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Vistide

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Vistide

Vistide

CLINICAL PHARMACOLOGY

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 cid-ofovir. 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 (M)
Wild-type CMV Isolates 0.5 - 2.8
HSV-1, HSV-2 12.7 - 31.7

Resistance: 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 7-15 M .

There are insufficient data at this time to assess the frequency or the clinical significance of the development of resistant isolates following VISTIDE (cidofovir) 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/fos-carnet-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 poly-merase gene. The clinical significance of the development of these cross-resistant isolates is not known.

Pharmacokinetics

VISTIDE (cidofovir) 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 (cidofovir) 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 (cidofovir) dose administered with concomitant probenecid was excreted as unchanged drug within 24 hr. When VISTIDE (cidofovir) 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 3.0 and 5.0 mg/kg Infusions, Without and With Probenecid*

PARAMETERS VISTIDE ADMINISTERED WITHOUT PROBENECID VISTIDE ADMINISTERED WITH PROBENECID
3 mg/kg
(n = 10)
5 mg/kg
(n = 2)
3 mg/kg
(n = 12)
5 mg/kg
(n = 6)
AUC (g•hr/mL) 20.0 ± 2.3 28.3 25.7 ± 8.5 40.8 ± 9.0
Cmax (end of infusion) (g/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)
* See DOSAGE AND ADMINISTRATION

In vitro, cidofovir was less than 6% bound to plasma or serum proteins over the cido-fovir concentration range 0.25 to 25 g/mL. CSF concentrations of cidofovir following intravenous infusion of VISTIDE (cidofovir) 5 mg/kg with concomitant probenecid and intravenous hydration were undetectable ( < 0.1 g/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 g/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 VISTIDE (cidofovir) 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.

Description Of Clinical Trials

Three phase II/III controlled trials of VISTIDE (cidofovir) have been conducted in HIV-infected patients with CMV retinitis.

Delayed Versus Immediate Therapy (Study 105): In stage 1 of this open-label trial, conducted by the Studies of the Ocular Complications of AIDS (SOCA) Clinical Research Group, 29 previously untreated patients with peripheral CMV retinitis were randomized to either immediate treatment with VISTIDE (cidofovir) (5 mg/kg once a week for 2 weeks, then 3 mg/kg every other week) or to have VISTIDE (cidofovir) delayed until progression of CMV retinitis13. In stage 2 of this trial, an additional 35 previously untreated patients with peripheral CMV retinitis were randomized to either immediate treatment with VISTIDE (cidofovir) (5 mg/kg once a week for 2 weeks, then 5 mg/kg every other week), immediate treatment with VISTIDE (cidofovir) (5 mg/kg once a week for 2 weeks, then 3 mg/kg every other week), or to have VISTIDE (cidofovir) delayed until progression of CMV retinitis. Of the 64 patients in this study, 12 were randomized to 5 mg/kg maintenance therapy, 26 to 3 mg/kg maintenance therapy, and 26 to delayed therapy. Of the 12 patients enrolled in the 5 mg/kg maintenance group, 5 patients progressed, 5 patients discontinued therapy and 2 patients had no progression at study completion. Based on masked readings of retinal photographs, the median [95% confidence interval (CI)] time to retinitis progression was not reached (25, not reached) for the 5 mg/kg maintenance group. Median (95% CI) time to the alternative endpoint of retinitis progression or study drug discontinuation was 44 days (24, 207) for the 5 mg/kg maintenance group. Patients receiving 5 mg/kg maintenance had delayed time to retinitis progression compared to patients receiving 3 mg/kg maintenance or deferred therapy.

Delayed Versus Immediate Therapy (Study 106): In an open-label trial, 48 previously untreated patients with peripheral CMV retinitis were randomized to either immediate treatment with VISTIDE (cidofovir) (5 mg/kg once a week for 2 weeks, then 5 mg/kg every other week), or to have VISTIDE (cidofovir) delayed until progression of CMV retinitis14. Patient baseline characteristics and disposition are shown in Table 3. Of 25 and 23 patients in the immediate and delayed groups respectively, 23 and 21 were evaluable for retinitis progression as determined by retinal photography. Based on masked readings of retinal photographs, the median [95% confidence interval (CI)] times to retinitis progression were 120 days (40, 134) and 22 days (10, 27) for the immediate and delayed therapy groups, respectively. This difference was statistically significant. However, because of the limited number of patients remaining on treatment over time (3 of 25 patients received VISTIDE (cidofovir) for 120 days or longer), the median time to progression for the immediate therapy group was difficult to precisely estimate. Median (95% CI) times to the alternative endpoint of retinitis progression or study drug discontinuation (including adverse events, withdrawn consent, and systemic CMV disease) were 52 days (37, 85) and 22 days (13, 27) for the immediate and delayed therapy groups, respectively. This difference was statistically significant. Time to progression estimates from this study may not be directly comparable to estimates reported for other therapies.

Table 3. Patient Characteristics and Disposition (Study 106)

  Immediate Therapy
(n = 25)
Delayed Therapy
(n = 23)
Baseline Characteristics
  Age (years) 38 38
  Sex (M/F) 24/1 22/1
  Median CD4 Cell Count 6 9
Endpoints
  CMV Retinitis Progression 10 18
  Discontinued Due to Adverse Event 6 0
  Withdrew Consent 3a 1
  Discontinued Due to Intercurrent Illness 2b 1b
  Discontinued Based on Ophthalmological Examination 1c 1c
  No Progression at Study Completion 1 0
  Not Evaluable at Baseline 2 2
aOne patient died 2 weeks after withdrawing consent.
bTwo patients on immediate therapy were diagnosed with CMV disease and discontinued from study. One patient on delayed therapy was diagnosed with CMV gastrointestinal disease.
cCMV retinitis progression not confirmed by retinal photography.

Dose-response study of VISTIDE (cidofovir) (Study 107): In an open-label trial, 100 patients with relapsing CMV retinitis were randomized to receive 5 mg/kg once a week for 2 weeks and then either 5 mg/kg (n = 49) or 3 mg/kg (n = 51) every other week. Enrolled patients had been diagnosed with CMV retinitis an average of 390 days prior to randomization and had received a median of 3.8 prior courses of systemic CMV therapy. Eighty-four of the 100 patients were considered evaluable for progression by serial retinal photographs (43 randomized to 5 mg/kg and 41 randomized to 3 mg/kg). Twenty-six and 21 patients discontinued therapy due to either an adverse event, intercurrent illness, excluded medication, or withdrawn consent in the 5 mg/kg and 3 mg/kg groups, respectively. Thirty-eight of the 100 randomized patients had progressed according to masked assessment of serial retinal photographs (13 randomized to 5 mg/kg and 25 randomized to 3 mg/kg). Using retinal photographs, the median (95% CI) times to retinitis progression for the 5 mg/kg and 3 mg/kg groups were 115 days (70, not reached) and 49 days (35, 52), respectively. This difference was statistically significant. Similar to Study 106, the median time to retinitis progression for the 5 mg/kg group was difficult to precisely estimate due to the limited number of patients remaining on treatment over time (4 of the 49 patients in the 5 mg/kg group were treated for 115 days or longer). Median (95% CI) times to the alternative endpoint of retinitis progression or study drug discontinuation were 49 days (38, 63) and 35 days (27, 39) for the 5 mg/kg and 3 mg/kg groups, respectively. This difference was statistically significant.

REFERENCES

1. Ho HT, Woods KL, Bronson JJ, De Boeck H, Martin JC and Hitchcock MJM. Intracellular Metabolism of the Antiherpesvirus Agent (S)-1-[3-hydroxy-2-(phos-phonylmethoxy)propyl]cytosine. Mol Pharmacol 41:197-202, 1992.

2. Cherrington JM, Allen SJW, McKee BH, and Chen MS. Kinetic Analysis of the Interaction Between the Diphosphate of (S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine, zalcitabineTP, zidovudineTP, and FIAUTP with Human DNA Polymerases b and g. Biochem Pharmacol 48:1986-1988, 1994.

3. Xiong X, Smith JL, Kim C, Huang E, and Chen MS. Kinetic Analysis of the Interaction of Cidofovir Diphosphate with Human Cytomegalovirus DNA Polymerase. Biochem Pharmacol 51:1563-1567, 1996.

4. Cherrington JM, Mulato AS, Fuller MD, Chen MS. In Vitro Selection of a Human Cytomegalovirus (HCMV) that is Resistant to Cidofovir. 35th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC), San Francisco, CA. Abstract H117, 1995.

5. Stanat SC, Reardon JE, Erice A, Jordan MC, Drew WL, and Biron KK. Ganciclovir-Resistant Cytomegalovirus Clinical Isolates: Mode of Resistance to Ganciclovir. Antimicrob Agents Chemother 35:2191-2197, 1991.

6. Sullivan V, Biron KK, Talarico C, Stanat SC, Davis M, Pozzi M, and Coen DM. A Point Mutation in the Human Cytomegalovirus DNA Polymerase Gene Confers Resistance to Ganciclovir and phosphonylmethoxyalkyl Derivatives. Antimicrob Agents Chemother 37:19-25, 1993.

7. Tatarowicz WA, Lurain NS, and Thompson KD. A Ganciclovir-Resistant Clinical Isolate of Human Cytomegalovirus Exhibiting Cross-Resistance to other DNA Polymerase Inhibitors. J Infect Dis 166:904-907, 1992.

8. Lurain NS, Thompson KD, Holmes EW, and Read GS. Point Mutations in the DNA Polymerase Gene of Human Cytomegalovirus that Result in Resistance to Antiviral Agents. J Virol 66:7146-7152, 1992.

9. Smith IL, Cherrington JM, Jiles RE, Fuller MD, Freeman WR, Spector SA. High-level Resistance of Cytomegalovirus to Ganciclovir is Associated with Alterations in both the UL97 and DNA Polymerase Genes. J Infect Dis 176:69-77, 1997.

10. Sullivan V and Coen DM. Isolation of Foscarnet-Resistant Human Cytomegalovirus Patterns of Resistance and Sensitivity to Other Antiviral Drugs. J Infect Dis 164:781-784, 1991.

11. Snoeck R, Andrei G, and De Clercq E. Patterns of Resistance and Sensitivity to Antiviral Compounds of Drug-Resistant Strains of Human Cytomegalovirus Selected in Vitro. Eur J Clin Microbiol Infect Dis 15:574-579, 1996.

12. Baldanti F, Underwood MR, Stanat SC, Biron KK, Chou S, Sarasini A, Silini E, and Gerna G. Single Amino Acid Changes in the DNA Polymerase Confer Foscarnet Resistance and Slow-Growth Phenotype, While Mutations in the UL97-Encoded Phosphotransferase Confer Ganciclovir Resistance in Three Double-Resistant Human Cytomegalovirus Strains Recovered from Patients with AIDS. J Virol 70:1390-1395, 1996.

13. The Studies of Ocular Complications of AIDS Research Group in Collaboration with the AIDS Clinical Trials Group. Cidofovir (HPMPC) for the Treatment of Cytomegalovirus Retinitis in Patients with AIDS: the HPMPC Peripheral Cytomegalovirus Retinitis Trial. Ann Intern Med 126:264-274, 1997.

14. Lalezari JP, Stagg RJ, Kupperman BD, et al. Intravenous Cidofovir for Peripheral Cytomegalovirus Retinitis in Patients with AIDS. A Randomized, Controlled Trial. Ann Intern Med 126:257-263, 1997.

Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.

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