Chemical formula: C₉H₁₃N₅O₄ Molecular mass: 255.231 g/mol PubChem compound: 3454
In CMV-infected cells, ganciclovir is initially phosphorylated to ganciclovir monophosphate by the viral protein kinase, UL97. Further phosphorylation occurs by several cellular kinases to produce ganciclovir triphosphate, which is then slowly metabolised intracellularly. This has been shown to occur in HSV- and HCMV-infected cells, with half-lives of 18 and 6-24 hours, respectively, after removal of extracellular ganciclovir. As the phosphorylation is largely dependent on the viral kinase, phosphorylation of ganciclovir occurs preferentially in virus-infected cells.
The virustatic activity of ganciclovir is a result of the inhibition of viral DNA synthesis by: (1) competitive inhibition of incorporation of deoxyguanosine triphosphate into DNA by DNA polymerase, and (2) incorporation of ganciclovir triphosphate into viral DNA, causing termination of, or very limited, viral DNA elongation.
Ganciclovir is a synthetic analogue of 2'-deoxyguanosine, which inhibits replication of herpes viruses both in vitro and in vivo. Sensitive human viruses include human cytomegalovirus (HCMV), herpes-simplex virus-1 and -2 (HSV-1 and HSV-2), human herpes virus -6, -7 and -8 (HHV-6, HHV-7, HHV-8), Epstein-Barr virus (EBV), varicella-zoster virus (VZV), and hepatitis B virus. Clinical studies have been limited to evaluation of efficacy in patients with CMV infection.
The mean effective dose (ED50) in vitro of ganciclovir on ocular clinical isolates of the herpes simplex virus is on average 0.23 μg/ml (0.06-0.50). Ganciclovir inhibits in vitro the replication of various adenovirus serotypes. The ED50 is 1.8 to 4.0 μg/ml for Ad 8 and Ad 19, those most frequently seen in ophthalmology.
Herpetic viruses induce one or more cellular kinases in the host cells, which phosphorylise the ganciclovir into its triphosphate derivative. This phosphorylation is carried out mainly in infected cells, as the concentrations of ganciclovir-triphosphate in non-infected cells are 10 times lower.
The in vitro antiviral activity, measured as IC50 of ganciclovir against CMV, is in the range of 0.08 μM (0.02 μg/ml) to 14 μM (3.57 μg/ml).
The systemic exposure (AUC0-∞) reported following dosing with a single 1-hour IV infusion of 5mg/kg ganciclovir in adult liver transplant patients was on average 50.6 µg.h/mL (CV% 40). In this patient population peak plasma concentration (Cmax) was on average 12.2 µg/mL (CV% 24).
The volume of distribution of intravenously administered ganciclovir is correlated to body weight. The steady state volume of distribution has a range of 0.54-0.87 L/kg. Plasma protein binding was 1%-2% over ganciclovir concentrations of 0.5 and 51 μg/mL. Ganciclovir penetrates the cerebrospinal fluid, where concentrations observed reach 24%-67% of the plasma concentrations.
Studies of ocular pharmacokinetics in rabbits have shown a rapid and relevant penetration of ganciclovir into the cornea and the anterior segment of the eye, allowing concentrations higher than the effective antiviral concentrations over several hours. In fact, after instillation of one drop of ganciclovir gel, the concentrations (Cmax) of ganciclovir measured in the cornea (17μg/g), the conjunctiva (160μg/g), the aqueous humour (1μg/g) and the iris/ciliary body (4μg/g), are higher than the inhibitory concentrations for herpes simplex viruses 1 and 2 (< 0.5μg/ml) over more than 4 hours.
The repeated instillation 4 times a day for 12 days in rabbits with herpetic keratitis does not result in an accumulation of ganciclovir in the plasma.
In man, after daily ocular instillations repeated 5 times a day for 11 to 15 days in the course of treatment of superficial herpetic keratitis, plasma levels determined by means of a precise analytical method (quantification limit: 0.005μg/ml) are very low: on average 0.013μg/ml (0-0.037) which is 640 times lower than levels following a one hour iv infusion of 5mg/kg (Cmax = 8.0 μg/ml).
Ganciclovir is not metabolised to a significant extent.
Ganciclovir is predominantly eliminated by renal excretion via glomerular filtration and active tubular secretion of unchanged ganciclovir. In patients with normal renal function, more than 90% of the intravenously administered ganciclovir dose is recovered unchanged in the urine within 24 hours. The mean systemic clearance ranged from 2.64 ± 0.38 mL/min/kg (N = 15) to 4.52 ± 2.79 mL/min/kg (N = 6) and renal clearance ranged from 2.57 ± 0.69 mL/min/kg (N = 15) to 3.48 ± 0.68 mL/min/kg (N = 20), corresponding to 90%-101% of administered ganciclovir. Half-lives in subjects without renal impairment ranged from 2.73 ± 1.29 (N = 6) to 3.98 ± 1.78 hours (N = 8).
Intravenous ganciclovir exhibits linear pharmacokinetics over the range of 1.6-5.0 mg/kg.
The total body clearance of ganciclovir is linearly correlated with creatinine clearance. In patients with mild, moderate, and severe renal impairment, mean systemic clearances of 2.1, 1 and 0.3 mL/min/kg were observed. Patients with renal impairment have an increased elimination half-life. In patients with severe renal impairment elimination half-life was increased by 10-fold (see section 4.2 for dose modifications required in patients with renal impairment).
Haemodialysis reduces plasma concentrations of ganciclovir by about 50% after intravenous administration during a 4-hour haemodialysis session.
During intermittent haemodialysis, estimates for the clearance of ganciclovir ranged from 42-92 mL/min, resulting in intra-dialytic half-lives of 3.3-4.5 hours. The fraction of ganciclovir removed during a single dialysis session varied from 50% to 63%. Estimates of ganciclovir clearance for continuous dialysis were lower (4.0-29.6 mL/min) but resulted in greater removal of ganciclovir over a dose interval.
The safety and efficacy of Cymevene have not been studied in patients with hepatic impairment. Hepatic impairment should not affect the pharmacokinetics of ganciclovir since it is excreted renally and, therefore, no specific dose recommendation is made (see section 4.2).
The pharmacokinetics of IV ganciclovir (administered as 200 mg/m² dose) were investigated across two studies in paediatric liver (n=18) and renal (n=25) transplant patients aged 3 months to 16 years and evaluated using a population pharmacokinetic model. Creatinine clearance (CrCL) was identified as statistically significant covariate for ganciclovir clearance and height of the patient as statistically significant covariate for ganciclovir clearance, steady state volume and peripheral volume of distribution. When CrCL and height were included in the model, the apparent differences in ganciclovir PK across various age groups was accounted for and neither age, gender, nor types of organ transplant were significant covariates in these populations. Table 1 gives the estimated pharmacokinetic parameters by age group.
Table 1 Pharmacokinetic parameters after ganciclovir IV given by BSA (200mg/m²) in renal and liver solid organ transplant patients expressed as medians (minimum-maximum).
| < 6 years n=17 | 6 to <12 years n=9 | ≥12 to <16 years n=17 | |
|---|---|---|---|
| CL(L/h) | 4.23 (2.11-7.92) | 4.03 (1.88-7.8) | 7.53 (2.89-16.8) |
| Vcent (L) | 1.83 (0.45-5.05) | 6.48 (3.34-9.95) | 12.1 (3.6-18.4) |
| Vperiph (L) | 5.81 (2.9-11.5) | 16.4 (11.3-20.1) | 27 (10.6-39.3) |
| Vss (L) | 8.06 (3.35-16.6) | 22.1 (14.6-30.1) | 37.9 (16.5-57.2) |
| AUC0-24h (μg.h/mL) | 24.3 (14.1-38.9) | 40.4 (17.7-48.6) | 37.6 (19.2-80.2) |
| Cmax (μg/mL) | 12.1 (9.17-15) | 13.3 (4.73-15) | 12.4 (4.57-30.8) |
Furthermore, the pharmacokinetics of intravenous ganciclovir given according to the dosing regimen approved for adults (5mg/kg IV infusion administered over 1 hour) were studied in a small group of infants and children with normal renal function and aged 9 months-12 years (n=10, average 3.1 years). Exposure as measured by mean AUC0-∞ on Day 1 (n=10) and AUC0-12 on Day 14 (n=7) were 19.4 ± 7.1 and 24.1 ± 14.6 μg.h/mL with corresponding Cmax values of 7.59 ± 3.21 μg/mL (Day 1) and 8.31 ± 4.9 μg/mL (Day 14) respectively. A trend towards lower exposures in younger paediatric patients was observed with body weight based dosing used in this study. In paediatric patients up to 5 years of age the average values for AUC0-∞ on Day 1 (n=7) and AUC0-12h on Day 14 (n=4) were 17.7 ± 5.5 and 17.1 ± 7.5 µg.h/mL.
The ganciclovir IV dosing regimen based on BSA and renal function (3x BSA x CrCLS), derived from the paediatric dosing algorithm with valganciclovir, leads to similar ganciclovir exposures in the paediatric population from birth to 16 years of age (see Table 2).
Table 2 Simulated* Ganciclovir AUC0-24h (μg • h/mL) for paediatric patients treated with ganciclovir dose (mg) of 3xBSAxCrCLS given as 1 hour infusion.
| < 4 months | ≥ 4 months to ≤ 2 years | > 2 to < 6 years | ≥ 6 to < 12 years | ≥ 12 to ≤ 16 years | All Patients | |
|---|---|---|---|---|---|---|
| No. patients simulated | 781 | 384 | 86 | 96 | 126 | 1473 |
| Median | 55.6 | 56.9 | 54.4 | 51.3 | 51.4 | 55.4 |
| Mean | 57.1 | 58.0 | 55.1 | 52.6 | 51.8 | 56.4 |
| Min | 24.9 | 24.3 | 16.5 | 23.9 | 22.6 | 16.5 |
| Max | 124.1 | 133.0 | 105.7 | 115.2 | 94.1 | 133.0 |
| Patients AUC <40 μg•h/mL | 89 (11%) | 38 (10%) | 13 (15%) | 23 (24%) | 28 (22%) | 191 (13%) |
| Patients AUC 40-60 μg•h/mL | 398 (51%) | 195 (51%) | 44 (51%) | 41 (43%) | 63 (50%) | 741 (50%) |
| Patients AUC >60 μg•h/mL | 294 (38%) | 151 (39%) | 29 (34%) | 32 (33%) | 35 (28%) | 541 (37%) |
AUC = area under the plasma concentration-time curve; BSA = body surface area; CrCL = creatinine clearance; max = maximum; min = minimum.
* Simulations were performed using a validated paediatric population PK model and demographic data from paediatric patients receiving valganciclovir or ganciclovir treatment in clinical studies (n=1473 data records)
No studies have been conducted in adults older than 65 years of age (see section 4.2).
Carcinogenic effects in animals were only seen following long term systemic exposure (20 mg/kg orally) with 50-fold the systemic exposure of patients treated with VIRGAN.
Ganciclovir was only positive in three of five different types of genotoxicity assay. Positive results were obtained in the most sensitive assay (mouse lymphoma) at 7,500-fold the systemic exposure in patients treated with VIRGAN, and in the mouse micronucleus assay at 50 mg/kg/iv corresponding to 15,000 times the plasma levels during ocular therapy with VIRGAN.
Intravenous and oral studies with ganciclovir in animals resulted in testicular and ovarian suppression with consequential effects on fertility. Toxicity to the male reproductive system occurred following the systemic exposure of 12-fold in dogs and 19-fold in mice of the systemic exposure of patients treated with VIRGAN. There was impairment of reproductive performance in male mice at 60-fold the systemic exposure of VIRGAN patients. Impairment of reproductive performance in female mice occurred at 3000-fold the systemic exposure of patients treated with VIRGAN. Ganciclovir had no effect on developing mouse foetuses at daily intravenous doses of 36mg/kg, but caused maternal/foetal toxicity and embryo death at daily doses of 108mg/kg. Teratogenic effects in rabbits occurred at 100-fold the systemic exposure in patients treated with VIRGAN.
Ocular use of VIRGAN during 28 days in rabbits, with 5 instillations per day, did not demonstrate any local or systemic toxic effect.
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