CLINICAL PHARMACOLOGY
Mechanism of Action
Valganciclovir is an antiviral drug [see Microbiology].
Pharmacokinetics
Because the major elimination pathway for ganciclovir is renal, dosage reductions according to creatinine clearance are required for Valcyte tablets and Valcyte for oral solution [see Dosage and Administration].
Pharmacokinetics in Adults: The pharmacokinetics of valganciclovir and 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.
The ganciclovir pharmacokinetic parameters following administration of 900 mg Valcyte tablets and 5 mg/kg intravenous ganciclovir and 1000 mg three times daily oral ganciclovir in HIV-positive/CMV-positive patients are summarized in
Table 9.
Table 9 Mean Ganciclovir PharmacokineticData 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. Measures in Healthy Volunteers and HIV-positive/CMV-positive Adults at Maintenance Dosage
| Formulation |
Valcyte Tablets |
Intravenous Ganciclovir |
Ganciclovir Capsules |
| Dosage |
900 mg once daily with food |
5 mg/kg once daily |
1000 mg three times daily with food |
| AUC0-24h (µg∙h/mL) |
29.1 ± 9.7
(3 studies, n=57) |
26.5 ± 5.9
(4 studies, n=68) |
Range of means 12.3 to 19.2
(6 studies, n=94) |
| Cmax (µg/mL) |
5.61 ± 1.52
(3 studies, n=58) |
9.46 ± 2.02
(4 studies, n=68) |
Range of means 0.955 to 1.40
(6 studies, n=94) |
| Absolute oral bioavailability (%) |
59.4 ± 6.1
(2 studies, n=32) |
Not Applicable |
Range of means 6.22 ± 1.29 to
8.53 ± 1.53 (2 studies, n=32) |
| Elimination half-life (hr) |
4.08 ± 0.76
(4 studies, n=73) |
3.81 ± 0.71
(4 studies, n=69) |
Range of means 3.86 to 5.03
(4 studies, n=61) |
| Renal clearance (mL/min/kg) |
3.21 ± 0.75
(1 study, n=20) |
2.99 ± 0.67
(1 study, n=16) |
Range of means 2.67 to 3.98
(3 studies, n=30) |
The area under the plasma concentration-time curve (AUC) of ganciclovir administered as Valcyte tablets (900 mg once daily) is comparable to the AUC of ganciclovir after administration of intravenous ganciclovir (5 mg/kg once daily). The Cmax of ganciclovir following Valcyte administration is 40% lower than the Cmax following intravenous ganciclovir administration. During maintenance dosing, ganciclovir AUC0-24h and Cmax following oral ganciclovir administration (1000 mg three times daily) are lower relative to Valcyte and intravenous ganciclovir. The ganciclovir Cmin following intravenous ganciclovir and Valcyte administration are less than the ganciclovir Cmin following oral ganciclovir administration. The clinical significance of the differences in ganciclovir pharmacokinetics after administration of Valcyte tablets, ganciclovir capsules, and intravenous ganciclovir is unknown.
Figure 1 Ganciclovir Plasma Concentration Time Profiles in HIV-positive/CMV-positive Patients*
*Plasma concentration-time profiles for ganciclovir (GCV) from valganciclovir (VGCV) and intravenous ganciclovir were obtained from a multiple dose study (n=21 and n=18, respectively) in HIV-positive/CMV-positive patients with CMV retinitis. The plasma concentration-time profile for oral ganciclovir was obtained from a multiple dose study (n=24) in HIV-positive/CMV-positive patients without CMV retinitis.
In solid organ transplant recipients, the mean systemic exposure to ganciclovir was 1.7x higher following administration of 900 mg Valcyte tablets once daily versus 1000 mg ganciclovir capsules three times daily, when both drugs were administered according to their renal function dosing algorithms. The systemic ganciclovir exposures attained were comparable across kidney, heart and liver transplant recipients based on a population pharmacokinetics evaluation (see
Table 10).
Table 10 Mean Ganciclovir Pharmacokinetic Measures by Organ Transplant Type
| Parameter |
Ganciclovir Capsules |
Valcyte Tablets |
| Dosage |
1000 mg three times daily with food |
900 mg once daily with food |
|
Heart Transplant Recipients
|
N=13 |
N=17 |
| AUC0-24h (µg∙h/mL) |
26.6 ± 11.6 |
40.2 ± 11.8 |
| Cmax (µg/mL) |
1.4 ± 0.5 |
4.9 ± 1.1 |
| Elimination half-life (hr) |
8.47 ± 2.84 |
6.58 ± 1.50 |
|
Liver Transplant Recipients
|
N=33 |
N=75 |
| AUC0-24h (µg∙h/mL) |
24.9 ± 10.2 |
46.0 ± 16.1 |
| Cmax (µg/mL) |
1.3 ± 0.4 |
5.4 ± 1.5 |
| Elimination half-life (hr) |
7.68 ± 2.74 |
6.18 ± 1.42 |
|
Kidney Transplant RecipientsIncludes kidney-pancreas
|
N=36 |
N=68 |
| AUC0-24h (µg∙h/mL) |
31.3 ± 10.3 |
48.2 ± 14.6 |
| Cmax (µg/mL) |
1.5 ± 0.5 |
5.3 ± 1.5 |
| Elimination half-life (hr) |
9.44 ± 4.37 |
6.77 ± 1.25 |
The pharmacokinetic parameters of ganciclovir following 200 days of Valcyte administration in high-risk kidney transplant patients were similar to those previously reported in solid organ transplant patients who received Valcyte for 100 days.
In a pharmacokinetic study in liver transplant patients, the ganciclovir AUC0-24h achieved with 900 mg valganciclovir was 41.7 ± 9.9 µg∙h/mL (n=28) and the AUC0-24h achieved with the approved dosage of 5 mg/kg intravenous ganciclovir was 48.2 ± 17.3 µg∙h/mL (n=27).
Absorption
: Valganciclovir, a prodrug of ganciclovir, is well absorbed from the gastrointestinal tract and rapidly metabolized in the intestinal wall and liver to ganciclovir. The absolute bioavailability of ganciclovir from Valcyte tablets following administration with food was approximately 60% (3 studies, n=18; n=16; n=28). Ganciclovir median Tmax following administration of 450 mg to 2625 mg Valcyte tablets ranged from 1 to 3 hours. Dose proportionality with respect to ganciclovir AUC following administration of Valcyte tablets was demonstrated only under fed conditions. Systemic exposure to the prodrug, valganciclovir, is transient and low, and the AUC24 and Cmax values are approximately 1% and 3% of those of ganciclovir, respectively.
Food Effects: When Valcyte tablets were administered with a high fat meal containing approximately 600 total calories (31.1 g fat, 51.6 g carbohydrates and 22.2 g protein) at a dose of 875 mg once daily to 16 HIV-positive subjects, the steady-state ganciclovir AUC increased by 30% (95% CI 12% to 51%), and the Cmax increased by 14% (95% CI -5% to 36%), without any prolongation in time to peak plasma concentrations (Tmax). Valcyte should be administered with food [see Dosage and Administration].
Distribution: Due to the rapid conversion of valganciclovir to ganciclovir, plasma protein binding of valganciclovir was not determined. Plasma protein binding of ganciclovir is 1% to 2% over concentrations of 0.5 and 51 µg/mL. When ganciclovir was administered intravenously, the steady-state volume of distribution of ganciclovir was 0.703 ± 0.134 L/kg (n=69).
After administration of Valcyte tablets, no correlation was observed between ganciclovir AUC and reciprocal weight; oral dosing of Valcyte tablets according to weight is not required.
Metabolism: Valganciclovir is rapidly hydrolyzed to ganciclovir; no other metabolites have been detected. No metabolite of orally administered radiolabeled ganciclovir (1000 mg single dose) accounted for more than 1% to 2% of the radioactivity recovered in the feces or urine.
Elimination: The major route of elimination of valganciclovir is by renal excretion as ganciclovir through glomerular filtration and active tubular secretion. Systemic clearance of intravenously administered ganciclovir was 3.07 ± 0.64 mL/min/kg (n=68) while renal clearance was 2.99 ± 0.67 mL/min/kg (n=16).
The terminal half-life (t½) of ganciclovir following oral administration of Valcyte tablets to either healthy or HIV-positive/CMV-positive subjects was 4.08 ± 0.76 hours (n=73), and that following administration of intravenous ganciclovir was 3.81 ± 0.71 hours (n=69). In heart, kidney, kidney-pancreas, and liver transplant patients, the terminal elimination half-life of ganciclovir following oral administration of Valcyte was 6.48 ± 1.38 hours, and following oral administration of ganciclovir capsules was 8.56 ± 3.62 hours.
Specific Populations:
Renal Impairment
: The pharmacokinetics of ganciclovir from a single oral dose of 900 mg Valcyte tablets were evaluated in 24 otherwise healthy individuals with renal impairment.
Table 11 Pharmacokinetics of Ganciclovir From a Single Oral Dose of 900 mg Valcyte Tablets
Estimated Creatinine Clearance
(mL/min) |
N |
Apparent Clearance
(mL/min)
Mean ± SD |
AUClast
(µg∙h/mL)
Mean ± SD |
Half-life
(hours)
Mean ± SD |
| 51-70 |
6 |
249 ± 99 |
49.5 ± 22.4 |
4.85 ± 1.4 |
| 21-50 |
6 |
136 ± 64 |
91.9 ± 43.9 |
10.2 ± 4.4 |
| 11-20 |
6 |
45 ± 11 |
223 ± 46 |
21.8 ± 5.2 |
| ≤10 |
6 |
12.8 ± 8 |
366 ± 66 |
67.5 ± 34 |
Decreased renal function results in decreased clearance of ganciclovir from valganciclovir, and a corresponding increase in terminal half-life. Therefore, dosage adjustment is required for patients with impaired renal function.
Hemodialysis reduces plasma concentrations of ganciclovir by about 50% following Valcyte administration. Adult patients receiving hemodialysis (CrCl <10 mL/min) cannot use Valcyte tablets because the daily dose of Valcyte tablets required for these patients is less than 450 mg [see Dosage and Administration and Use in Specific Populations].
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. In this study, patients received oral doses of valganciclovir (either Valcyte for oral solution or tablets) to produce exposure equivalent to an adult 900 mg dose [see Dosage and Administration, Adverse Reactions, Use in Specific Populations, Clinical Studies].
The pharmacokinetics of ganciclovir were similar across organ types and age ranges. Population pharmacokinetic modeling suggested that bioavailability was approximately 60%. Clearance was positively influenced by both body surface area and renal function. The mean total clearance was 5.3 L/hr (88.3 mL/min) for a patient with creatinine clearance of 70.4 mL/min. The mean Cmax and AUC by age and organ type are listed in
Table 12.
Table 12 Mean (SD) Pharmacokinetics of Ganciclovir by Age in Pediatric Solid Organ Transplant Patients
|
PK Parameter |
Age Group in Years |
|
|
|
≤ 2 (n=2)
|
> 2 to < 12 (n=10)There was one subject in this age group who received both a kidney and liver transplant. The pharmacokinetic profile for this subject has not been included in this table as it is not possible to determine whether the effects observed are from the kidney/liver transplant or neither.
,
The pharmacokinetic profiles for two subjects in this age group who received kidney transplants have not been included in this table as the data were determined to be non-evaluable.
|
≥ 12 (n=19)
|
|
Kidney
|
AUC0-24h (µg∙h/mL) |
67.6 |
55.9 (12.1) |
47.8 (12.4) |
|
(N=31)
|
Cmax (µg/mL) |
10.4 (0.4) |
8.7 (2.1) |
7.7 (2.1) |
|
| t1/2 (h) |
4.5 (1.5) |
4.8 (1.0) |
6.0 (1.3) |
|
|
|
≤ 2 (n=9)
|
> 2 to < 12 (n=6)
|
≥ 12 (n=2)
|
|
Liver
|
AUC0-24h (µg∙h/mL) |
69.9 (37.0) |
59.4 (8.1) |
35.4 (2.8) |
|
(N=17)
|
Cmax (µg/mL) |
11.9 (3.7) |
9.5 (2.3) |
5.5 (1.1) |
|
| t1/2 (h) |
2.8 (1.5) |
3.8 (0.7) |
4.4 (0.2) |
|
|
|
≤ 2 (n=6)
|
> 2 to < 12 (n=2)
|
≥ 12 (n=4)
|
|
Heart
|
AUC0-24h (µg∙h/mL) |
55.4 (22.8) |
59.6 (21.0) |
60.6 (25.0) |
|
(N=12)
|
Cmax (µg/mL) |
8.2 (2.5) |
12.5 (1.2) |
9.5 (3.3) |
|
| t1/2 (h) |
3.8 (1.7) |
2.8 (0.9) |
4.9 (0.8) |
Pharmacokinetics in Geriatric Patients: The pharmacokinetic characteristics of Valcyte in elderly patients have not been established. Because elderly individuals frequently have a reduced glomerular filtration rate, renal function should be assessed before and during administration of Valcyte [see Dosage and Administration, Use in Specific Populations].
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 Valcyte [see Drug Interactions (7) ].
Drug-drug interaction studies were conducted in patients with normal renal function. Patients with impaired renal function may have increased concentrations of ganciclovir and the coadministered drug following concomitant administration of Valcyte and drugs excreted by the same pathway as ganciclovir. Therefore, these patients should be closely monitored for toxicity of ganciclovir and the coadministered drug.
Table 13
and
Table 14
provide a listing of established drug interaction studies with ganciclovir.
Table 13
provides the effects of coadministered drug on ganciclovir plasma pharmacokinetic parameters, whereas
Table 14
provides the effects of ganciclovir on plasma pharmacokinetic parameters of coadministered drug.
Table 13 Results of Drug Interaction Studies With Ganciclovir: Effects of Coadministered Drug on Ganciclovir Pharmacokinetic Parameters
| Coadministered Drug |
Ganciclovir Dosage |
N |
Ganciclovir Pharmacokinetic (PK) Parameter |
| Zidovudine 100 mg every 4 hours |
1000 mg every 8 hours |
12 |
AUC ↓ 17 ± 25%
(range: -52% to 23%) |
| Probenecid 500 mg every 6 hours |
1000 mg every 8 hours |
10 |
AUC ↑ 53 ± 91%
(range: -14% to 299%)
Ganciclovir renal clearance ↓ 22 ± 20%
(range: -54% to -4%) |
| Mycophenolate Mofetil (MMF) 1.5 g single dose |
IV ganciclovir 5 mg/kg single dose |
12 |
No effect on ganciclovir PK parameters observed (patients with normal renal function) |
| Didanosine 200 mg every 12 hours administered 2 hours before ganciclovir |
1000 mg every 8 hours |
12 |
AUC ↓ 21 ± 17%
(range: -44% to 5%)
|
| Didanosine 200 mg every 12 hours simultaneously administered with ganciclovir |
1000 mg every 8 hours |
12 |
No effect on ganciclovir PK parameters observed |
| IV ganciclovir 5 mg/kg twice daily |
11 |
No effect on ganciclovir PK parameters observed |
| IV ganciclovir 5 mg/kg once daily |
11 |
No effect on ganciclovir PK parameters observed |
| Trimethoprim 200 mg once daily |
1000 mg every 8 hours |
12 |
Ganciclovir renal clearance ↓ 16.3%
Half-life ↑15% |
Table 14 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 |
| Zidovudine 100 mg every 4 hours |
1000 mg every 8 hours |
12 |
AUC0-4 ↑ 19 ± 27%
(range: -11% to 74%) |
| Mycophenolate Mofetil (MMF) 1.5 g single dose |
IV ganciclovir 5 mg/kg single dose |
12 |
No PK interaction observed (patients with normal renal function) |
| Didanosine 200 mg every 12 hours when administered 2 hours prior to or concurrent with ganciclovir |
1000 mg every 8 hours |
12 |
AUC0-12 ↑111 ± 114%
(range: 10% to 493%) |
| Didanosine 200 mg every 12 hours |
IV ganciclovir 5 mg/kg twice daily |
11 |
AUC0-12 ↑70 ± 40%
(range: 3% to 121%) |
|
|
|
| Cmax↑49 ± 48%
(range: -28% to 125%) |
| Didanosine 200 mg every 12 hours |
IV ganciclovir 5 mg/kg once daily |
11 |
AUC0-12 ↑50 ± 26%
(range: 22% to 110%) |
|
|
|
| Cmax ↑36 ± 36%
(range: -27% to 94%) |
| Trimethoprim 200 mg once daily |
1000 mg every 8 hours |
12 |
Increase (12%) in Cmin
|
Microbiology
Mechanism of Action: Valganciclovir is an L-valyl ester (prodrug) of ganciclovir that exists as a mixture of two diastereomers. After oral administration, both diastereomers are rapidly converted to ganciclovir by intestinal and hepatic esterases. 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 (half-life 18 hours). 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, synthesis 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 reported EC50 values of ganciclovir that inhibit human CMV replication in cell culture (laboratory and clinical isolates) have ranged from 0.08 to 22.94 µM (0.02 to 5.75 µg/mL). The distribution and range in susceptibility observed in one assay evaluating 130 clinical isolates was 0 to 1 µM (35%), 1.1 to 2 µM (20%), 2.1 to 3 µM (27%), 3.1 to 4 µM (13%), 4.1 to 5 µM (5%), > 5 µM (<1%). Ganciclovir inhibits mammalian cell proliferation (CIC50) in cell culture at higher concentrations ranging from 40 to > 1,000 µM (10.21 to > 250 µg/mL). Bone marrow-derived colony-forming cells are more sensitive [CIC50 value = 2.7 to 12 µM (0.69 to 3.06 µg/mL)].
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 (M460I/V, L595S, G598D, and K599T) and the viral DNA polymerase pUL54 (D301N, N410K, F412V, P488R, L516R, C539R, L545S, F595I, V812L, P829S, L862F, D879G, and V946L).
In vivo: Viruses resistant to ganciclovir can arise after prolonged treatment or prophylaxis with valganciclovir 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 15
Table 15: Summary of Resistance-associated Amino Acid Substitutions Observed in the CMV of Patients Failing Ganciclovir Treatment or Prophylaxis
| Note: Many additional pathways to ganciclovir resistance likely exist |
| pUL97 |
L405P, A440V, M460I/V, V466G/M, H520Q, del 590-593, A591D/V, C592G, A594E/G/T/V/P, L595F/S/T/W, del 595, del 595-603, E596D/G, K599E/M, del 600-601, del 597-600, del 601-603, C603W/R/S/Y, C607F/S/Y |
| pUL54
|
E315D, N408D/K/S, F412C/L/S, D413A/E, L501F/I, T503I, K513E/N/R, I521T, P522A/L/S, L545S/W, Q578H/L, D588E/N, G629S, S695T, I726T/V, E756K, V781I, V787L, L802M, A809V, T813S, T821I, A834P, G841A/S, D879G, A972V, del 981-982, A987G |
The presence of known ganciclovir resistance-associated amino acid substitutions 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 Clinical Studies]. 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.
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. Whereas, amino acid substitutions conferring cross-resistance to foscarnet are diverse, but concentrate at and between regions II (codon 696-742) and III (codon 805-845). The amino acid substitutions that resulted in reduced susceptibility to ganciclovir and either cidofovir and/or foscarnet are summarized in
Table 16.
Table 16 Summary of pUL54 Amino Acid Substitutions with Cross-Resistance between Ganciclovir, Cidofovir, and/or Foscarnet
|
Cross-resistant to cidofovir
|
D301N, N408D/K, N410K, F412C/L/S/V, D413E, L501I, T503I, K513E/N, L516R, I521T, P522S/A, L545S/W, Q578H, D588N, I726T/V, E756K, V812L, T813S, A834P, G841A, del 981-982, A987G |
|
Cross-resistant to foscarnet
|
F412C, Q578H/L, D588N, E756K, V781I, V787L, L802M, A809V, V812L, T813S, T821I, A834P, G841A, del 981-982 |
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term carcinogenicity studies have not been conducted with Valcyte. However, upon oral administration, valganciclovir is rapidly and extensively converted to ganciclovir. Therefore, like ganciclovir, valganciclovir is a potential carcinogen.
Ganciclovir was carcinogenic in the mouse at oral doses that produced exposures approximately 0.1x and 1.4x, respectively, the mean drug exposure in humans following the recommended intravenous dose of 5 mg/kg, based on area under the plasma concentration curve (AUC) comparisons. At the higher dose there was a significant increase in the incidence of tumors of the preputial gland in males, forestomach (nonglandular mucosa) in males and females, and reproductive tissues (ovaries, uterus, mammary gland, clitoral gland and vagina) and liver in females. At the lower dose, a slightly increased incidence of tumors was noted in the preputial and harderian glands in males, forestomach in males and females, and liver in females. Ganciclovir should be considered a potential carcinogen in humans.
Valganciclovir increases mutations in mouse lymphoma cells. In the mouse micronucleus assay, valganciclovir was clastogenic. Valganciclovir was not mutagenic in the Ames Salmonella assay. Ganciclovir increased mutations in mouse lymphoma cells and DNA damage in human lymphocytes in vitro. In the mouse micronucleus assay, ganciclovir was clastogenic. Ganciclovir was not mutagenic in the Ames Salmonella assay.
Valganciclovir is converted to ganciclovir and therefore is expected to have similar reproductive toxicity effects as ganciclovir [see Warnings and Precautions]. Ganciclovir caused decreased mating behavior, decreased fertility, and an increased incidence of embryolethality in female mice following intravenous doses that produced an exposure approximately 1.7x the mean drug exposure in humans following the dose of 5 mg/kg, based on AUC comparisons. Ganciclovir caused decreased fertility in male mice and hypospermatogenesis in mice and dogs following daily oral or intravenous administration. Systemic drug exposure (AUC) at the lowest dose showing toxicity in each species ranged from 0.03 to 0.1x the AUC of the recommended human intravenous dose. Valganciclovir caused similar effects on spermatogenesis in mice, rats, and dogs. It is considered likely that ganciclovir (and valganciclovir) could cause inhibition of human spermatogenesis.
Reproductive and Developmental Toxicology
Valganciclovir is converted to ganciclovir and therefore is expected to have reproductive toxicity effects similar to ganciclovir. Ganciclovir has been shown to be embryotoxic in rabbits and mice following intravenous administration, and teratogenic in rabbits. Fetal resorptions were present in at least 85% of rabbits and mice administered doses that produced 2x the human exposure based on AUC comparisons (all dose comparisons presented are based on the human AUC following administration of a single 5 mg/kg infusion of intravenous ganciclovir). Effects observed in rabbits included: fetal growth retardation, embryolethality, teratogenicity and/or maternal toxicity. Teratogenic changes included cleft palate, anophthalmia/microphthalmia, aplastic organs (kidney and pancreas), hydrocephaly and brachygnathia. In mice, effects observed were maternal/fetal toxicity and embryolethality.
Daily intravenous doses administered to female mice prior to mating, during gestation, and during lactation caused hypoplasia of the testes and seminal vesicles in the month-old male offspring, as well as pathologic changes in the nonglandular region of the stomach [see Warnings and Precautions]. The drug exposure in mice as estimated by the AUC was approximately 1.7x the human AUC.
Data obtained using an ex vivo human placental model show that ganciclovir crosses the placenta and that simple diffusion is the most likely mechanism of transfer. The transfer was not saturable over a concentration range of 1 to 10 mg/mL and occurred by passive diffusion.
|
CLINICAL STUDIES
Adult Patients
Induction Therapy of CMV Retinitis
: In one randomized open-label controlled study, 160 patients with AIDS and newly diagnosed CMV retinitis were randomized to receive treatment with either Valcyte tablets (900 mg twice daily for 21 days, then 900 mg once daily for 7 days) or with intravenous ganciclovir solution (5 mg/kg twice daily for 21 days, then 5 mg/kg once daily for 7 days). Study participants were: male (91%), White (53%), Hispanic (31%), and Black (11%). The median age was 39 years, the median baseline HIV-1 RNA was 4.9 log10, and the median CD4 cell count was 23 cells/mm3. A determination of CMV retinitis progression by the masked review of retinal photographs taken at baseline and Week 4 was the primary outcome measurement of the 3-week induction therapy.
Table 17
provides the outcomes at 4 weeks.
Table 17 Week 4 Masked Review of Retinal Photographs in CMV Retinitis Study
|
Intravenous Ganciclovir |
Valcyte Tablets |
| Determination of CMV retinitis progression at Week 4 |
N=80 |
N=80 |
| Progressor |
7 |
7 |
| Non-progressor |
63 |
64 |
| Death |
2 |
1 |
| Discontinuations due to Adverse Events |
1 |
2 |
| Failed to return |
1 |
1 |
| CMV not confirmed at baseline or no interpretable baseline photos |
6 |
5 |
Maintenance Therapy of CMV Retinitis
: No comparative clinical data are available on the efficacy of Valcyte tablets for the maintenance therapy of CMV retinitis because all patients in the CMV retinitis study received open-label Valcyte tablets after Week 4. However, the AUC for ganciclovir is similar following administration of 900 mg Valcyte tablets once daily and 5 mg/kg intravenous ganciclovir once daily. Although the ganciclovir Cmax is lower following Valcyte tablets administration compared to intravenous ganciclovir, it is higher than the Cmax obtained following oral ganciclovir administration [see
Figure 1
in Clinical Pharmacology]. Therefore, use of Valcyte tablets as maintenance therapy is supported by a plasma concentration-time profile similar to that of two approved products for maintenance therapy of CMV retinitis.
Prevention of CMV Disease in Heart, Kidney, Kidney-Pancreas, or Liver Transplantation
: A double blind, double-dummy active comparator study was conducted in 372 heart, liver, kidney, or kidney-pancreas transplant patients at high risk for CMV disease (D+/R-). Patients were randomized (2 Valcyte: 1 oral ganciclovir) to receive either Valcyte tablets (900 mg once daily) or oral ganciclovir (1000 mg three times a day) starting within 10 days of transplantation until Day 100 post-transplant. The proportion of patients who developed CMV disease, including CMV syndrome and/or tissue-invasive disease during the first 6 months post-transplant was similar between the Valcyte tablets arm (12.1%, N=239) and the oral ganciclovir arm (15.2%, N=125). However, in liver transplant patients, the incidence of tissue-invasive CMV disease was significantly higher in the Valcyte group compared with the ganciclovir group. These results are summarized in
Table 18.
Mortality at six months was 3.7% (9/244) in the Valcyte group and 1.6% (2/126) in the oral ganciclovir group.
Table 18 Percentage of Patients With CMV Disease, Tissue-Invasive CMV Disease or CMV syndrome by Organ Type: Endpoint Committee, 6 Month ITT Population
|
CMV DiseaseNumber of patients with CMV disease = Number of patients with tissue-invasive CMV disease or CMV syndrome
|
Tissue-Invasive CMV Disease |
CMV SyndromeCMV syndrome was defined as evidence of CMV viremia accompanied with fever ≥ 38°C on two or more occasions separated by at least 24 hours within a 7-day period and one or more of the following: malaise, leukopenia, atypical lymphocytosis, thrombocytopenia, and elevation of hepatic transaminases
|
| GCV = oral ganciclovir; VGCV = valganciclovir |
|
Organ
|
VGCV
(N=239) |
GCV
(N=125) |
VGCV
(N=239) |
GCV
(N=125) |
VGCV
(N=239) |
GCV
(N=125) |
Liver
(n=177) |
19%
(22 / 118) |
12%
(7 / 59) |
14%
(16 / 118) |
3%
(2 / 59) |
5%
(6 / 118) |
9%
(5 / 59) |
Kidney
(n=120) |
6%
(5 / 81) |
23%
(9 / 39) |
1%
(1 / 81) |
5%
(2 / 39) |
5%
(4 / 81) |
18%
(7 / 39) |
Heart
(n=56) |
6%
(2 / 35) |
10%
(2 / 21) |
0%
(0 / 35) |
5%
(1 / 21) |
6%
(2 / 35) |
5%
(1 / 21) |
Kidney / Pancreas
(n=11) |
0%
(0 / 5) |
17%
(1 / 6) |
0%
(0 / 5) |
17%
(1 / 6) |
0%
(0 / 5) |
0%
(0 / 6) |
Prevention of CMV Disease in Kidney Transplantation: A double-blind, placebo-controlled study was conducted in 326 kidney transplant patients at high risk for CMV disease (D+/R-) to assess the efficacy and safety of extending Valcyte CMV prophylaxis from 100 to 200 days post-transplant. Patients were randomized (1:1) to receive Valcyte tablets (900 mg once daily) within 10 days of transplantation either until Day 200 post-transplant or until Day 100 post-transplant followed by 100 days of placebo. Extending CMV prophylaxis with Valcyte until Day 200 post-transplant demonstrated superiority in preventing CMV disease within the first 12 months post-transplant in high risk kidney transplant patients compared to the 100 day dosing regimen (primary endpoint). These results are summarized in
Table 19.
Table 19 Percentage of Kidney Transplant Patients With CMV Disease, Tissue-Invasive CMV Disease or CMV Syndrome, 12 Month ITT Population
|
CMV DiseaseNumber of patients with CMV disease = Number of patients with tissue-invasive CMV disease or CMV syndrome
|
Tissue-Invasive CMV Disease |
CMV SyndromeCMV syndrome was defined as evidence of CMV viremia accompanied with at least one of the following: fever (≥ 38°C), severe malaise, leukopenia, atypical lymphocytosis, thrombocytopenia, and elevation of hepatic transaminases
|
| VGCV = valganciclovir. |
|
| 100 Days
VGCV
(N=163) |
200 Days
VGCV
(N=155) |
100 Days
VGCV
(N=163) |
200 Days
VGCV
(N=155) |
100 Days
VGCV
(N=163) |
200 Days
VGCV
(N=155) |
| Cases |
36.8%
(60/163) |
16.8%
(26/155) |
1.8%
(3/163)Two patients in the 100 day group had both tissue-invasive CMV disease and CMV syndrome; however, these patients are counted as having only tissue-invasive CMV disease.
|
0.6%
(1/155) |
35. 0%
(57/163) |
16.1%
(25/155) |
The percentage of kidney transplant patients with CMV disease at 24 months post-transplant was 38.7% (63/163) for the 100 day dosing regimen and 21.3% (33/155) for the 200 day dosing regimen.
Pediatric Patients
Prevention of CMV in Pediatric Solid Organ Transplant Recipients: Sixty-three children, 4 months to 16 years of age, who had a solid organ transplant (kidney 33, liver 17, heart 12, and kidney/liver 1) and were at risk for developing CMV disease, were enrolled in an open-label, safety, and pharmacokinetic study of oral Valcyte (Valcyte for oral solution or tablets). Patients received Valcyte once daily as soon as possible after transplant until a maximum of 100 days post-transplant. The daily doses of Valcyte were calculated at each study visit based on body surface area and a modified creatinine clearance [see Dosage and Administration].
The pharmacokinetics of ganciclovir were similar across organ transplant types and age ranges. The mean daily ganciclovir exposures in pediatric patients were comparable to those observed in adult solid organ transplant patients receiving Valcyte 900 mg once daily [see Clinical Pharmacology]. No case of CMV disease was reported during the study. CMV viremia was reported in 7 (11%) patients during the study; however, none of these events fulfilled the definition of CMV syndrome. Based on the pharmacokinetic, safety, and efficacy data from this study and extrapolated efficacy data from the adult study, oral Valcyte is indicated for the prevention of CMV disease in kidney and heart transplant children 4 months to 16 years of age at risk for developing CMV disease. Valcyte is not approved in adults for CMV prophylaxis in liver transplant patients; therefore, Valcyte is not recommended for CMV prophylaxis in pediatric liver transplant patients because efficacy cannot be extrapolated from adults.
|
