. In gestating mice, transplacental diffusion was observed, with a fetal-to-maternal blood ratio of 0.5. In newborn mice, the plasma concentration profile of Ganciclovir demonstrated a peak at 2 h followed by a gradual decrease. In adult mice, the concentration peaked at 1 h, but became undetectable by 2 h after injection. Dramatically diminished white blood cells, red blood cells and platelets in newborn mice.

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Animal/Disease Models: Female SCID (severe combined immunodeficient) mouse inoculated with MCMV[6]
Doses: 0, 1, 10, 80 and 160 mg/kg
Route of Administration: subcutaneous (sc) injection, one time/day for 5 days
Experimental Results: Dose dependently delayed the wasting syndrome and mortality in a dose

Absorption, Distribution and Excretion
Poorly absorbed systemically following oral administration. Bioavailability under fasting conditions is approximately 5%, and when administered with food, 6 to 9% (about 30% with a fatty meal).
Renal excretion of unchanged drug by glomerular filtration and active tubular secretion is the major route of elimination of ganciclovir.
0.74 ± 0.15 L/kg
128 +/- 63 mL/min [Patients with Renal Impairment (Clcr=50-79 mL/min)]
57+/- 8 mL/min [Patients with Renal Impairment (Clcr=25-49 mL/min)]
30 +/- 13 mL/min [Patients with Renal Impairment (Clcr<25 mL/min)]
4.7+/- 2.2 mL/min/kg [pediatric patients, aged 9 months to 12 years]
Ganciclovir is absorbed poorly from the GI tract. Following oral administration of an aqueous solution of ganciclovir sodium, 7% or less of a 10 to 20 mg/kg dose appears to be absorbed, based on urinary recovery, and relative oral bioavailability appears to decrease with increasing dose and multiple administration. Plasma ganciclovir concentrations required for therapeutic antiviral activity currently are not known. Although peak plasma ganciclovir concentrations achieved after oral administration of 20 mg/kg every 6 hr have exceeded the in vitro ID50 (concentration of the drug required to produce 50% inhibition of viral plaque formation) of many strains of cytomegalovirus, the ID50 for many other susceptible strains of the virus exceed peak plasma concentrations achievable with this oral dosage; therefore, iv administration of the drug currently is preferred. In a study in several adults with acquired immunodeficiency syndrome and cytomegalovirus retinitis receiving an oral ganciclovir dosage of 20 mg/kg every 6 hr, peak plasma concentrations of the drug were achieved within 1 hr and averaged about 0.76 ug/ml at steady state; steady state trough plasma concentrations prior to a dose averaged about 0.27 g/ml. /Ganciclovir sodium/
In a limited number of immunocompromised patients with cytomegalovirus infections and normal renal function who received a ganciclovir dosage of 5 mg/kg every 12 hr by iv infusion over 1 hr, peak plasma concentrations of the drug obtained at the end of the infusion and averaged 9.5-11.6 ug/ml (range: 3.1-24.1 ug/ml) and trough plasma concentrations obtained just prior to a dose averaged 1.6 ug/ml (range: 0.11-3.5 ug/ml). Somewhat lower peak and trough concentrations (averaging 6.6-8.3 and 0.56-1 ug/ml, respectively) were achieved after the first dose. Peak and trough plasma concentrations of the drug following iv infusion over 1 hr of 2.5 mg/kg every 8 hr averaged 4.09-5.36 (range: 1.66-7.78 ug/ml) and 0.33-1.07 ug/ml (range: 0.2-1.66 ug/ml), respectively, in immunocompromised patients with cytomegalovirus infections and normal renal function. In a limited number of such patients receiving 5 mg/kg every 8 hr by iv infusion over 1 hr, peak and trough plasma concentrations averaged 6.53-11.41 and 1.13-2.23 ug/ml, respectively. Accumulation of the drug does not appear to occur in patients with normal renal function receiving iv dosages of 3-15 mg/kg daily in divided doses. /Ganciclovir sodium/
Limited data suggest that minimal systemic absorption of ganciclovir occurs following intravitreal injection of the drug, although adequate intravitreal ganciclovir concentrations appear to be achievable with such administration. In a patient with cytomegalovirus retinitis receiving five 200 ug intravitreal doses over 15 days, systemic plasma ganciclovir concentrations achieved during therapy were less than 0.1 ug/ml. A vitreous humor concentration of 1.17 ug/ml and an aqueous humor concentration of 0.66 ug/ml were achieved 51.4 hr after the initial dose in this patient, and a vitreous humor concentration of 0.1 ug/ml was achieved 97.3 hr after the fourth dose. Data from rabbits also indicate that antiviral intravitreal concentrations of the drug are achievable with small intravitreal but not subconjunctival doses of ganciclovir. Following intravitreal injection of a single 400 ug dose in rabbits, vitreous humor ganciclovir concentrations averaged 543, 423, 57.7, 16, 2.02, and 1.2 ug/ml 2, 5, 12, 24, 48, and 60 hr after injection. Following subconjunctival injection of a single 1.25-mg dose in rabbits, ganciclovir concentrations 1, 2, 3, and 8 hr after injection averaged 0.09, 0.31, 0.16, and 0.02 ug/ml, respectively, in vitreous humor and 2.18, 3.27, 2.22, and 0.07 ug/ml, respectively, in aqueous humor. /Ganciclovir sodium/
Distribution of ganciclovir into human body tissues and fluids has not been fully elucidated. Autopsy findings in several patients receiving the drug iv suggest that ganciclovir concentrates in the kidney, with substantially lower concentrations occurring in lung, liver, brain, and testes. While efficacy of the drug in cytomegalovirus pneumonitis has been substantially less than in many other infections (eg, retinitis) with the virus to date, lung ganciclovir concentrations that exceed the ID50 for cytomegalovirus appear to be achievable with usual iv dosages. Concentrations attained in lung and liver were 99 and 92%, respectively, of those attained concurrently in heart blood in several adults receiving the drug iv. Following iv administration in mice, ganciclovir was distributed widely, achieving highest concentrations in the kidney and lowest concentrations in the brain. Substantial distribution of ganciclovir into lung, liver, heart, spleen, stomach, intestines, muscle, and testes also occurred, exceeding concurrent blood concentrations in these tissues; concentrations achieved in brain, eyes, and fat were lower than concurrent blood concentrations. Accumulation of the drug did not appear to occur, although measurable concentrations persisted for at least 30 hr in stomach, liver, and intestines in these animals. In addition, there was no evidence of testicular ganciclovir accumulation in several humans receiving 15 mg/kg iv daily for 8-13 days.
For more Absorption, Distribution and Excretion (Complete) data for GANCICLOVIR (12 total), please visit the HSDB record page.

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Metabolism / Metabolites
Little to no metabolism, about 90% of plasma ganciclovir is eliminated unchanged in the urine.
With the exception of intracellular phosphorylation of the drug, ganciclovir does not appear to be metabolized appreciably in humans.

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Biological Half-Life
2.5 to 3.6 hours (mean 2.9 hours) when administered intravenously in adults. 3.1 to 5.5 hours when administered orally in adults. Renal function impairment causes a marked increase in half life (9 to 30 hours intravenously, 15.7 to 18.2 hours orally).
Plasma concentrations of ganciclovir appear to decline in a biphasic manner. In adults with normal renal function, the half-life of ganciclovir in the initial distribution phase averages 0.23-0.76 hr and the half-life in the terminal elimination phase averages 2.53-3.6 hr. Plasma concentrations of the drug may be higher and the elimination half-life prolonged in patients with impaired renal function. In adults with moderate to severe renal impairment (creatinine clearances less than 50 ml/min/1.73 sq m), the terminal half-life of ganciclovir ranged from 4.4-30 hr, depending on the degree of impairment.
The elimination half-life of ganciclovir from the vitreous humor after intravitreal injection was estimated to be 13.3 hr in a patient with cytomegalovirus retinitis.
In rabbits, the elimination half-life from vitreous humor after intravitreal injection of a single 400 ug dose was 8.6 hr.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Several factors might affect the decision to use ganciclovir in a nursing mother. No information is available on the clinical use of ganciclovir during breastfeeding. Cytomegalovirus (CMV) can be transmitted to infants though breastmilk, with preterm and immunocompromised infants at greatest risk. No information is available on any changes in the risk of transmission if the mother is being treated with ganciclovir. Although the manufacturer recommends avoiding breastfeeding during ganciclovir use because of the risk of infant drug toxicity, neonates with CMV infections are often treated directly with ganciclovir. If the mother has a concurrent infection with HIV, breastfeeding is not recommended in the United States and other developed countries.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
1 to 2%

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Interactions
Results of an in vitro study using H9 cells inoculated with HIV (strain HTLV-IIIB) indicate that ganciclovir antagonizes the antiretroviral activity of didanosine against HIV.
Results of an in vitro study using H9 cells inoculated with HIV (strain HTLV-IIIB) indicate that ganciclovir antagonizes the antiretroviral activity of zidovudine against HIV. ... Concomitant use of zidovudine with ganciclovir can increase the risk of hematologic toxicity. Both zidovudine and ganciclovir alone produce direct, dose-dependent inhibitory effects on myeloid and erythroid progenitor cells, and combined use of the drugs may result in additive or synergistic myelotoxic effects. In several studies in patients with AIDS and cytomegalovirus infections, profound, intolerable myelosuppression, evidenced principally as severe neutropenia, occurred in all patients receiving zidovudine (200 mg orally every 4 hr) concomitantly with ganciclovir (5 mg/kg iv 1-4 times daily); anemia also occurred in many of these patients. Severe hematologic toxicity, which required a reduction in zidovudine dosage, also occurred in more than 80% of patients receiving zidovudine (100 mg orally every 4 hr) concomitantly with ganciclovir (5 mg/kg iv 1-2 times daily). Several other patients with initially stable hematologic findings on ganciclovir alone, developed prolonged pancytopenia during concomitant therapy with oral zidovudine and iv ganciclovir. The increased risk of hematologic toxicity does not appear to be related to a pharmacokinetic interaction between ganciclovir and zidovudine since there is no evidence that concomitant use affects the pharrnacokinetic parameters of either drug.
Foscarnet has exhibited additive or synergistic antiviral activity with ganciclovir in vitro and/or in vivo against cytomegalovirus and herpes simplex virus type 2. In addition, combined therapy with the drugs may be effective in the treatment of cytomegalovirus infection resistant to either drug alone.
Although renal excretion of ganciclovir appears to occur principally via glomerular filtration, limited renal secretion of the drug also may occur. Therefore, ... the possibility that probenecid or other drugs that inhibit renal tubular secretion or reabsorption may interfere with the renal clearance and urinary excretion of ganciclovir should be considered.
For more Interactions (Complete) data for GANCICLOVIR (10 total), please visit the HSDB record page.

[1]. Ganciclovir. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in cytomegalovirus infections. Drugs. 1990;39(4):597-638.

[2]. In vitro efficacy of ganciclovir, cidofovir, penciclovir, foscarnet, idoxuridine, and acyclovir against feline herpesvirus type-1. Am J Vet Res. 2004 Apr;65(4):399-403.

[3]. Pharmacokinetics and tissue diffusion of ganciclovir in mice and rats. Antiviral Res. 2016;132:111-115.

[4]. Evaluation of ganciclovir for cytomegalovirus disease. DICP. 1989 Jan;23(1):5-12.

[5]. Antiviral activity and mechanism of action of ganciclovir. Rev Infect Dis. 1988 Jul-Aug;10 Suppl 3:S490-4.

[6]. Duan J, Paris W, Kibler P, Bousquet C, Liuzzi M, Cordingley MG. Dose and duration-dependence of ganciclovir treatment against murine cytomegalovirus infection in severe combined immunodeficient mice. Antiviral Res. 1998;39(3):189-197.

Therapeutic Uses
Antiviral Agents
IV ganciclovir is used for the treatment of cytomegalovirus (CMV) retinitis in immunocompromised patients, including patients with acquired immunodeficiency syndrome (AIDS). ... Some clinicians suggest that IV ganciclovir, IV foscarnet, IV cidofovir, oral valganciclovir, or intravitreal fomivirsen currently are appropriate initial choices for induction and maintenance therapy of CMV retinitis. ... Ganciclovir also has been used for the treatment of other cytomegalovirus infections (eg, GI infections, pneumonitis) in immunocompromised patients, but experience with the drug in these extraocular infections is less extensive, and safety and efficacy remain to be established. Despite this lack of experience inextraocular infections, ganciclovir has been considered the drug of choice for cytomegalovirus infections when antiviral therapy is warranted. While the safety and efficacy of ganciclovir compared with foscarnet for the treatment of cytomegalovirus infections other than retinitis remain to be established, some clinicians state that pending further accumulation of data, ganciclovir may offer some advantages over foscarnet secondary to patient tolerance and patient acceptability, and the choice of antiviral agent for cytomegalovirus infections should be individualized.

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Drug Warnings
Patients allergic to acyclovir may also be allergic to ganciclovor because of chemial similarity of the 2 medications.
Because ganciclovir therapy frequently is associated with hematologic toxicity, principally neutropenia and/or thrombocytopenia, blood cell counts should be monitored frequently. Patients should be informed of the potential hematologic toxicities of the drug and of the importance of close monitoring of blood cell counts. Neutrophil and platelet counts should be performed several times weekly (every other day or 2 or 3 times weekly) during iv induction therapy with the drug and at least weekly thereafter during maintenance therapy. More frequent monitoring is recommended for patients who have previously experienced leukopenia with ganciclovir or another nucleoside analog or in whom neutrophil counts are less than 1000/cu mm prior to initiating therapy with the drug; the manufacturer recommends that neutrophil counts be monitored daily in such patients. However, some clinicians state that less frequent monitoring (eg, twice weekly) may be sufficient in such patients during maintenance therapy. Also, it is recommended that neutrophil and platelet counts be monitored daily in patients undergoing hemodialysis. If neutropenia and/or thrombocytopenia occur, dosage adjustment and/or interruption of ganciclovir therapy may be necessary.
Ganciclovir should be used with caution in patients with preexisting cytopenias or a history of cytopenic reactions to other drugs, chemicals, or radiation therapy. In addition, /it is/ recommended that parenteral ganciclovir therapy not be administered to patients whose absolute neutrophil count is less than 500/cu mm or whose platelet count is less than 25,000/cu mm. Because the drugs may have additive or synergistic hematologic toxicity, the concomitant use of ganciclovir and zidovudine currently is not recommended; however, modified regimens with the drugs occasionally have been employed with extreme caution. AIDS patients should be counseled about the possible risks of combined therapy with the drugs, and the decision to discontinue zidovudine and initiate ganciclovir should be made by the patient and clinician, carefully weighing the potential risks and benefits.
Parenteral ganciclovir therapy should be accompanied by adequate patient hydration since the drug is almost entirely excreted renally and normal clearance depends on adequate renal function. Ganciclovir should be used with caution and at reduced dosage in patients with impaired renal function. In addition, because of the importance of adequate renal function in eliminating the drug, the manufacturer recommends that serum creatinine or creatinine clearance be determined at least every other week in all patients receiving the drug parenterally and that necessary adjustments in dosage be made if abnormalities are observed. Because impaired renal function has been reported frequently in controlled studies evaluating use of ganciclovir in transplant recipients, patients receiving ganciclovir for prevention of cytomegalovirus disease after transplantation, especially those receiving concomitant therapy with potentially nephrotoxic drugs (eg, cyclosporine, amphotericin B), should be counseled regarding the possibility of this adverse effect.
For more Drug Warnings (Complete) data for GANCICLOVIR (15 total), please visit the HSDB record page.

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Pharmacodynamics
Ganciclovir is a synthetic nucleoside analogue of 2'-deoxyguanosine that inhibits replication of herpes viruses both in vitro and in vivo. Sensitive human viruses include cytomegalovirus (CMV), herpes simplex virus -1 and -2 (HSV-1, HSV-2), Epstein-Barr virus (EBV) and varicella zoster virus (VZV), however clinical studies have been limited to assessment of efficacy in patients with CMV infection. Ganciclovir is a prodrug that is structurally similar to acyclovir. It inhibits virus replication by its encorporation into viral DNA. This encorporation inhibits dATP and leads to defective DNA, ceasing or retarding the viral machinery required to spread the virus to other cells.

C9H13N5O4

255.23

255.096

C, 42.35; H, 5.13; N, 27.44; O, 25.07

82410-32-0

Ganciclovir sodium;107910-75-8;Ganciclovir-d5;1189966-73-1;Ganciclovir hydrate;1359968-33-4

135398740

White to off-white solid powder

1.8±0.1 g/cm3

657.0±65.0 °C at 760 mmHg

250°C

351.1±34.3 °C

0.0±2.1 mmHg at 25°C

1.761

-3.62

4

6

5

18

346

0

O=C1C2N=CN(C=2NC(N)=N1)COC(CO)CO

IRSCQMHQWWYFCW-UHFFFAOYSA-N

InChI=1S/C9H13N5O4/c10-9-12-7-6(8(17)13-9)11-3-14(7)4-18-5(1-15)2-16/h3,5,15-16H,1-2,4H2,(H3,10,12,13,17)

2-amino-1,9-dihydro-9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]-6H-purin-6-one

2'-Nor-2'-deoxyguanosine, BW-759 BW 759

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~60 mg/mL (~235.08 mM)
H2O : ~1.67 mg/mL (~6.54 mM)

Solubility in Formulation 1: 2.08 mg/mL (8.15 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.08 mg/mL (8.15 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (8.15 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 3.33 mg/mL (13.05 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C).

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 (Please use freshly prepared in vivo formulations for optimal results.)