Cytovene (Ganciclovir) - Description and Clinical Pharmacology

DESCRIPTION

Ganciclovir is a synthetic guanine derivative active against cytomegalovirus (CMV). CYTOVENE-IV and CYTOVENE are the brand names for ganciclovir sodium for injection and ganciclovir capsules, respectively.

CYTOVENE-IV is available as sterile lyophilized powder in strength of 500 mg per vial for intravenous administration only. Each vial of CYTOVENE-IV contains the equivalent of 500 mg ganciclovir as the sodium salt (46 mg sodium). Reconstitution with 10 mL of Sterile Water for Injection, USP, yields a solution with pH 11 and a ganciclovir concentration of approximately 50 mg/mL. Further dilution in an appropriate intravenous solution must be performed before infusion (see DOSAGE AND ADMINISTRATION).

CYTOVENE is available as 250 mg and 500 mg capsules. Each capsule contains 250 mg or 500 mg ganciclovir, respectively, and inactive ingredients croscarmellose sodium, magnesium stearate and povidone. Both hard gelatin shells consist of gelatin, titanium dioxide, yellow iron oxide and FD&C Blue No. 2.

Ganciclovir is a white to off-white crystalline powder with a molecular formula of C₉H₁₃N₅O₄ and a molecular weight of 255.23. The chemical name for ganciclovir is 9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]guanine. Ganciclovir is a polar hydrophilic compound with a solubility of 2.6 mg/mL in water at 25°C and an n-octanol/water partition coefficient of 0.022. The pK_a s for ganciclovir are 2.2 and 9.4.

Ganciclovir, when formulated as monosodium salt in the IV dosage form, is a white to off-white lyophilized powder with a molecular formula of C₉H₁₂N₅NaO₄, and a molecular weight of 277.22. The chemical name for ganciclovir sodium is 9-[[2-hydroxy-1-(hydroxymethyl) ethoxy]methyl]guanine, monosodium salt. The lyophilized powder has an aqueous solubility of greater than 50 mg/mL at 25°C. At physiological pH, ganciclovir sodium exists as the un-ionized form with a solubility of approximately 6 mg/mL at 37°C.

All doses in this insert are specified in terms of ganciclovir.

VIROLOGY

Mechanism of Action:    Ganciclovir is an acyclic nucleoside analogue of 2'-deoxyguanosine that inhibits replication of herpes viruses. Ganciclovir has been shown to be active against cytomegalovirus (CMV) and herpes simplex virus (HSV) in human clinical studies.

To achieve anti-CMV activity, ganciclovir is phosphorylated first to the monophosphate form by a CMV-encoded (UL97 gene) protein kinase homologue, then to the di- and triphosphate forms by cellular kinases. Ganciclovir triphosphate concentrations may be 100-fold greater in CMV-infected than in uninfected cells, indicating preferential phosphorylation in infected cells. Ganciclovir triphosphate, once formed, persists for days in the CMV-infected cell. Ganciclovir triphosphate is believed to inhibit viral DNA synthesis by (1) competitive inhibition of viral DNA polymerases; and (2) incorporation into viral DNA, resulting in eventual termination of viral DNA elongation.

Antiviral Activity:   The median concentration of ganciclovir that inhibits CMV replication (IC₅₀) in vitro (laboratory strains or clinical isolates) has ranged from 0.02 to 3.48 µg/mL. Ganciclovir inhibits mammalian cell proliferation (CIC₅₀) in vitro at higher concentrations ranging from 30 to 725 µg/mL. Bone marrow-derived colony-forming cells are more sensitive (CIC₅₀0.028 to 0.7 µg/mL). The relationship of in vitro sensitivity of CMV to ganciclovir and clinical response has not been established.

Clinical Antiviral Effect of CYTOVENE-IV and CYTOVENE Capsules:    CYTOVENE-IV: In a study of CYTOVENE-IV treatment of life- or sight-threatening CMV disease in immunocompromised patients, 121 of 314 patients had CMV cultured within 7 days prior to treatment and sequential posttreatment viral cultures of urine, blood, throat and/or semen. As judged by conversion to culture negativity, or a greater than 100-fold decrease in in vitro CMV titer, at least 83% of patients had a virologic response with a median response time of 7 to 15 days.

Antiviral activity of CYTOVENE-IV was demonstrated in two randomized studies for the prevention of CMV disease in transplant recipients (see table below).

CYTOVENE Capsules: In trials comparing CYTOVENE-IV with CYTOVENE capsules for the maintenance treatment of CMV retinitis in patients with AIDS, serial urine cultures and other available cultures (semen, biopsy specimens, blood and others) showed that a small proportion of patients remained culture-positive during maintenance therapy with no statistically significant differences in CMV isolation rates between treatment groups.

A study of CYTOVENE capsules (1000 mg q8h) for prevention of CMV disease in individuals with advanced HIV infection (ICM 1654) evaluated antiviral activity as measured by CMV isolation in culture; most cultures were from urine. At baseline, 40% (176/436) and 44% (92/210) of ganciclovir and placebo recipients, respectively, had positive cultures (urine or blood). After 2 months on treatment, 10% vs 44% of ganciclovir vs placebo recipients had positive cultures.

Viral Resistance:    The current working definition of CMV resistance to ganciclovir in in vitro assays is IC₅₀>3.0 µg/mL (12.0 µM). CMV resistance to ganciclovir has been observed in individuals with AIDS and CMV retinitis who have never received ganciclovir therapy. Viral resistance has also been observed in patients receiving prolonged treatment for CMV retinitis with CYTOVENE-IV. In a controlled study of oral ganciclovir for prevention of AIDS-associated CMV disease, 364 individuals had one or more cultures performed after at least 90 days of ganciclovir treatment. Of these, 113 had at least one positive culture. The last available isolate from each subject was tested for reduced sensitivity, and 2 of 40 were found to be resistant to ganciclovir. These resistant isolates were associated with subsequent treatment failure for retinitis.

The possibility of viral resistance should be considered in patients who show poor clinical response or experience persistent viral excretion during therapy. The principal mechanism of resistance to ganciclovir in CMV is the decreased ability to form the active triphosphate moiety; resistant viruses have been described that contain mutations in the UL97 gene of CMV that controls phosphorylation of ganciclovir. Mutations in the viral DNA polymerase have also been reported to confer viral resistance to ganciclovir.

CLINICAL PHARMACOLOGY

PHARMACOKINETICS:

BECAUSE THE MAJOR ELIMINATION PATHWAY FOR GANCICLOVIR IS RENAL, DOSAGE REDUCTIONS ACCORDING TO CREATININE CLEARANCE ARE REQUIRED FOR CYTOVENE-IV AND SHOULD BE CONSIDERED FOR CYTOVENE CAPSULES. FOR DOSING INSTRUCTIONS IN PATIENTS WITH RENAL IMPAIRMENT, REFER TO DOSAGE AND ADMINISTRATION.

Absorption:    The absolute bioavailability of oral ganciclovir under fasting conditions was approximately 5% (n=6) and following food was 6% to 9% (n=32). When ganciclovir was administered orally with food at a total daily dosage of 3 g/day (500 mg q3h, 6 times daily and 1000 mg tid), the steady-state absorption as measured by area under the serum concentration vs time curve (AUC) over 24 hours and maximum serum concentrations (C_max) were similar following both regimens with an AUC_0-24 of 15.9 ± 4.2 (mean ± SD) and 15.4 ± 4.3 µg·hr/mL and C_max of 1.02 ± 0.24 and 1.18 ± 0.36 µg/mL, respectively (n=16).

At the end of a 1-hour intravenous infusion of 5 mg/kg ganciclovir, total AUC ranged between 22.1 ± 3.2 (n=16) and 26.8 ± 6.1 µg·hr/mL (n=16) and C_max ranged between 8.27 ± 1.02 (n=16) and 9.0 ± 1.4 µg/mL (n=16).

Food Effects:    When CYTOVENE capsules were given with a meal containing 602 calories and 46.5% fat at a dosage of 1000 mg every 8 hours to 20 HIV-positive subjects, the steady-state AUC increased by 22 ± 22% (range: -6% to 68%) and there was a significant prolongation of time to peak serum concentrations (T_max) from 1.8 ± 0.8 to 3.0 ± 0.6 hours and a higher C_max(0.85 ± 0.25 vs 0.96 ± 0.27 µg/mL) (n=20).

Distribution:    The steady-state volume of distribution of ganciclovir after intravenous administration was 0.74 ± 0.15 L/kg (n=98). For CYTOVENE capsules, no correlation was observed between AUC and reciprocal weight (range: 55 to 128 kg); oral dosing according to weight is not required. Cerebrospinal fluid concentrations obtained 0.25 to 5.67 hours postdose in 3 patients who received 2.5 mg/kg ganciclovir intravenously q8h or q12h ranged from 0.31 to 0.68 µg/mL representing 24% to 70% of the respective plasma concentrations. Binding to plasma proteins was 1% to 2% over ganciclovir concentrations of 0.5 and 51 µg/mL.

Metabolism:    Following oral administration of a single 1000 mg dose of¹⁴ C-labeled ganciclovir, 86 ± 3% of the administered dose was recovered in the feces and 5 ± 1% was recovered in the urine (n=4). No metabolite accounted for more than 1% to 2% of the radioactivity recovered in urine or feces.

Elimination:    When administered intravenously, ganciclovir exhibits linear pharmacokinetics over the range of 1.6 to 5.0 mg/kg and when administered orally, it exhibits linear kinetics up to a total daily dose of 4 g/day. Renal excretion of unchanged drug by glomerular filtration and active tubular secretion is the major route of elimination of ganciclovir. In patients with normal renal function, 91.3 ± 5.0% (n=4) of intravenously administered ganciclovir was recovered unmetabolized in the urine. Systemic clearance of intravenously administered ganciclovir was 3.52 ± 0.80 mL/min/kg (n=98) while renal clearance was 3.20 ± 0.80 mL/min/kg (n=47), accounting for 91 ± 11% of the systemic clearance (n=47). After oral administration of ganciclovir, steady-state is achieved within 24 hours. Renal clearance following oral administration was 3.1 ± 1.2 mL/min/kg (n=22). Half-life was 3.5 ± 0.9 hours (n=98) following IV administration and 4.8 ± 0.9 hours (n=39) following oral administration.

Special Populations:    Renal Impairment: The pharmacokinetics following intravenous administration of CYTOVENE-IV solution were evaluated in 10 immunocompromised patients with renal impairment who received doses ranging from 1.25 to 5.0 mg/kg.

The pharmacokinetics of ganciclovir following oral administration of CYTOVENE capsules were evaluated in 44 patients, who were either solid organ transplant recipients or HIV positive. Apparent oral clearance of ganciclovir decreased and AUC_0-24h increased with diminishing renal function (as expressed by creatinine clearance). Based on these observations, it is necessary to modify the dosage of ganciclovir in patients with renal impairment (see DOSAGE AND ADMINISTRATION).

Hemodialysis reduces plasma concentrations of ganciclovir by about 50% after both intravenous and oral administration.

Race/Ethnicity and Gender:    The effects of race/ethnicity and gender were studied in subjects receiving a dose regimen of 1000 mg every 8 hours. Although the numbers of blacks (16%) and Hispanics (20%) were small, there appeared to be a trend towards a lower steady-state C_max and AUC_0-8 in these subpopulations as compared to Caucasians. No definitive conclusions regarding gender differences could be made because of the small number of females (12%); however, no differences between males and females were observed.

Pediatrics:    Ganciclovir pharmacokinetics were studied in 27 neonates, aged 2 to 49 days. At an intravenous dose of 4 mg/kg (n=14) or 6 mg/kg (n=13), the pharmacokinetic parameters were, respectively, C_max of 5.5 ± 1.6 and 7.0 ± 1.6 µg/mL, systemic clearance of 3.14 ± 1.75 and 3.56 ± 1.27 mL/min/kg, and t_½ of 2.4 hours (harmonic mean) for both.

Ganciclovir phrmacokinetics were also studied in 10 pediatric patients, aged 9 months to 12 years. The pharmacokinetic characteristics of ganciclovir were the same after single and multiple (q12h) intravenous doses (5 mg/kg). The steady-state volume of distribution was 0.64 ± 0.22 L/kg, C_max was 7.9 ± 3.9 µg/mL, systemic clearance was 4.7 ± 2.2 mL/min/kg, and t_½ was 2.4 ± 0.7 hours. The pharmacokinetics of intravenous ganciclovir in pediatric patients are similar to those observed in adults.

Elderly:    No studies have been conducted in adults older than 65 years of age.