Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

Mechanism of Action
CYMEVENE (ganciclovir for injection) is a synthetic nucleoside analogue of guanine which inhibits the replication of herpes viruses both in vitro and in vivo.
Intracellular ganciclovir is phosphorylated to ganciclovir monophosphate by a cellular deoxyguanosine kinase. Further phosphorylation occurs by several cellular kinases to produce ganciclovir triphosphate. It has been shown in vitro that the levels of ganciclovir triphosphate are as much as 100-fold greater in CMV-infected cells than non-infected cells. Thus, there is a preferential phosphorylation of ganciclovir in virus-infected cells. In virus-infected cells, ganciclovir triphosphate is metabolized slowly, with 60 to 70% remaining intracellularly 18 hours after removal of ganciclovir from the extracellular fluid. The antiviral activity of ganciclovir is the result of inhibition of viral DNA synthesis by two modes: (1) ganciclovir triphosphate competitively inhibits dGTP incorporation into DNA by DNA polymerase and (2) incorporation of ganciclovir triphosphate into viral DNA causes subsequent termination or very limited viral DNA elongation.

Ganciclovir inhibits mammalian cell proliferation in vitro at concentrations from 10 to 60 µg/mL, with bone marrow colony forming cells being most sensitive (IC50 of 10 µg/mL).

Pharmacokinetic Properties

12.3 Pharmacokinetics
Absorption
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 mcg·hr/mL (n=16) and Cmax ranged between 8.27 ± 1.02 (n=16) and 9.0 ± 1.4 mcg/mL (n=16).

Distribution
The steady-state volume of distribution of ganciclovir after intravenous administration was 0.74 ± 0.15 L/kg (n=98).
Ganciclovir diffuses across the placenta. Cerebrospinal fluid concentrations obtained 0.25 to 5.67 hours post-dose in 3 patients who received 2.5 mg/kg ganciclovir intravenously every 8 hours or every 12 hours ranged from 0.31 to 0.68 mcg/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 mcg/mL.



Elimination
When administered intravenously, ganciclovir exhibits linear pharmacokinetics over the range of 1.6 to 5.0 mg/kg. 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). Half-life was 3.5 ± 0.9 hours (n=98) following intravenous administration.

Specific Populations
Pharmacokinetics in Patients with Renal Impairment
The pharmacokinetics following intravenous administration of CYMEVENE 500 MG solution were evaluated in 10 immunocompromised patients with renal impairment who received doses ranging from 1.25 to 5.0 mg/kg. Decreased renal function results in decreased clearance of ganciclovir (Table 7).

Table 7. Ganciclovir Pharmacokinetics in Patients with Renal Impairment Estimated Creatinine                                          Clearance               Half-life Clearance                                               (mL/min)                 (hours) (mL/min)              n              Dose              Mean ± SD              Mean ± SD 50–79               4           3.2–5 mg/kg            128 + 63               4.6 ± 1.4 25–49               3            3–5 mg/kg               57 + 8               4.4 + 0.4
<25                3          1.25–5 mg/kg             30 + 13              10.7 + 5.7 Plasma concentrations of ganciclovir are reduced by about 50% during a 4 hour hemodialysis session.

Pharmacokinetics in Geriatric Patients
The pharmacokinetic profiles of CYMEVENE 500 MG in patients 65 years of age and older have not been established. As 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 patients 65 years of age and older [see Dosage and Administration (2.5), Use in Specific Populations (8.5)].

Drug Interaction Studies
Table 8 and Table 9 provide a listing of established drug interaction studies with ganciclovir. Table 8 provides the effects of coadministered drug on ganciclovir plasma pharmacokinetic parameters, whereas Table 9 provides the effects of ganciclovir on plasma pharmacokinetic parameters of coadministered drug.

Table 8. Results of Drug Interaction Studies with Ganciclovir: Effects of Coadministered Drug on Ganciclovir Pharmacokinetic Parameters


Ganciclovir Pharmacokinetic (PK)
Coadministered Drug           Ganciclovir Dosage         N
Parameter
Mycophenolate mofetil           5 mg/kg IV single dose     12     No effect on ganciclovir PK parameters (MMF) 1.5 g single dose                                           observed (patients with normal renal function)

Trimethoprim 200 mg once        1000 mg orally every       12     No effect on ganciclovir PK parameters daily                           8 hours                           observed.

Didanosine 200 mg every 12      5 mg/kg IV twice daily     11     No effect on ganciclovir PK parameters hours simultaneously                                              observed administered with ganciclovir
5 mg/kg IV once daily      11     No effect on ganciclovir PK parameters observed


Ganciclovir Pharmacokinetic (PK)
Coadministered Drug              Ganciclovir Dosage          N
Parameter
Probenecid 500 mg every 6          1000 mg orally every        10     AUC  53 ± 91% hours                              8 hours                            (range: -14% to 299%) 
Ganciclovir renal clearance  22 ± 20%
(range: -54% to -4%)


Table 9. Results of Drug Interaction Studies with Ganciclovir: Effects of Ganciclovir on Pharmacokinetic Parameters of Coadministered Drug
Coadministered Drug
Coadministered Drug             Ganciclovir Dosage          N
Pharmacokinetic (PK) Parameter

Oral ciclosporin at therapeutic    5 mg/kg infused over 1       93    In a retrospective analysis of liver doses                              hour every 12 hours                allograft recipients, there was no evidence of an effect on ciclosporin whole blood concentrations.
Mycophenolate mofetil              5 mg/kg IV single dose       12    No PK interaction observed (patients (MMF) 1.5 g single dose                                               with normal renal function) Trimethoprim 200 mg once           1000 mg orally every 8       12    No effect on trimethoprim PK daily                              hours                              parameters observed.

Didanosine 200 mg every            5 mg/kg IV twice daily       11    AUC0-12 70 ± 40% 12 hours                                                              (range: 3% to 121%) 
Cmax49 ± 48%
(range: -28% to 125%)

Didanosine 200 mg every            5 mg/kg IV once daily        11    AUC0-12 50 ± 26% 12 hours                                                              (range: 22% to 110%) 
Cmax 36 ± 36%
(range: -27% to 94%)

12.4 Microbiology

Mechanism of Action
Ganciclovir is a synthetic analogue of 2'-deoxyguanosine, which inhibits replication of human CMV in cell culture and in vivo. 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 metabolized intracellularly. 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 the viral DNA polymerase, pUL54, by ganciclovir triphosphate.

Antiviral Activity
The quantitative relationship between the cell culture susceptibility of human herpes viruses to antivirals and clinical response to antiviral therapy has not been established, and virus sensitivity testing has not been standardized. Sensitivity test results, expressed as the concentration of drug required to inhibit the growth of virus in cell culture by 50% (EC50), vary greatly depending upon a number of factors including the assay used. Thus the median concentration of ganciclovir that inhibits CMV replication (EC50 value) in cell culture (laboratory strains or clinical isolates) has ranged from 0.08 to 13.6 µM (0.02 to 3.48 mcg/mL). Ganciclovir inhibits mammalian cell proliferation (CC50 value) in cell culture at higher concentrations ranging from 118 to 2840 µM (30 to 725 mcg/mL). Bone marrow-derived colony-forming cells are more sensitive [CC50 value = 0.1 to 2.7 µM (0.028 to 0.7 mcg/mL)]. The relationship between the antiviral activity in cell culture and clinical response has not been established.
Viral Resistance
Cell Culture: CMV isolates with reduced susceptibility to ganciclovir have been selected in cell culture. Growth of CMV strains in the presence of ganciclovir resulted in the selection of amino acid substitutions in the viral protein kinase pUL97 and the viral DNA polymerase pUL54.
In vivo: Viruses resistant to ganciclovir can arise after prolonged treatment or prophylaxis with ganciclovir by selection of substitutions in pUL97 and/or pUL54. Limited clinical data are available on the development of clinical resistance to ganciclovir and many pathways to resistance likely exist. In clinical isolates, seven canonical pUL97 substitutions, (M460V/I, H520Q, C592G, A594V, L595S, C603W) are the most frequently reported ganciclovir resistance-associated substitutions. These and other substitutions less frequently reported in the literature, or observed in clinical trials, are listed in Table 10.
Table 10. Summary of Resistance-associated Amino Acid Substitutions Observed in the CMV of Patients Failing Ganciclovir Treatment or Prophylaxis
L405P, A440V, M460I/V/T/L, V466G/M, C518Y, H520Q, P521L, del 590-593, A591D/V, C592G, pUL97                                  A594E/G/T/V/P, L595F/S/T/W, del 595, del 595-603, E596D/G/Y, K599E/M, del 600-601, del 597- 600, del 601-603, C603W/R/S/Y, C607F/S/Y, I610T, A613V
E315D, N408D/K/S, F412C/L/S, D413A/E/N, L501F/I, T503I, K513E/N/R, D515E, L516W, I521T, P522A/L/S, V526L, C539G, L545S/W, Q578H/L, D588E/N, G629S, S695T, I726T/V, E756K, pUL54
L773V, V781I, V787L, L802M, A809V, T813S, T821I, A834P, G841A/S, D879G, A972V, del 981- 982, A987G
Note: Many additional pathways to ganciclovir resistance likely exist 

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 CYMEVENE 500 MG. 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.

Cross-Resistance
Cross-resistance has been reported for amino acid substitutions selected in cell culture by ganciclovir, cidofovir or foscarnet.
In general, amino acid substitutions in pUL54 conferring cross-resistance to ganciclovir and cidofovir are located within the exonuclease domains and region V of the viral DNA polymerase. Whereas, amino acid substitutions conferring cross-resistance to foscarnet are diverse, but concentrate at and between regions II (codons 696-742) and III (codons 805-845). The amino acid substitutions that resulted in reduced susceptibility to ganciclovir and either cidofovir and/or foscarnet are summarized in Table 11.

Table 11. Summary of pUL54 Amino Acid Substitutions with Cross-resistance between Ganciclovir, Cidofovir, and/or Foscarnet
D301N, N408D/K, N410K, F412C/L/S/V, D413E/N, P488R, L501I, T503I, K513E/N, L516R/W, I521T, Cross-resistant to
P522S/A, V526L, C539G/R, L545S/W, Q578H, D588N, I726T/V, E756K, L773V, V812L, T813S, A834P, cidofovir
G841A, del 981-982, A987G
Cross-resistant to              F412C, Q578H/L, D588N, V715A/M, E756K, L773V, V781I, V787L, L802M, A809V, V812L, T813S, foscarnet                       T821I, A834P, G841A/S, del 981-982