Valganciclovir Hydrochloride For Oral (Page 5 of 9)

11 DESCRIPTION

Valganciclovir Hydrochloride for Oral Solution contains valganciclovir hydrochloride, USP (valganciclovir HCl), a hydrochloride salt of the L-valyl ester of ganciclovir that exists as a mixture of two diastereomers. Ganciclovir is a synthetic guanine derivative active against CMV.

Valganciclovir is available as a powder blend for oral solution, which when constituted with water as directed contains 50 mg/mL valganciclovir free base. The inactive ingredients of valganciclovir hydrochloride for oral solution are mannitol, sodium benzoate, sucralose, tartaric acid and tutti-frutti flavoring.

Valganciclovir HCl, USP is a white to almost white powder. The chemical name for valganciclovir HCl, USP is L-Valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3-hydroxypropyl ester, monohydrochloride. Valganciclovir HCl, USP is a polar hydrophilic compound with a solubility of 70 mg/mL in water at 25°C at a pH of 7.0 and an n-octanol/water partition coefficient of 0.0095 at pH 7.0. The pKa for valganciclovir HCl, USP is 7.6.

The chemical structure of valganciclovir HCl, USP is:

The chemical structure of valganciclovir HC1.
(click image for full-size original)

C14 H22 N6 O5 ·HCl M.W.390.83

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

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.3 Pharmacokinetics

Valganciclovir is a prodrug of ganciclovir. Valganciclovir Cmax and AUC are approximately 1% and 3% of those of ganciclovir, respectively.

Pharmacokinetics in Adults: The pharmacokinetics of ganciclovir after administration of valganciclovir tablets have been evaluated in HIV- and CMV-seropositive patients, patients with AIDS and CMV retinitis, and in solid organ transplant patients (Table 10).

Table 10 Ganciclovir Pharmacokinetics* in Healthy Volunteers and HIV-positive/CMV-positive Adults Administered Valganciclovir Tablets 900 mg Once Daily with Food
PK parameter N Value (Mean ± SD)
AUC0-24h (mcg h/mL) 57 29.1 ± 9.7
Cmax (mcg/mL) 58 5.61 ± 1.52
Absolute oral bioavailability (%) 32 59.4 ± 6.1
Elimination half-life (hr) 73 4.08 ± 0.76
Renal clearance (mL/min/kg) 20

3.21 ± 0.75

*Data were obtained from single and multiple dose studies in healthy volunteers, HIV-positive patients, and HIV-positive/CMV-positive patients with and without retinitis. Patients with CMV retinitis tended to have higher ganciclovir plasma concentrations than patients without CMV retinitis.

The systemic ganciclovir exposures attained following administration of 900 mg valganciclovir tablets once daily were comparable across kidney, heart and liver transplant recipients (Table 11).

Table 11 Ganciclovir Pharmacokinetics in Solid Organ Transplant Recipients Administered Valganciclovir Tablets 900 mg Once Daily with Food
Value (Mean ± SD)
Parameter

Heart Transplant Recipients

(N=17)
Liver Transplant Recipients (N=75)

Kidney Transplant Recipients*

(N=68)
AUC0-24h (mcg· h/mL) 40.2 ± 11.8 46.0 ± 16.1 48.2 ± 14.6
Cmax (mcg/mL) 4.9 ± 1.1 5.4 ± 1.5 5.3 ± 1.5
Elimination half-life (hr) 6.58 ± 1.50 6.18 ± 1.42 6.77 ± 1.25

* Includes kidney-pancreas

The pharmacokinetic parameters of ganciclovir following 200 days of valganciclovir administration in high-risk kidney transplant patients were similar to those in solid organ transplant patients who received valganciclovir for 100 days.

Absorption, Distribution, Metabolism, and Excretion

The pharmacokinetic (PK) properties of valganciclovir hydrochloride are provided in Table 12.

Table 12 Pharmacokinetic Properties of Ganciclovir and Valganciclovir Associated with Valganciclovir Hydrochloride
Valganciclovir Ganciclovir
Absorption
Tmax (h) median (min-max) (fed conditions) 2.18 1.7h to 3.0h
Food effect (high fat meal/fasting): PK parameter ratio and 90% confidence intervala Cmax :1.14 (0.95, 1.36)

AUC:1.30 (1.07, 1.51)a

max : ↔
Distribution
% Bound to human plasma proteins (ex vivo) Unknown 1 to 2% over 0.5­-51 mcg/mL

Cerebrospinal fluid penetration

Unknown Yes
Metabolism
Hydrolyzed by intestinal and liver esterases No significant metabolism
Elimination

Dose proportionality

AUC was dose proportional under fed conditions across a valganciclovir dose range of 450 to 2625 mg
Major route of elimination Metabolism to ganciclovir Glomerular filtration and active tubular secretion
t1/2 (h) See Tables 10 and 11
% Of dose excreted in urine Unknown
% Of dose excreted in feces Unknown

a Steady state ganciclovir PK was assessed after administration of valganciclovir tablets (875 mg once daily) with a high fat meal containing approximately 600 total calories (31.1 g fat, 51.6 g carbohydrates and 22.2 g protein) to 16 HIV-positive subjects.

Specific Populations:

Renal Impairment: The pharmacokinetics of ganciclovir from a single oral dose of 900 mg valganciclovir hydrochloride tablets were evaluated in 24 otherwise healthy individuals with renal impairment. Decreased renal function results in decreased clearance of ganciclovir and increased terminal half-life (Table 13).

Table 13 Pharmacokinetics of Ganciclovir from a Single Oral Dose of 900 mg Valganciclovir Hydrochloride Tablets
Estimated Apparent Clearance AUC last Half-life
Creatinine Clearance* (mL/m i n) (mcg · h/mL) (hours)
(mL/min) N Mean ± SD Mean ± SD Mean ± S D
51 to 70 6 249 ± 99 49.5 ± 22.4 4.85 ± 1.4
21 to 50 6 136 ± 64 91.9 ± 43.9 10.2 ± 4.4
11 to 20 6 45 ± 11 223 ± 46 21.8 ± 5.2
≤10 6 12.8 ± 8 366 ± 66 67.5 ± 34

*Creatinine clearance calculated from 24-hour urine collection.

Hemodialysis reduces plasma concentrations of ganciclovir by about 50% following valganciclovir administration. Adult patients receiving hemodialysis (CrCl less than 10 mL/min) cannot use valganciclovir hydrochloride tablets because the daily dose of valganciclovir hydrochloride tablets required for these patients is less than 450 mg [see Use in Specific Populations (8.6)].

Pharmacokinetics in Pediatric Patients: The pharmacokinetics of ganciclovir were evaluated following the administration of valganciclovir in 63 pediatric solid organ transplant patients aged 4 months to 16 years, and in 16 pediatric heart transplant patients less than 4 months of age. In these studies, patients received oral doses of valganciclovir (either valganciclovir hydrochloride for oral solution or tablets) to produce exposure equivalent to an adult 900 mg dose [see Dosage and Administration (2.3), Adverse Reactions (6.1), Use in Specific Populations (8.4), Clinical Studies (14.2)].

In studies using the pediatric valganciclovir dosing algorithm, the pharmacokinetics of ganciclovir were similar across organ types and age ranges (Table 14). Relative to adult transplant patients (Table 11), AUC values in pediatric patients were somewhat increased, but were within the range considered safe and effective in adults.

Table 14 Ganciclovir Pharmacokinetics by Age in Pediatric Solid Organ Transplant Patients Administered Valganciclovir Hydrochloride

Organ

PK Parameter mean (SD)

Age Group

< 4 months

4 months to ≤ 2 years

> 2 to < 12 years

≥ 12 years

Heart

(N=26)

N

AUC0-24h (mcg∙h/mL)

Cmax (mcg/mL)

t1/2 (h)

14a

66.3 (20.5)

10.8 (3.30)

3.5 (0.87)

6

55.4 (22.8)

8.2 (2.5)

3.8 (1.7)

2

59.6 (21.0)

12.5 (1.2)

2.8 (0.9)

4

60.6 (25.0)

9.5 (3.3)

4.9 (0.8)

Kidney

(N=31)

N

AUC0-24h (mcg∙h/mL)

Cmax (mcg/mL)

t1/2 (h)

NA

2

67.6 (13.0)

10.4 (0.4)

4.5 (1.5)

10

55.9 (12.1)

8.7 (2.1)

4.8 (1.0)

19

47.8 (12.4)

7.7 (2.1)

6.0 (1.3)

Liver

(N=17)

N

AUC0-24h (mcg h/mL)

Cmax (mcg/mL)

t1/2 (h)

NA

9

69.9 (37.0)

11.9 (3.7)

2.8 (1.5)

6

59.4 (8.1)

9.5 (2.3)

3.8 (0.7)

2

35.4 (2.8)

5.5 (1.1)

4.4 (0.2)

N= number of patients, NA=not applicablea Ages ranged from 26 to 124 days.

Pharmacokinetics in Geriatric Patients: The pharmacokinetic characteristics of valganciclovir in elderly patients have not been established.

Drug Interactions: In vivo drug-drug interaction studies were not conducted with valganciclovir. However, because valganciclovir is rapidly and extensively converted to ganciclovir, interactions associated with ganciclovir will be expected for valganciclovir [see Drug Interactions (7)].

Table 15 and Table 16 provide a listing of established drug interaction studies with ganciclovir. Table 15 provides the effects of coadministered drug on ganciclovir plasma pharmacokinetic parameters, whereas Table 16 provides the effects of ganciclovir on plasma pharmacokinetic parameters of coadministered drug.

Table 15 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 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 every 8 hours 10

AUC ↑ 53 ± 91%

(range: -14% to 299%)

Ganciclovir renal clearance ↓

22 ± 20%

Table 16 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 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%) Cmax ↑49 ± 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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