Cidofovir clinical pharmacology

Cidofovir
VISTIDE® FDA Package Insert
Description
Clinical Pharmacology
Microbiology
Indications and Usage
Contraindications
Warnings and Precautions
Adverse Reactions
Drug Interactions
Overdosage
Clinical Studies
Dosage and Administration
How Supplied
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Clinical Pharmacology

PHARMACOKINETICS

VISTIDE must be administered with probenecid. The pharmacokinetics of cidofovir, administered both without and with probenecid, are described below. The pharmacokinetics of cidofovir without probenecid were evaluated in 27 HIV-infected patients with or without asymptomatic CMV infection. Dose-independent pharmacokinetics were demonstrated after one hr infusions of 1.0 (n = 5), 3.0 (n = 10), 5.0 (n = 2) and 10.0 (n = 8) mg/kg (See Table 2 for pharmacokinetic parameters). There was no evidence of cidofovir accumulation after 4 weeks of repeated administration of 3 mg/kg/week (n = 5) without probenecid. In patients with normal renal function, approximately 80 to 100% of the VISTIDE dose was recovered unchanged in urine within 24 hr (n = 27). The renal clearance of cidofovir was greater than creatinine clearance, indicating renal tubular secretion contributes to the elimination of cidofovir. The pharmacokinetics of cidofovir administered with probenecid were evaluated in 12 HIV-infected patients with or without asymptomatic CMV infection and 10 patients with relapsing CMV retinitis. Dose-independent pharmacokinetics were observed for cidofovir, administered with probenecid, after one hr infusions of 3.0 (n = 12), 5.0 (n = 6), and 7.5 (n = 4) mg/kg (See Table 2). Approximately 70 to 85% of the VISTIDE dose administered with concomitant probenecid was excreted as unchanged drug within 24 hr. When VISTIDE was administered with probenecid, the renal clearance of cidofovir was reduced to a level consistent with creatinine clearance, suggesting that probenecid blocks active renal tubular secretion of cidofovir.

In vitro, cidofovir was less than 6% bound to plasma or serum proteins over the cidofovir concentration range 0.25 to 25 µg/mL. CSF concentrations of cidofovir following intravenous infusion of VISTIDE 5 mg/kg with concomitant probenecid and intravenous hydration were undetectable (< 0.1 µg/mL, assay detection threshold) at 15 minutes after the end of a 1 hr infusion in one patient whose corresponding serum concentration was 8.7 µg/mL.

SPECIAL POPULATIONS

Renal Insufficiency Pharmacokinetic data collected from subjects with creatinine clearance values as low as 11 mL/min indicate that cidofovir clearance decreases proportionally with creatinine clearance. High-flux hemodialysis has been shown to reduce the serum levels of cidofovir by approximately 75%. Initiation of therapy with VISTIDE is contraindicated in patients with serum creatinine > 1.5 mg/dL, a calculated creatinine clearance ≤ 55 mL/min, or a urine protein ≥ 100 mg/dL (equivalent to ≥2+ proteinuria) (See CONTRAINDICATIONS). Geriatric/Gender/Race The effects of age, gender, and race on cidofovir pharmacokinetics have not been investigated.

References

Adapted from the FDA Package Insert.