CIDOFOVIR DIHYDRATE
CIDOFOVIR DIHYDRATE- cidofovir injection, solution
Heritage Pharmaceuticals Inc. d/b/a Avet Pharmaceuticals Inc.
WARNING
RENAL IMPAIRMENT IS THE MAJOR TOXICITY OF CIDOFOVIR INJECTION. CASES OF ACUTE RENAL FAILURE RESULTING IN DIALYSIS AND/OR CONTRIBUTING TO DEATH HAVE OCCURRED WITH AS FEW AS ONE OR TWO DOSES OF CIDOFOVIR INJECTION. TO REDUCE POSSIBLE NEPHROTOXICITY, INTRAVENOUS PREHYDRATION WITH NORMAL SALINE AND ADMINISTRATION OF PROBENECID MUST BE USED WITH EACH CIDOFOVIR INFUSION. RENAL FUNCTION (SERUM CREATININE AND URINE PROTEIN) MUST BE MONITORED WITHIN 48 HOURS PRIOR TO EACH DOSE OF CIDOFOVIR INJECTION AND THE DOSE OF CIDOFOVIR INJECTION MODIFIED FOR CHANGES IN RENAL FUNCTION AS APPROPRIATE (SEE DOSAGE AND ADMINISTRATION). CIDOFOVIR INJECTION IS CONTRAINDICATED IN PATIENTS WHO ARE RECEIVING OTHER NEPHROTOXIC AGENTS.
NEUTROPENIA HAS BEEN OBSERVED IN ASSOCIATION WITH CIDOFOVIR INJECTION TREATMENT. THEREFORE, NEUTROPHIL COUNTS SHOULD BE MONITORED DURING CIDOFOVIR INJECTION THERAPY.
CIDOFOVIR INJECTION IS INDICATED ONLY FOR THE TREATMENT OF CMV RETINITIS IN PATIENTS WITH ACQUIRED IMMUNODEFICIENCY SYNDROME.
IN ANIMAL STUDIES CIDOFOVIR WAS CARCINOGENIC, TERATOGENIC AND CAUSED HYPOSPERMIA (SEE CARCINOGENESIS, MUTAGENESIS, & IMPAIRMENT OF FERTILITY).
DESCRIPTION
The chemical name of cidofovir USP is 1-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]cytosine dihydrate (HPMPC), with the molecular formula of C8 H14 N3 O6 P•2 H2 O and a molecular weight of 315.22 (279.19 for anhydrous). The chemical structure is:
Cidofovir USP is a white crystalline powder with an aqueous solubility of ≥ 170 mg/mL at pH 6 to 8 and a log P (octanol/aqueous buffer, pH 7.1) value of -3.3.
Cidofovir Injection, USP is a sterile, hypertonic aqueous solution for intravenous infusion only. The solution is clear and colorless. It is supplied in clear glass vials, each containing 375 mg of anhydrous cidofovir USP in 5 mL aqueous solution at a concentration of 75 mg/mL.
The formulation is pH-adjusted to 7.4 (range 7.1 to 7.7) with sodium hydroxide and/or hydrochloric acid and contains no preservatives. The appropriate volume of Cidofovir Injection must be removed from the single-dose vial and diluted prior to administration (see DOSAGE AND ADMINISTRATION).
MICROBIOLOGY
Mechanism of Action
Cidofovir suppresses cytomegalovirus (CMV) replication by selective inhibition of viral DNA synthesis. Biochemical data support selective inhibition of CMV DNA polymerase by cidofovir diphosphate, the active intracellular metabolite of cidofovir. Cidofovir diphosphate inhibits herpesvirus polymerases at concentrations that are 8- to 600-fold lower than those needed to inhibit human cellular DNA polymerases alpha, beta, and gamma1, 2, 3. Incorporation of cidofovir into the growing viral DNA chain results in reductions in the rate of viral DNA synthesis.
In Vitro Susceptibility
Cidofovir is active in vitro against a variety of laboratory and clinical isolates of CMV and other herpesviruses (Table 1). Controlled clinical studies of efficacy have been limited to patients with AIDS and CMV retinitis.
Table 1. Cidofovir Inhibition of Virus Multiplication in Cell Culture
| Virus | IC50 (μM) |
| Wild-type CMV Isolates | 0.5 to 2.8 |
| HSV-1, HSV-2 | 12.7 to 31.7 |
CMV isolates with reduced susceptibility to cidofovir have been selected in vitro in the presence of high concentrations of cidofovir4. IC50 values for selected resistant isolates ranged from 7 to 15 μM.
There are insufficient data at this time to assess the frequency or the clinical significance of the development of resistant isolates following cidofovir injection administration to patients.
The possibility of viral resistance should be considered for patients who show a poor clinical response or experience recurrent retinitis progression during therapy.
Cross Resistance
Cidofovir-resistant isolates selected in vitro following exposure to increasing concentrations of cidofovir were assessed for susceptibility to ganciclovir and foscarnet4. All were cross resistant to ganciclovir, but remained susceptible to foscarnet. Ganciclovir or ganciclovir/foscarnet-resistant isolates that are cross resistant to cidofovir have been obtained from drug naive patients and from patients following ganciclovir or ganciclovir/ foscarnet therapy. To date, the majority of ganciclovir-resistant isolates are UL97 gene product (phosphokinase) mutants and remain susceptible to cidofovir5.
Reduced susceptibility to cidofovir, however, has been reported for DNA polymerase mutants of CMV which are resistant to ganciclovir6–9. To date, all clinical isolates which exhibit high level resistance to ganciclovir, due to mutations in both the DNA polymerase and UL97 genes, have been shown to be cross resistant to cidofovir. Cidofovir is active against some, but not all, CMV isolates which are resistant to foscarnet10–12. The incidence of foscarnet-resistant isolates that are resistant to cidofovir is not known.
A few triple-drug resistant isolates have been described. Genotypic analysis of two of these triple-resistant isolates revealed several point mutations in the CMV DNA polymerase gene. The clinical significance of the development of these cross-resistant isolates is not known.
CLINICAL PHARMACOLOGY
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.
| 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 m2) | 179 ± 23.1 (n = 12) | 148 ± 38.8 (n = 18) | ||
| Renal Clearance (mL/min/1.73 m2) | 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 pharmacokinetics of zidovudine.
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 cidofovir injection 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.
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