Cidofovir (5 mg/kg/day) administered subcutaneously for five days dramatically lowers the average virus infectivity titer in the salivary gland, spleen, lung, and blood of infected guinea pigs. Infected animals with cidofovir have significantly lower splenic average tissue index and lymphocytosis.[2]. All signs (skin lesions, hindlimb paralysis, and death) in hairless mice intracutaneously infected with HSV-1 or HSV-2 are suppressed by cidofovir. The most noteworthy aspect of cidofovir is that it provides strong protection against HSV-1 or HSV-2 infection with just one dose—even up to four days after infection. Cidofovir suppresses the growth of the extremely aggressive melanoma tumor that develops from subcutaneously grafted mouse melanoma B16 cells in C57B16/J mice.[5]

Cell Line: Crandell-Reese feline kidney(CRFK) cells
Concentration: 10-100 μM
Incubation Time: 72 hours
Result: Reduced CRFK cells by 9.1%.

Female weanling BALB/c mice infected with cowpox virus (CPV)
100 mg/kg
Subcutaneous injection; 3-6 days interval; 21 days

Absorption, Distribution and Excretion
100%
537 ± 126 mL/kg [VISTIDE ADMINISTERED WITHOUT PROBENECID]
410 ± 102 mL/kg [VISTIDE ADMINISTERED WITH PROBENECID]
179 +/- 23.1 mL/min/1.73 m2 [WITHOUT PROBENECID]
148 +/- 38.8 mL/min/1.73 m2 [WITH PROBENECID]
Volume of distribution is 537 ml/kg without concurrent probenecid administration and 410 ml/kg with concurrent probenecid administration.
Concentrations of cidofovir were undetectable 15 minutes after the end of a 1 hour infusion in one patient who had a corresponding serum concentration of 8.7 ug/mL.
Renal (without concurrent probenecid administration): Approximately 80 to 100% of an administered cidofovir dose was recovered unchanged in the urine within 24 hours.
Cidofovir is dianionic at physiological pH and have low oral bioavailability in animals and humans. After intravenous administration to HIV-infected patients, the pharmacokinetics of /cidofovir is/ independent of dose and are consistent with preclinical data. Systemic exposure is proportional to the intravenous dose and /the drug is cleared/ by the kidney and excreted extensively as unchanged drug in the urine. Intracellular activation of a small fraction (< 10%) of the dose by cellular kinases leads to prolonged antiviral effects that are not easily predicted from conventional pharmacokinetic studies. The observed rate of elimination of cidofovir ... from the serum may not reflect the true duration of action of these drugs, since the antiviral effect is dependent on concentrations of the active phosphorylated metabolites that are present within cells. For /cidofovir/, > 90% of an iv dose is recovered unchanged in the urine over 24 hours.
This study was undertaken to evaluate the intravitreal and plasma concentrations of cidofovir (HPMPC) after intravitreal and intravenous administration in AIDS patients with cytomegalovirus retinitis. Cohort series; undiluted vitreous and blood were collected from 9 patients at the time of pars plana vitrectomy. Vitreous samples from 9 eyes of 9 patients and plasma samples from 4 patients were assayed with high-performance liquid chromatography to determine cidofovir levels. The only eye that had a detectable vitreous concentration (673.7 ng/ml) was injected with 20 microg 24 hours prior to the surgery. The remaining samples including plasma were below the detection point of the assay (100 ng/ml) and were injected between 5 and 40 days prior to sampling. The intravitreal concentration of cidofovir in humans is consistent with pharmacokinetics data in laboratory animals, and suggests that the long duration of antiviral effect (1-3 months) in clinical trials is due to a prolonged intracellular half-life in retinal tissue.

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Metabolism / Metabolites
Cidofovir is converted via cellular enzymes to the pharmacologically active diphosphate metabolite ... .
This study was designed to evaluate the intraocular distribution and metabolism of the antiviral nucleotide analogs cidofovir and cyclic 1-[(S)-3-hydroxy-2-(phosphonomethoxy) propyl]cytosine (HPMPC) in New Zealand white rabbits following intravitreal administration. ...Male rabbits received either 14C-cidofovir or 14C-cyclic HPMPC by intravitreal injection into both eyes (50 micrograms/eye, 11 microCi/eye). Two animals/group were sacrificed at 24, 48, 72 or 240 hr post-dose. Ocular tissues, kidney and liver were oxidized to determine total radioactivity and metabolites were determined by HPLC. ...At 24 hr post-dose, total radioactivity was 9.96 and 5.18 micrograms-equiv/g for cidofovir and cyclic HPMPC, respectively, in vitreous and 20.9 and 3.54 micrograms-equiv/g, respectively, in retina. Although the initial vitreal clearance was 2-fold faster for the cyclic analog, the estimated terminal elimination half-lives in vitreous (42 hr) and in retina (66-77 hr) were similar for both drugs. By 240 hr post-dose, radioactivity in all ocular tissues was approx ten-fold higher for cidofovir. Radioactivity in vitreous at 240 hr after intravitreal dosing with either drug contained cidofovir, cyclic HPMPC and cidofovir-phosphocholine. ...The long retinal half-life observed presumably reflects formation of phosphorylated cidofovir within retinal cells. Cidofovir achieved a ten-fold higher level of phosphorylated drug in retina than cyclic HPMPC. Therefore, intravitreal cidofovir may be expected to suppress progression of retinitis for a longer period than an equivalent intravitreal dose of cyclic HPMPC. The intravitreal half-life of cidofovir was 20-fold longer than that of ganciclovir in the same animal model.
Pyrimidine nucleoside monophosphate kinase converts cidofovir to cidofovir monophosphate, which is further converted to the diphosphate and cidofovir phosphate-choline via other cellular enzymes.

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Biological Half-Life
2.4 to 3.2 hours
...Male rabbits received either 14C-cidofovir ...by intravitreal injection into both eyes (50 micrograms/eye...). ...The estimated terminal elimination half-lives /were/ in vitreous (42 hr) and in retina (66-77 hr)... .
...Levels of cidofovir in serum following iv infusion were dose proportional over the dose range of 1.0-10.0 mg/kg bw and declined biexponentially with an overall mean +/- standard deviation terminal half-life of 2.6 +/- 1.2 hr (n=25).

Hepatotoxicity
Intravenous cidofovir therapy is associated with mild-to-moderate elevations in serum ALT levels in a proportion of patients, but the elevations are usually self-limited and do not require dose modification. Nephrotoxicity is often dose limiting, which may account for the absence of clinically significant cases of liver injury associated with cidofovir therapy. Cases of clinically apparent liver injury have been reported during cidofovir therapy, but the role of this agent has been difficult to define because most patients who receive cidofovir have severe immunodeficiency and are receiving multiple other agents, some of which are known hepatotoxins. Several instances of acute liver failure, lactic acidosis and fatty liver have been described in patients taking cidofovir, but other nucleoside analogues such as zidovudine, stavudine or didanosine were being taken concurrently.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of cidofovir during breastfeeding. The manufacturer recommends that breastfeeding be discontinued during cidofovir therapy. An alternate drug is preferred, especially while nursing a newborn or preterm infant.
◉ 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
6%

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Interactions
Concomitant administration of cidofovir with potentially nephrotoxic agents (e.g., amphotericin B, aminoglycosides, foscarnet, nonsteriodal antiinflammatory agents, IV pentamidine, vancomycin) is contraindicated, and the manufacturer recommends that at least 7 days elapse between discontinuance of such drugs and administration of cidofovir.
Placement of a ganciclovir ocular implant in patients receiving IV cidofovir has resulted in profound hypotony in some patients, and some clinicians suggest that IV cidofovir not be administered within one month before or after placement of a ganciclovir ocular implant.

[1]. Antimicrob Agents Chemother . 1988 Dec;32(12):1839-44.

[2]. Antiviral Res . 1990 May;13(5):237-52.

[3]. Antiviral Res . 1992 Sep;19(3):181-92.

[4]. Antimicrob Agents Chemother . 1991 Apr;35(4):701-6.

[5]. Br J Dermatol . 2000 Oct;143(4):741-8.

Therapeutic Uses
Cidofovir is used for the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS).
Cidofovir has been used for the management of acyclovir-resistant herpes simplex virus (HSV-1 and HSV-2) infections in immunocompromised patients.
The role, if any, of cidofovir in the treatment of smallpox remains to be determined. Cidofovir is active in vitro against poxviruses, including variola virus (the causative agent of smallpox) and has in vivo activity in mice against cowpox and vaccinia virus. Although limited in vitro and in vivo data suggest that cidofovir might prove useful in preventing smallpox infection if administered within 1-2 days after exposure, there currently is no evidence that the antiviral would be more effective than vaccination in this early period.
Topical cidofovir gel eliminates virus shedding and lesions in some HIV-infected patients with acyclovir-resistant mucocutaneous HSV infections and has been use in treating anogenital warts and molluscum contagiosum in immunocompromised patients and cervical intraepithelial neoplasia in women. Intralesional cidofovir induces remission in adults or chlidren with respiratory papillomatosis.
For more Therapeutic Uses (Complete) data for CIDOFOVIR (15 total), please visit the HSDB record page.

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Drug Warnings
Placement of a ganciclovir ocular implant in patients receiving IV cidofovir has resulted in profound hypotomy in some patients, and some clinicians suggest that IV cidofovir not be administered within one month before or after placement of a ganciclovir ocular implant.
.... Because evidence from clinical trials indicates that previous exposure to foscarnet may increase the risk of cidofovir-related nephrotoxicity, patients treated previously with foscarnet should receive cidofovir only when the potential benefits exceed the possible risks.
Patients should be advised that cidofovir therapy is not curative, and that progression of their retinitis is possible during or following therapy with the drug.
Safety and efficacy of cidofovir in geriatric patients older than 60 years of age have not been established. Because geriatric patients frequently have reduced glomerular filtration, particular attention should be paid to monitoring renal function prior to and during cidofovir therapy in this age group, and doses of the drug should be modified in response to changes in renal function that occur during therapy.
For more Drug Warnings (Complete) data for CIDOFOVIR (20 total), please visit the HSDB record page.

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Pharmacodynamics
Cidofovir is a new anti-viral drug. It is classified as a nucleotide analogue and is active against herpes cytomegalovirus (CMV) retinitis infection. Most adults are infected with CMV. Cidofovir suppresses cytomegalovirus (CMV) replication by selective inhibition of viral DNA synthesis.

C8H14N3O6P

279.19

279.062

C, 34.42; H, 5.05; N, 15.05; O, 34.38; P, 11.09

113852-37-2

149394-66-1

60613

White to off-white solid powder

1.8±0.1 g/cm3

609.5±65.0 °C at 760 mmHg

260ºC

322.4±34.3 °C

0.0±4.0 mmHg at 25°C

1.656

-3.37

4

6

6

18

417

1

OC[C@@H](OCP(O)(O)=O)CN1C=CC(N)=NC1=O

VWFCHDSQECPREK-LURJTMIESA-N

InChI=1S/C8H14N3O6P/c9-7-1-2-11(8(13)10-7)3-6(4-12)17-5-18(14,15)16/h1-2,6,12H,3-5H2,(H2,9,10,13)(H2,14,15,16)/t6-/m0/s1

[(2S)-1-(4-amino-2-oxopyrimidin-1-yl)-3-hydroxypropan-2-yl]oxymethylphosphonic acid

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)

Solubility in Formulation 1: 4.55 mg/mL (16.30 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication (<60°C).

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