Valcyte Pharmacology, Pharmacokinetics, Studies, Metabolism - valganciclovir

Valcyte Pharmacology, Pharmacokinetics, Studies, Metabolism - valganciclovir

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 ganciclovir pharmacokinetic measures following administration of 900 mg valganciclovir and 5 mg/kg intravenous ganciclovir and 1000 mg three times daily oral ganciclovir are summarized in Table 1.

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 valganciclovir 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 valganciclovir and intravenous ganciclovir. The ganciclovir C _min following intravenous ganciclovir and valganciclovir 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.

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 valganciclovir tablets ranged from 1 to 3 hours. Dose proportionality with respect to ganciclovir AUC following administration of valganciclovir tablets was demonstrated only under fed conditions. Systemic exposure to the prodrug, valganciclovir, is transient and low, and the AUC ₂₄ and C _max values are approximately 1% and 3% of those of ganciclovir, respectively.

Food Effects

When valganciclovir 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 12-51%), and the C _max increased by 14% (95% CI -5-36%), 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 valganciclovir tablets, no correlation was observed between ganciclovir AUC and reciprocal weight; oral dosing of valganciclovir 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 _1/2 ) of ganciclovir following oral administration of valganciclovir 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).

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.

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 valganciclovir 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 ).

Liver Transplant Patients

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).

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 log ₁₀ , and the median CD4 cell count was 23 cells/mm ³ . 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 three week induction therapy. Table 3 provides the outcomes at four weeks.

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 valganciclovir once daily and 5 mg/kg intravenous ganciclovir once daily. Although the ganciclovir C _max is lower following valganciclovir administration compared to intravenous ganciclovir, it is higher than the C _max obtained following oral ganciclovir administration (see Figure 1 in

CLINICAL PHARMACOLOGY