Ganciclovir (Page 6 of 9)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ganciclovir is an antiviral drug with activity against CMV [see Microbiology (12.4)].

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 ± 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 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 ganciclovir for injection solution were evaluated in 10 immunocompromised patients with renal impairment who received doses ranging from 1.25 to 5 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

(mL/min)

n

Dose

Clearance (mL/min)

Mean ± SD

Half-life (hours)

Mean ± SD

50 to 79

25 to 49

<25

4

3

3

3.2 to 5 mg/kg

3 to 5 mg/kg

1.25 to 5 mg/kg

128 + 63

57 + 8

30 + 13

4.6 ± 1.4

4.4 + 0.4

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 ganciclovir 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

Tables 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

Coadministered Drug

Ganciclovir Dosage

N

Ganciclovir Pharmacokinetic (PK) Parameter

Mycophenolate mofetil (MMF)

1.5 g single dose

5 mg/kg IV single dose

12

No effect on ganciclovir PK parameters observed (patients with normal renal function)

Trimethoprim 200 mg once daily

1000 mg orally every 8 hours

12

No effect on ganciclovir PK parameters observed.

Didanosine 200 mg every 12 hours simultaneously administered with ganciclovir

5 mg/kg IV twice daily

11

No effect on ganciclovir PK parameters observed

5 mg/kg IV once daily

11

No effect on ganciclovir PK parameters observed

Probenecid 500 mg every 6 hours

1000 mg orally every 8 hours

10

AUC ­ 53 ± 91%

(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

Ganciclovir Dosage

N

Coadministered Drug Pharmacokinetic (PK) Parameter

Oral cyclosporine at therapeutic doses

5 mg/kg infused over 1 hour every 12 hours

93

In a retrospective analysis of liver allograft recipients, there was no evidence of an effect on cyclosporine whole blood concentrations.

Mycophenolate mofetil (MMF)

1.5 g single dose

5 mg/kg IV single dose

12

No PK interaction observed (patients with normal renal function)

Trimethoprim 200 mg once daily

1000 mg orally every 8 hours

12

No effect on trimethoprim PK parameters observed.

Didanosine 200 mg every 12 hours

5 mg/kg IV twice daily

11

AUC0-12 ­70 ± 40%

(range: 3% to 121%)

Cmax­49 ± 48%

(range: -28% to 125%)

Didanosine 200 mg every 12 hours

5 mg/kg IV once daily

11

AUC0-12 ­50 ± 26%

(range: 22% to 110%)

Cmax ­36 ± 36% (range: -27% to 94%)


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