Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Tillomed Laboratories Limited, 220 Butterfield, Great Marlings, Luton, LU2 8DL, United Kingdom
Pharmacotherapeutic group: Antivirals for systemic use, nucleosides and nucleotides excluding reverse transcriptase inhibitors
ATC code: J05AB12
Cidofovir is a cytidine analogue with in vitro and in vivo activity against human cytomegalovirus (HCMV). HCMV strains resistant to ganciclovir may still be susceptible to cidofovir.
Cidofovir suppresses HCMV replication by selective inhibition of viral DNA synthesis. Biochemical data support selective inhibition of HSV-1, HSV-2 and HCMV DNA polymerases by cidofovir diphosphate, the active intracellular metabolite of cidofovir.
Cidofovir diphosphate inhibits these viral polymerases at concentrations that are 8- to 600-fold lower than those needed to inhibit human cellular DNA polymerases alpha, beta, and gamma. Incorporation of cidofovir into viral DNA results in reductions in the rate of viral DNA synthesis.
Cidofovir enters cells by fluid-phase endocytosis and is phosphorylated to cidofovir monophosphate and subsequently to cidofovir diphosphate. Prolonged antiviral effects of cidofovir are related to the half-lives of its metabolites; cidofovir diphosphate persists inside cells with a half-life of 17-65 hours and a cidofovir phosphate-choline adduct has a half-life of 87 hours.
Cidofovir is active in vitro against HCMV, a member of the herpesviridae family. Antiviral activity is seen at concentrations significantly below those which cause cell death.
The in vitro sensitivity to cidofovir is shown in the following table:
| Cidofovir inhibition of virus multiplication in cell culture | |
|---|---|
| Virus | IC50 (μM) |
| wild-type CMV isolates | 0.7 (± 0.6) |
| ganciclovir-resistant CMV isolates | 7.5 (± 4.3) |
| foscarnet-resistant CMV isolates | 0.59 (± 0.07) |
In vivo activity against HCMV was confirmed with controlled clinical studies of cidofovir for the treatment of CMV retinitis in patients with AIDS, which demonstrated statistically significant delays in time to CMV retinitis progression for patients on cidofovir when compared to control patients. The median times to retinitis progression in the two efficacy studies (GS-93-106 and GS-93-105), were 120 days and not reached for the treatment arms vs. 22 days and 21 days for the untreated (deferred treatment) arms, respectively.
In study GS-93-107 conducted in patients who had relapsed after treatment with other agents, the median time to retinitis progression was 115 days.
Following in vitro selection of ganciclovir-resistant HCMV isolates, cross-resistance between ganciclovir and cidofovir was seen with ganciclovir-selected mutations in the HCMV DNA polymerase gene but not with mutations in the UL97 gene. No cross-resistance between foscarnet and cidofovir was seen with foscarnet-selected mutants. Cidofovir-selected mutants had a mutation in the DNA polymerase gene and were cross-resistant to ganciclovir, but susceptible to foscarnet.
The major route of elimination of cidofovir was by renal excretion of unchanged drug by a combination of glomerular filtration and tubular secretion. In patients with normal renal function, 80 to 100% of the intravenous dose was recovered in the urine over 24 hours as unchanged cidofovir. No metabolites of cidofovir have been detected in serum or urine of patients.
At the end of a one-hour infusion of cidofovir 5 mg/kg administered with concomitant oral probenecid, the mean (± SD) serum concentration of cidofovir was 19.6 (± 7.18) μg/ml. The mean values of total serum clearance, volume of distribution at steady-state and terminal elimination half-life were 138 (± 36) ml/h/kg, 388 (± 125) ml/kg and 2.2 (± 0.5) h, respectively. Dose-independent kinetics were demonstrated with single doses of cidofovir given over the dose range 3 to 7.5 mg/kg.
In vitro protein binding of cidofovir to plasma or serum protein was 10% or less over the cidofovir concentration range 0.25 to 25 μg/ml.
Preclinical animal studies demonstrated that nephrotoxicity was the major dose-limiting toxicity of cidofovir. Evidence for a nephroprotective effect for probenecid was shown in a 52-week study conducted in cynomolgus monkeys administered cidofovir 2.5 mg/kg once weekly intravenously with 1 g of probenecid given orally.
In a 26-week intravenous toxicity study, a significant increase in incidence of mammary adenocarcinomas was seen in female rats and of Zymbal’s gland carcinomas in male and female rats at subtherapeutic plasma levels of cidofovir. In a separate study, once weekly subcutaneous injections of cidofovir for 19 consecutive weeks resulted in mammary adenocarcinomas in female rats at doses as low as 0.6 mg/kg/week. In both studies, tumours were observed within 3 months of dosing. No tumours were observed in cynomolgus monkeys administered cidofovir intravenously once weekly for 52 weeks at doses up to 2.5 mg/kg/week.
Studies have shown that cidofovir is clastogenic in vitro at 100 μg/ml and is embryotoxic in rats and rabbits.
No mutagenic response was elicited by cidofovir at dose levels up to 5 mg/plate, in the presence and absence of metabolic activation by rat liver S-9 fraction, in microbial assays involving Salmonella typhimurium for base pair substitutions or frameshift mutations (Ames) and Escherichia coli for reverse mutations.
An increase in formation of micronucleated polychromatic erythrocytes was observed in vivo in mice receiving a high, toxic intraperitoneal dose of cidofovir (≥2,000 mg/kg).
Cidofovir induced chromosomal aberrations in human peripheral blood lymphocytes in vitro without metabolic activation (S-9 fraction). At the 4 cidofovir levels (12.5 to 100 μg/ml) tested, the percentage of damaged metaphases and number of aberrations per cell increased in a concentration-dependent manner.
Male patients should be advised that cidofovir caused reduced testes weight and hypospermia in animals. No adverse effects on fertility or general reproduction were seen following once weekly intravenous injections of cidofovir in male rats for 13 consecutive weeks at doses up to 15 mg/kg/week. Female rats dosed intravenously once weekly at 1.2 mg/kg/week or higher for up to 6 weeks prior to mating and for 2 weeks post mating had decreased litter sizes and live births per litter and increased early resorptions per litter.
Peri- and post-natal development studies in which female rats received subcutaneous injections of cidofovir once daily at doses up to 1.0 mg/kg/day from day 7 of gestation through day 21 postpartum (approximately 5 weeks) resulted in no adverse effects on viability, growth, behaviour, sexual maturation or reproductive capacity in the offspring. Daily intravenous administration of cidofovir during the period of organogenesis led to reduced fetal body weights when administered to pregnant rats at 1.5 mg/kg/day and to pregnant rabbits at 1.0 mg/kg/day. A significantly increased foetal incidence of external, soft tissue and skeletal anomalies occurred in rabbits at 1.0 mg/kg/day, which was also maternally toxic. The no-observable-effect doses for embryotoxicity were 0.5 mg/kg/day in rats and 0.25 mg/kg/day in rabbits.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
