Valcyte (Valganciclovir Hydrochloride) - Description and Clinical Pharmacology

DESCRIPTION

Valcyte (valganciclovir HCl tablets) contains valganciclovir hydrochloride (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 cytomegalovirus (CMV).

Valcyte is available as a 450 mg tablet for oral administration. Each tablet contains 496.3 mg of valganciclovir HCl (corresponding to 450 mg of valganciclovir), and the inactive ingredients microcrystalline cellulose, povidone K-30, crospovidone and stearic acid. The film-coat applied to the tablets contains Opadry Pink^®.

Valganciclovir HCl is a white to off-white crystalline powder with a molecular formula of C₁₄H₂₂N₆O₅•HCl and a molecular weight of 390.83. The chemical name for valganciclovir HCl is L-Valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3-hydroxypropyl ester, monohydrochloride. Valganciclovir HCl 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 is 7.6.

The chemical structure of valganciclovir HCl is:

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

VIROLOGY

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 cytomegalovirus in vitro 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 viral DNA synthesis by ganciclovir triphosphate.

Antiviral Activity

The quantitative relationship between the in vitro susceptibility of human herpesviruses 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% (IC₅₀), vary greatly depending upon a number of factors. Thus the IC₅₀ of ganciclovir that inhibits human CMV replication in vitro (laboratory and clinical isolates) has ranged from 0.02 to 5.75 µg/mL (0.08 to 22.94 µM). Ganciclovir inhibits mammalian cell proliferation (IC₅₀) in vitro at higher concentrations ranging from 10.21 to >250 µg/mL (40 to >1000 µM). Bone marrow-derived colony-forming cells are more sensitive (IC₅₀ = 0.69 to 3.06 µg/mL: 2.7 to 12 µM).

Viral Resistance

Viruses resistant to ganciclovir can arise after prolonged treatment with valganciclovir by selection of mutations in either the viral protein kinase gene (UL97) responsible for ganciclovir monophosphorylation and/or in the viral DNA polymerase gene (UL54). Virus with mutations in the UL97 gene is resistant to ganciclovir alone, whereas virus with mutations in the UL54 gene may show cross-resistance to other antivirals that target the same sites on viral DNA polymerase.

The current working definition of CMV resistance to ganciclovir in in vitro assays is IC₅₀≥ 1.5 µg/mL (≥ 6.0 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 ganciclovir. The possibility of viral resistance should be considered in patients who show poor clinical response or experience persistent viral excretion during therapy.

CLINICAL PHARMACOLOGY

Pharmacokinetics

BECAUSE THE MAJOR ELIMINATION PATHWAY FOR GANCICLOVIR IS RENAL, DOSAGE REDUCTIONS ACCORDING TO CREATININE CLEARANCE ARE REQUIRED FOR VALCYTE TABLETS. FOR DOSING INSTRUCTIONS IN PATIENTS WITH RENAL IMPAIRMENT, REFER TO DOSAGE AND ADMINISTRATION.

The pharmacokinetic properties of valganciclovir have been evaluated in HIV- and CMV-seropositive patients, patients with AIDS and CMV retinitis and in solid organ transplant patients.

The ganciclovir pharmacokinetic measures following administration of 900 mg Valcyte and 5 mg/kg intravenous ganciclovir and 1000 mg three times daily oral ganciclovir in HIV-positive/CMV-positive patients are summarized in Table 1.

Table 1 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	Cytovene®-IV	Ganciclovir Capsules
Dosage	900 mg once daily with food	5 mg/kg once daily	1000 mg three times daily with food
AUC0-24 hr (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) for ganciclovir administered as Valcyte tablets is comparable to the ganciclovir AUC for intravenous ganciclovir. Ganciclovir C_max following Valcyte administration is 40% lower than following intravenous ganciclovir administration. During maintenance dosing, ganciclovir AUC_{0-24 hr} and C_max following oral ganciclovir administration (1000 mg three times daily) are lower relative to Valcyte and intravenous ganciclovir. The ganciclovir C_min following intravenous ganciclovir and Valcyte administration are less than the ganciclovir C_min following oral ganciclovir administration. The clinical significance of the differences in ganciclovir pharmacokinetics for these three ganciclovir delivery systems is unknown.

Figure 1 Ganciclovir Plasma Concentration Time Profiles in HIV-positive/CMV-positive Patients*

*Plasma concentration-time profiles for ganciclovir (GCV) from Valcyte (VGCV) and intravenous ganciclovir were obtained from a multiple dose study (WV15376 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 (GAN2230 n=24) in HIV-positive/CMV-positive patients without CMV retinitis.

In solid organ transplant recipients, the mean systemic exposure to ganciclovir was 1.7 × 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 2).

Table 2 Mean Ganciclovir Pharmacokinetic Measures by Organ Type (Study PV16000)

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
AUC0-24 hr (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
AUC0-24 hr (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
AUC0-24 hr (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

In a pharmacokinetic study in liver transplant patients, the ganciclovir AUC_{0-24 hr} achieved with 900 mg valganciclovir was 41.7 ± 9.9 µg∙h/mL (n=28) and the AUC_{0-24 hr} 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 T_max 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 C_max 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 C_max increased by 14% (95% CI -5% to 36%), without any prolongation in time to peak plasma concentrations (T_max). Valcyte tablets 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 (t_½) 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.

Special 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 3 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 (see PRECAUTIONS: General).

Hemodialysis

Hemodialysis reduces plasma concentrations of ganciclovir by about 50% following Valcyte administration. 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 PRECAUTIONS: General and DOSAGE AND ADMINISTRATION: Hemodialysis Patients).

Patients With Hepatic Impairment

The safety and efficacy of Valcyte tablets have not been studied in patients with hepatic impairment. 

Race/Ethnicity and Gender

Insufficient data are available to demonstrate any effect of race or gender on the pharmacokinetics of valganciclovir.

Pediatrics

Valcyte tablets have not been studied in pediatric patients; the pharmacokinetic characteristics of Valcyte tablets in these patients have not been established (see PRECAUTIONS: Pediatric Use).

Geriatrics

No studies of Valcyte tablets have been conducted in adults older than 65 years of age (see PRECAUTIONS: Geriatric Use).

CLINICAL TRIALS

Induction Therapy of CMV Retinitis

Study WV15376

In a 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 4 provides the outcomes at 4 weeks.

Table 4 Week 4 Masked Review of Retinal Photographs in Study WV15376

	Cytovene-IV	Valcyte
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 for the maintenance therapy of CMV retinitis because all patients in study WV15376 received open-label Valcyte 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 C_max is lower following Valcyte administration compared to intravenous ganciclovir, it is higher than the C_max obtained following oral ganciclovir administration (see Figure 1 in CLINICAL PHARMACOLOGY). Therefore, use of Valcyte 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, and Liver Transplantation

A double-blind, double-dummy active comparator study was conducted in 372 heart, liver, kidney, and kidney-pancreas transplant patients at high-risk for CMV disease (D+/R-). Patients were randomized (2 Valcyte: 1 oral ganciclovir) to receive either Valcyte (900 mg once daily) or oral ganciclovir (1000 mg three times a day) starting within 10 days of transplantation until Day 100 posttransplant. The proportion of patients who developed CMV disease, including CMV syndrome and/or tissue-invasive disease during the first 6 months posttransplant was similar between the Valcyte 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 5.

Mortality at six months was 3.7% (9/244) in the Valcyte group and 1.6% (2/126) in the oral ganciclovir group. 

Table 5 Percentage of Patients With CMV Disease and Tissue-Invasive CMV Disease by Organ Type: Endpoint Committee, 6 Month ITT Population

	CMV DiseaseNumber of Patients with CMV Disease = Number of Patients with Tissue-Invasive CMV Disease + Number of Patients with CMV Syndrome.		Tissue-Invasive CMV Disease		CMV Syndrome
GCV = oral ganciclovir; VGCV = Valcyte
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)