Avet Lifesciences

CIDOFOVIR

cidofovir dihydrate

Post-LOE

INTRAVENOUS · SOLUTION

CLINICAL PHARMACOLOGY PHARMACOKINETICS Cidofovir injection 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 (n = 5), 3 (n = 10), 5 (n = 2) and 10 (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 cidofovir injection 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 (n = 12), 5 (n = 6), and 7.5 (n = 4) mg/kg (See Table 2). Approximately 70 to 85% of the cidofovir injection dose administered with concomitant probenecid was excreted as unchanged drug within 24 hr. When cidofovir injection 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. Table 2. Cidofovir Pharmacokinetic Parameters Following 3 and 5 mg/kg Infusions, Without and With Probenecid* *See PARAMETERS CIDOFOVIR INJECTION ADMINISTERED WITHOUT PROBENECID CIDOFOVIR INJECTION ADMINISTERED WITH PROBENECID 3 mg/kg (n = 10) 5 mg/kg (n = 2) 3 mg/kg (n = 12) 5 mg/kg (n = 6) AUC (mcg·hr/mL) 20 ± 2.3 28.3 25.7 ± 8.5 40.8 ± 9 Cmax (end of infusion) (mcg/mL) 7.3 ± 1.4 11.5 9.8 ± 3.7 19.6 ± 7.2 Vdss (mL/kg) 537 ± 126 (n = 12) 410 ± 102 (n = 18) Clearance (mL/min/1.73 m) 179 ± 23.1 (n = 12) 148 ± 38.8 (n = 18) Renal Clearance (mL/min/1.73 m) 150 ± 26.9 (n = 12) 98.6 ± 27.9 (n = 11) In vitro , cidofovir was less than 6% bound to plasma or serum proteins over the cidofovir concentration range 0.25 to 25 mcg/mL. CSF concentrations of cidofovir following intravenous infusion of cidofovir injection 5 mg/kg with concomitant probenecid and intravenous hydration were undetectable (< 0.1 mcg/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 mcg/mL. DRUG-DRUG INTERACTIONS Zidovudine The pharmacokinetics of zidovudine were evaluated in 10 patients receiving zidovudine alone or with intravenous cidofovir (without probenecid). There was no evidence of an effect of cidofovir on the pharma

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