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Pharmacology: Pharmacodynamics: Mechanism of action: Valganciclovir is an L-valyl ester (prodrug) of ganciclovir. After oral administration, valganciclovir is rapidly and extensively metabolised to ganciclovir by intestinal and hepatic esterases. Ganciclovir is a synthetic analogue of 2'-deoxyguanosine and inhibits replication of herpes viruses 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, HHV8), Epstein-Barr virus (EBV), varicella-zoster virus (VZV) and hepatitis B virus (HBV).
In CMV-infected cells, ganciclovir is initially phosphorylated to ganciclovir monophosphate by the viral protein kinase, pUL97. Further phosphorylation occurs by cellular kinases to produce ganciclovir triphosphate, which is then slowly metabolised intracellularly. Triphosphate metabolism has been shown to occur in HSVand HCMV- infected cells with half-lives of 18 and between 6 and 24 hours respectively, after the 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 due to inhibition of viral DNA synthesis by: (a) competitive inhibition of incorporation of deoxyguanosine-triphosphate into DNA by viral DNA polymerase, and (b) incorporation of ganciclovir triphosphate into viral DNA causing termination of, or very limited, further viral DNA elongation.
Antiviral activity: The in-vitro anti-viral activity, measured as IC50 of ganciclovir against CMV, is in the range of 0.08 ?M (0.02 mg/ml) to 14 mM (3.5 mg/ml).
The clinical antiviral effect of Valganciclovir has been demonstrated in the treatment of AIDS patients with newly diagnosed CMV retinitis. CMV shedding was decreased in urine from 46% (32/69) of patients at study entry to 7% (4/55) of patients following four weeks of Valganciclovir treatment.
Clinical efficacy and safety: Adult patients: Treatment of CMV retinitis: Clinical studies of Valganciclovir have been conducted in patients with AIDS and CMV retinitis. Valganciclovir has shown comparable efficacy for induction treatment of CMV retinitis to intravenous ganciclovir.
Patients with newly diagnosed CMV retinitis were randomized in one study to induction therapy with either Valganciclovir or intravenous ganciclovir. The proportion of patients with progression of CMV retinitis at week 4 was the same in both treatment groups.
Following induction treatment dosing, patients in this study received maintenance treatment with Valganciclovir given at the dose of 900 mg daily. The mean (median) time from randomization to progression of CMV retinitis in the group receiving induction and maintenance treatment with Valganciclovir was 226 (160) days and in the group receiving induction treatment with intravenous ganciclovir and maintenance treatment with Valganciclovir was 219 (125) days. Safety and efficacy of valganciclovir have not been demonstrated in transplant patients.
Valganciclovir allows systemic exposure of ganciclovir similar to that achieved with recommended doses of intravenous ganciclovir, which has been shown to be efficacious in the treatment of CMV retinitis. Ganciclovir AUC has been shown to correlate with time to progression of CMV retinitis.
Prevention of CMV disease in transplantation: A double-blind, double-dummy clinical active comparator study has been conducted in heart, liver and kidney transplant patients at high-risk of CMV disease (D+/R-) who received either Valganciclovir (900 mg od) or oral ganciclovir (1000 mg three times a day) starting within 10 days of transplantation until Day 100 posttransplant. The incidence of CMV disease (CMV syndrome + tissue invasive disease) as adjudicated by an independent Endpoint Committee, during the first 6 months post-transplant was 12.1% in the Valganciclovir arm (n=239) compared with 15.2% in the oral ganciclovir arm (n=125). The majority of cases occurred following cessation of prophylaxis (post-Day 100) with cases in the valganciclovir arm occurring on average later than those in the oral ganciclovir arm. The incidence of acute rejection in the first 6 months was 29.7% in patients randomized to valganciclovir compared with 36.0% in the oral ganciclovir arm. However, in liver transplant patients, the incidence of tissue-invasive CMV disease was significantly higher in the Valganciclovir group (14%) compared with the ganciclovir group (3%).
A double-blind, placebo controlled study has been conducted in 326 kidney transplant patients at high risk of CMV disease (D+/R-) to assess the efficacy and safety of extending valganciclovir CMV prophylaxis from 100 to 200 days post-transplant.
The inclusion criteria in this study required the patients to have adequate haematological (absolute neutrophil count > 1000 cells/μL, platelets > 25,000/μL, haemoglobin > 8 g/dL) and renal function (creatinine clearance > 15 mL/min and improving) in the immediate post-transplant period. The mean age of the patients who participated in this trial was about 48 years.
Patients were randomised (1:1) to receive Valganciclovir tablets (900 mg once daily) within 10 days of transplantation until Day 200 post-transplant or until Day 100 post-transplant followed by 100 days placebo.
The proportion of patients who developed CMV disease during the first 12 months post-transplant is shown in the table as follows. (See Table 1.)
Click on icon to see table/diagram/imageThe graft survival rate at 12 months post-transplant was 98.2% (160/163) for the 100 day dosing regimen and 98.1% (152/155) for the 200 day dosing regimen.
The incidence of biopsy proven acute rejection at 12 months post-transplant was 17.2% (28/163) for the 100 day dosing regimen and 11.0% (17/155) for the 200 day dosing regimen.
Viral resistance: Virus resistant to ganciclovir can arise after chronic dosing with valganciclovir by selection of mutations in the viral kinase gene (UL97) responsible for ganciclovir monophosphorylation and/or the viral polymerase gene (UL54).
UL97 mutations arise earlier and more frequently than mutations in UL54. Virus containing mutations in the UL97 gene is resistant to ganciclovir alone, with M460V/I, H520Q, C592G, A594V, L595S, C603W being the most frequently reported ganciclovir resistance-associated substitutions. Mutations in the UL54 gene may show cross-resistance to other antivirals targeting the viral polymerase, and vice versa. Amino acid substitutions in UL54 conferring cross-resistance to ganciclovir and cidofovir are generally located within the exonuclease domains and region V, however amino acid substitutions conferring cross-resistance to foscamet are diverse, but concentrate at and between regions II (codon 696-742) and III (codon 805-845).
Treatment of CMV retinitis: Genotypic analysis of CMV in polymorphonuclear leucocytes (PMNL) isolates from 148 patients with CMV retinitis enrolled in one clinical study has shown that 2.2%, 6.5%, 12.8%, and 15.3% contain UL97 mutations after 3, 6, 12 and 18 months, respectively, of valganciclovir treatment.
Prevention of CMV disease in transplantation: Resistance was studied by genotypic analysis of CMV in PMNL samples collected i) on Day 100 (end of study drug prophylaxis) and ii) in cases of suspected CMV disease up to 6 months after transplantation. From the 245 patients randomised to receive valganciclovir, 198 Day 100 samples were available for testing and no ganciclovir resistance mutations were observed. This compares with 2 ganciclovir resistance mutations detected in the 103 samples tested (1.9%) for patients in the oral ganciclovir comparator arm.
Of the 245 patients randomised to receive valganciclovir, samples from 50 patients with suspected CMV disease were tested and no resistance mutations were observed. Of the 127 patients randomised on the ganciclovir comparator arm, samples from 29 patients with suspected CMV disease were tested, from which two resistance mutations were observed, giving an incidence of resistance of 6.9%.
Resistance was evaluated in a study that extended valganciclovir CMV prophylaxis from 100 days to 200 days post-transplant in adult kidney transplant patients at high risk for CMV disease (D+/R-) (see Efficacy/Clinical Studies previously mentioned). Five subjects from the 100 day group and four subjects from the 200 day group meeting the resistance analysis criteria had known ganciclovir resistance-associated amino acid substitutions detected. In six subjects, the following resistance associated amino acid substitutions were detected within pUL97: 100 day group: A440V, M460V, C592G; 200 day group: M460V, C603W. In three subjects, the following resistance-associated amino acid substitutions were detected within pUL54: 100 day group: E315D, 200 day group: E315D, P522S. Overall, the detection of known ganciclovir resistance-associated amino acid substitutions was observed more frequently in patients during prophylaxis therapy than after the completion of prophylaxis therapy (during therapy: 5/12 [42%] versus after therapy: 4/58 [7%]). The possibility of viral resistance should be considered in patients who show poor clinical response or experience persistent viral excretion during therapy.
Pharmacokinetics: The pharmacokinetic properties of valganciclovir have been evaluated in HIV- and CMV-seropositive patients, patients with AIDS and CMV retinitis and in solid organ transplant patients.
The parameters which control the exposure of ganciclovr from valganciclovir are bioavailability and renal function. The bioavailability of ganciclovr from valganciclovir is comparable across all the patient populations studied. The systemic exposure of ganciclovir to heart, kidney and liver transplant recipients was similar after oral administration of valganciclovir according to the renal function dosing algorithm.
Dose proportionality with respect to ganciclovir AUC following administration of valganciclovir in the dose range 450 to 2625 mg was demonstrated only under fed conditions.
Absorption: Valganciclovir is a prodrug of ganciclovir. which is well absorbed from the gastrointestinal tract and rapidly and extensively metabolised in the intestinal wall and liver to ganciclovir. The absolute bioavailability of ganciclovir from valganciclovir is approximately 60% Systemic exposure to valganciclovir is transient and low. AUC24 and Cmax values are approximately 1% and 3% of those of ganciclovir, respectively.
When valganciclovir was given with food at the recommended dose of 900 mg, increases were seen in both mean ganciclovir AUC24 (approximately 30%) and mean ganciclovir Cmax values (approximately 14%). Also the inter-individual variation in exposure of ganciclovir decreases when taking Valganciclovir with food. Valganciclovir has only been administered with food in clinical studies. Therefore, it is recommended that Valganciclovir be administered with food. For ganciclovir, average AUC0-24 has been shown to correlate with time to progression of CMV retinitis (see Dosage & Administration).
Distribution: Because of rapid conversion of valganciclovir to ganciclovir, protein binding of valganciclovir was not determined The steady state volume of distribution (Vd) of ganciclovir after intravenous administration was 0.680 ± 0.161 l/kg.
For IV ganciclovir, the volume of distribution is correlated with body weight with values for the steady state volume of distribution ranging from 0.54 - 0.87 L/kg. Ganciclovir penetrates the cerebrospinal fluid. Binding to plasma proteins was 1%-2% over ganciclovir concentrations of 0.5 and 51 μg/mL.
Biotransformation: Valganciclovir is rapidly hydrolyzed to ganciclovir; no other metabolites have been detected.
Ganciclovir itself is not metabolized to a significant extent.
Elimination: Following dosing with oral valganciclovir, the drug is rapidly hydrolyzed to ganciclovir. Ganciclovir is eliminated from the systemic circulation by glomerular filtration and active tubular secretion. In patients with normal renal function greater than 90% of IV administered ganciclovir was recovered un-metabolized in the urine within 24 hours. Post peak plasma concentrations of valganciclovir decline with a half-life of 0.4 to 2-0 h in subjects with normal renal function. In these patients ganciclovir concentrations decline with a half-life ranging from 3.5 to 4.5 hours similarly to that observed after direct IV administration of ganciclovir.
Geriatric Population: No investigations on valganciclovir or ganciclovir pharmacokinetics in adults older than 65 years of age have been undertaken. However as valganciclovir is a prodrug of ganciclovir and because ganciclovir is mainly renally excreted and since renal clearance decreases with age, a decrease in ganciclovir total body clearance and a prolongation of ganciclovir half-life can be anticipated in elderly (see Special dosage instructions under Dosage & Administration).
Patients with renal impairment: The pharmacokinetics of ganciclovir from a single oral dose of 900 mg valganciclovir were evaluated in 24 otherwise healthy individuals with renal impairment. (See Table 2.)
Click on icon to see table/diagram/imageDecreasing renal function resulted in decreased clearance of ganciclovir from valganciclovir with a corresponding increase in terminal half-life. Therefore, dosage adjustment is required for renally impaired patients (see Special dosage instructions under Dosage & Administration and Precautions).
Patients undergoing hemodialysis: Ganciclovir is readily removable by hemodialysis. Data obtained during intermittent haemodialysis in patients dosed with valganciclovir showed estimated dialysis clearance as 138 mL/min ± 9.1% (N = 3) and intra-dialysis half-life estimated to 3.47 h (N = 6).
55% of ganciclovir was removed during a 3 hour dialysis session.
Stable liver transplant patients: The pharmacokinetics of ganciclovir from valganciclovir in stable liver transplant patients were investigated in one open label 4-part crossover study (n = 28). The bioavailability of ganciclovir from valganciclovir, following a single dose of 900 mg valganciclovir under fed conditions, was approximately 60%. Ganciclovir AUC0-24 was comparable to that achieved by 5 mg/kg intravenous ganciclovir in liver transplant patients.
Hepatic impairment: No pharmacokinetic study has been conducted and no population PK data was collected in patients with hepatic impairment undergoing valganciclovir therapy.
Toxicology: Preclinical safety data: Valganciclovir is a pro-drug of ganciclovir and therefore effects observed with ganciclovir apply equally to valganciclovir. Toxicity of valganciclovir in pre-clinical safety studies was the same as that seen with ganciclovir and was induced at ganciclovir exposure levels comparable to, or lower than, those in humans given the induction dose.
These findings were gonadotoxicity (testicular cell loss) and nephrotoxicity (uraemia, cell degeneration), which were irreversible; myelotoxicity (anaemia, neutropenia, lymphocytopenia) and gastrointestinal toxicity (mucosal cell necrosis), which were reversible.
Further studies have shown ganciclovir to be mutagenic, carcinogenic, teratogenic, embryotoxic, aspermatogenic (i.e. impairs male fertility) and to suppress female fertility.
