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
Ganciclovir is poorly absorbed systemically after oral administration. Its bioavailability on an empty stomach is approximately 5%, and 6% to 9% when taken with food (approximately 30% when taken with a fatty meal). The primary pathway of ganciclovir elimination is through glomerular filtration and active tubular secretion. 0.74 ± 0.15 L/kg 128 ± 63 mL/min [Patients with renal impairment (creatinine clearance = 50-79 mL/min)] 57 ± 8 mL/min [Patients with renal impairment (creatinine clearance = 25-49 mL/min)] 30 ± 13 mL/min [Patients with renal impairment (creatinine clearance < 25 mL/min)] 4.7 ± 2.2 mL/min/kg [Patients aged 9 months to 12 years] Ganciclovir is poorly absorbed from the kidneys via the gastrointestinal tract. Following oral administration of ganciclovir sodium aqueous solution, only 7% or less of the 10–20 mg/kg dose is absorbed, based on urinary recovery rates, and relative oral bioavailability appears to decrease with increasing dose and repeated administration. The plasma ganciclovir concentrations required to achieve therapeutic antiviral activity are currently unknown. While peak plasma ganciclovir concentrations achieved after oral administration of 20 mg/kg every 6 hours exceed the in vitro ID50 (the concentration required to inhibit 50% viral plaque formation) of many cytomegalovirus strains, the ID50 of many other susceptible viral strains exceeds the peak plasma concentrations achievable with this oral dose; therefore, intravenous administration is currently the preferred method. In a study of several adults with acquired immunodeficiency syndrome and cytomegalovirus retinitis, oral administration of 20 mg/kg ganciclovir every 6 hours resulted in peak plasma concentrations reached within 1 hour, averaging approximately 0.76 ug/ml at steady state; the average steady-state trough concentration before administration was approximately 0.27 g/ml. Ganciclovir sodium was administered intravenously at a dose of 5 mg/kg every 12 hours in a small number of immunocompromised patients with cytomegalovirus infection and normal renal function, over a 1-hour infusion period. The mean peak plasma concentration at the end of the infusion was 9.5–11.6 μg/ml (range: 3.1–24.1 μg/ml), and the mean trough plasma concentration before administration was 1.6 μg/ml (range: 0.11–3.5 μg/ml). After the first dose, both peak and trough concentrations decreased slightly (meaning 6.6–8.3 μg/ml and 0.56–1 μg/ml, respectively). In immunocompromised patients with concurrent cytomegalovirus infection and normal renal function, after intravenous infusion of 2.5 mg/kg every 8 hours, the mean peak and trough plasma concentrations were 4.09–5.36 μg/ml (range: 1.66–7.78 μg/ml) and 0.33–1.07 μg/ml (range: 0.2–1.66 μg/ml), respectively. In a small number of such patients receiving intravenous infusion of 5 mg/kg every 8 hours, the mean peak and trough plasma concentrations were 6.53–11.41 μg/ml and 1.13–2.23 μg/ml, respectively. For patients with normal renal function, daily divided intravenous infusions of 3–15 mg/kg do not appear to result in drug accumulation. Limited data on ganciclovir sodium suggest minimal systemic absorption after intravitreal injection, but this route of administration appears to achieve adequate intravitreal ganciclovir concentrations. In one patient with cytomegalovirus retinitis, five intravitreal injections of 200 μg each were administered over 15 days, achieving a systemic plasma ganciclovir concentration below 0.1 μg/mL during treatment. At 51.4 hours after the first dose, the vitreous fluid concentration reached 1.17 μg/mL, and the aqueous humor concentration reached 0.66 μg/mL; at 97.3 hours after the fourth dose, the vitreous fluid concentration reached 0.1 μg/mL. Data from rabbits also indicate that low-dose intravitreal injections (rather than subconjunctival injections) of ganciclovir can achieve antiviral intravitreal drug concentrations. Following a single intravitreal injection of 400 μg ganciclovir in a rabbit eye, the mean ganciclovir concentrations in the vitreous fluid at 2, 5, 12, 24, 48, and 60 hours post-injection were 543, 423, 57.7, 16, 2.02, and 1.2 μg/mL, respectively. Following a single subconjunctival injection of 1.25 mg ganciclovir in rabbit eyes, the mean concentrations of ganciclovir in vitreous fluid at 1, 2, 3, and 8 hours post-injection were 0.09, 0.31, 0.16, and 0.02 μg/ml, respectively, and in aqueous humor, the mean concentrations were 2.18, 3.27, 2.22, and 0.07 μg/ml, respectively. The distribution of ganciclovir sodium in human tissues and fluids is not fully elucidated. Autopsy results from several patients treated with intravenous ganciclovir showed that ganciclovir was primarily concentrated in the kidneys, with significantly lower concentrations in the lungs, liver, brain, and testes. Although the drug's efficacy in cytomegalovirus pneumonia has been far less than its efficacy in many other viral infections (e.g., retinitis) to date, it appears that standard intravenous doses can achieve ganciclovir concentrations in the lungs exceeding cytomegalovirus ID50 levels. In several adult patients treated with intravenous ganciclovir, drug concentrations in the lungs and liver reached 99% and 92% of the corresponding blood concentrations in the heart, respectively. In mice, following intravenous administration of ganciclovir, the drug was widely distributed, with the highest concentration in the kidneys and the lowest in the brain. Ganciclovir was significantly distributed in the lungs, liver, heart, spleen, stomach, intestines, muscles, and testes, with concentrations in these tissues exceeding concurrent blood concentrations; concentrations in the brain, eyes, and adipose tissue were lower than concurrent blood concentrations. Although drug concentrations were detectable in the stomach, liver, and intestines of these animals for at least 30 hours, no drug accumulation appeared to occur. Furthermore, no evidence of ganciclovir accumulation in the testes was found in several subjects who received daily intravenous injections of 15 mg/kg for 8–13 days. For more complete data on absorption, distribution, and excretion of ganciclovir (12 items in total), please visit the HSDB records page. Metabolism/Metabolites
Metabolism is minimal or nonexistent; approximately 90% of plasma ganciclovir is excreted unchanged in the urine.
Apart from intracellular phosphorylation, ganciclovir appears to have no significant metabolism in the human body.
Biological Half-Life
The half-life is 2.5 to 3.6 hours (mean 2.9 hours) after intravenous injection in adults. It is 3.1 to 5.5 hours after oral administration in adults. Renal impairment leads to a significantly prolonged half-life (9 to 30 hours after intravenous injection, 15.7 to 18.2 hours after oral administration). Ganciclovir plasma concentrations exhibit a biphasic decline. In adults with normal renal function, the mean half-life of ganciclovir in the initial distribution phase is 0.23–0.76 hours, and the mean half-life in the terminal elimination phase is 2.53–3.6 hours. Patients with impaired renal function may have higher plasma drug concentrations and a prolonged elimination half-life. In adult patients with moderate to severe renal impairment (creatinine clearance less than 50 ml/min/1.73 m²), the terminal half-life of ganciclovir ranged from 4.4 to 30 hours, depending on the degree of renal impairment. In a patient with cytomegalovirus retinitis, the estimated half-life of ganciclovir elimination from the vitreous body following intravitreal injection was 13.3 hours. In rabbits, the half-life of ganciclovir elimination from the vitreous body following a single intravitreal injection of a 400 μg dose was 8.6 hours.

Effects During Pregnancy and Lactation
◉ Overview of Drug Use During Lactation
Multiple factors may influence a breastfeeding woman's decision to use ganciclovir. There is currently no clinical information regarding the use of ganciclovir during breastfeeding. Cytomegalovirus (CMV) can be transmitted to infants through breast milk, with preterm and immunocompromised infants at the highest risk. There is currently no information on changes in the risk of transmission during maternal treatment with ganciclovir. Although the manufacturer recommends avoiding breastfeeding while taking ganciclovir due to the risk of drug toxicity in infants, newborns infected with CMV are usually treated directly with ganciclovir. Breastfeeding is not recommended in the United States and other developed countries if the mother is also infected with HIV.
◉ Effects on Breastfed Infants
No published information found as of the revision date.
◉ Effects on Lactation and Breast Milk
No published information found as of the revision date. Protein binding 1% to 2% interaction An in vitro study using H9 cells inoculated with HIV (HTLV-IIIB strain) showed that ganciclovir antagonized the antiretroviral activity of didanoxin against HIV. An in vitro study using H9 cells inoculated with HIV (HTLV-IIIB strain) showed that ganciclovir antagonized the antiretroviral activity of zidovudine against HIV. Concomitant use of zidovudine and ganciclovir increases the risk of hematologic toxicity. Both zidovudine and ganciclovir, when used alone, produce direct, dose-dependent inhibition of myeloid and erythroid progenitor cells, while combination therapy may lead to additive or synergistic myelotoxicity. In multiple studies of HIV-positive patients with cytomegalovirus infection, all patients receiving zidovudine (200 mg orally every 4 hours) in combination with ganciclovir (5 mg/kg intravenously 1–4 times daily) experienced severe, intolerable myelosuppression, primarily manifested as severe granulocytopenia; many also developed anemia. More than 80% of patients receiving zidovudine (100 mg orally every 4 hours) in combination with ganciclovir (5 mg/kg intravenously 1–2 times daily) experienced severe hematologic toxicity, requiring dose reduction of zidovudine. Several other patients initially with stable hematologic parameters on ganciclovir alone developed persistent pancytopenia during combined treatment with oral zidovudine and intravenous ganciclovir. The increased risk of hematologic toxicity appeared unrelated to pharmacokinetic interactions between ganciclovir and zidovudine, as there was no evidence that concomitant use of these two drugs affected the pharmacokinetic parameters of either drug.
In vitro and/or in vivo, sodium foscarnet, when used in combination with ganciclovir, exhibits additive or synergistic antiviral activity against cytomegalovirus and herpes simplex virus type 2. Furthermore, combination therapy with these two drugs may be effective against cytomegalovirus infections that are unresponsive to either drug alone.
While ganciclovir appears to be primarily excreted by glomerular filtration, a small amount of renal secretion may also occur. Therefore, probenecid or other drugs that inhibit renal tubular secretion or reabsorption should be considered as potentially interfering with renal clearance and urinary excretion of ganciclovir.
For more (complete) data on interactions of ganciclovir (10 in 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 Drugs
Intravenous ganciclovir is used to treat cytomegalovirus (CMV) retinitis in immunocompromised patients, including those with acquired immunodeficiency syndrome (AIDS). …Some clinicians consider intravenous ganciclovir, intravenous foscarnet, intravenous cidofovir, oral valganciclovir, or intravitreal fomivirexon to be appropriate initial options for induction and maintenance therapy of CMV retinitis. …Ganciclovir has also been used to treat other CMV infections in immunocompromised patients (e.g., gastrointestinal infections, pneumonia), but experience with its use in these extraocular infections is limited, and its safety and efficacy remain to be determined. Despite the lack of experience with extraocular infections, ganciclovir is considered the first-line treatment for CMV infections when antiviral therapy is required. While the safety and efficacy of ganciclovir compared to foscarnet in treating cytomegalovirus infections other than retinitis remain to be determined, some clinicians have noted that ganciclovir may be superior to foscarnet due to its advantages in patient tolerability and acceptance until further data are accumulated, and the choice of antiviral drug for cytomegalovirus infection should be individualized.
Drug Warnings

Because acyclovir and ganciclovir have similar chemical structures, patients allergic to either of these drugs may also be allergic to ganciclovir.
Because ganciclovir treatment is often associated with hematologic toxicity, primarily neutropenia and/or thrombocytopenia, blood cell counts should be closely monitored. Patients should be informed of the potential hematologic toxicity of this drug and the importance of close monitoring of blood cell counts.
During intravenous induction therapy, neutrophil and platelet counts should be performed several times a week (every other day or 2-3 times a week), and thereafter at least once a week during maintenance therapy. For patients with a history of leukopenia from ganciclovir or other nucleoside analogues, or those with a neutrophil count below 1000/mm³ before starting treatment with this drug, more frequent monitoring is recommended; the manufacturer recommends daily neutrophil count monitoring for these patients. However, some clinicians believe that a lower monitoring frequency (e.g., twice weekly) may be sufficient for these patients during maintenance therapy. Additionally, daily monitoring of neutrophil and platelet counts is recommended for patients undergoing hemodialysis. If neutropenia and/or thrombocytopenia occur, dose adjustment and/or discontinuation of ganciclovir treatment may be necessary. Ganciclovir should be used with caution in patients with a history of leukopenia or a history of cytopenic reactions to other drugs, chemicals, or radiation therapy. Furthermore, parenteral ganciclovir treatment is not recommended for patients with an absolute neutrophil count below 500/mm³ or a platelet count below 25,000/mm³. Because these drugs may have additive or synergistic hematologic toxicities, concomitant use of ganciclovir and zidovudine is currently not recommended; however, modified combination regimens may occasionally be used in extremely cautious situations. HIV patients should be informed of the potential risks of combination therapy. The decision to discontinue zidovudine and begin ganciclovir should be made collaboratively by the patient and clinician, carefully weighing the potential risks against the benefits. Since ganciclovir is almost entirely excreted by the kidneys, and normal clearance depends on renal function, adequate fluid resuscitation should be ensured when administering parenteral ganciclovir. Ganciclovir should be used with caution and at a reduced dose in patients with impaired renal function. Furthermore, given the critical role of renal function in drug clearance, the manufacturer recommends that all patients receiving parenteral administration have their serum creatinine or creatinine clearance measured at least every two weeks, and that the dose be adjusted promptly if abnormalities are detected. Because reports of renal impairment are common in controlled studies evaluating the use of ganciclovir in transplant recipients, patients receiving ganciclovir for prophylaxis of post-transplant cytomegalovirus infection, especially those concurrently receiving potentially nephrotoxic drugs (such as cyclosporine or amphotericin B), should be informed of the possibility of this adverse reaction. For more complete data on ganciclovir (15 in total), please visit the HSDB records page.

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Pharmacodynamics
Ganciclovir is a synthetic nucleoside analog of 2'-deoxyguanosine that inhibits the replication of herpesviruses, both in vitro and in vivo. Human viruses susceptible to ganciclovir include cytomegalovirus (CMV), herpes simplex virus types 1 and 2 (HSV-1, HSV-2), Epstein-Barr virus (EBV), and varicella-zoster virus (VZV), but current clinical studies are limited to evaluating its efficacy in patients with CMV infection. Ganciclovir is a prodrug with a structure similar to acyclovir. It inhibits viral replication by incorporating into viral DNA. This incorporation inhibits dATP production, leading to DNA defects, thereby blocking or delaying the mechanisms required for viral spread 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.)