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Mechanism Of Action
FOSCAVIR is an organic analogue of inorganic pyrophosphate that inhibits replication of herpes viruses in vitro including cytomegalovirus (CMV) and herpes simplex virus types 1 and 2 (HSV-1 and HSV-2).
FOSCAVIR exerts its antiviral activity by a selective inhibition at the pyrophosphate binding site on virus-specific DNA polymerases at concentrations that do not affect cellular DNA polymerases. FOSCAVIR does not require activation (phosphorylation) by thymidine kinase or other kinases and therefore is active in vitro against HSV TK deficient mutants and CMV UL97 mutants. Thus, HSV strains resistant to acyclovir or CMV strains resistant to ganciclovir may be sensitive to FOSCAVIR. However, acyclovir or ganciclovir resistant mutants with alterations in the viral DNA polymerase may be resistant to FOSCAVIR and may not respond to therapy with FOSCAVIR. The combination of FOSCAVIR and ganciclovir has been shown to have enhanced activity in vitro.
Antiviral Activity In Vitro And In Vivo
The quantitative relationship between the in vitro susceptibility of human cytomegalovirus (CMV) or herpes simplex virus 1 and 2 (HSV-1 and HSV-2) to FOSCAVIR and clinical response to therapy has not been established and virus sensitivity testing has not been standardized. Sensitivity test results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (IC50), vary greatly depending on the assay method used, cell type employed and the laboratory performing the test. A number of sensitive viruses and their IC50 values are listed below (Table 1).
TABLE 1: FOSCARNET Inhibition of Virus Multiplication
in Cell Culture
|Ganciclovir resistant CMV||190|
|HSV-TK negative mutant||67|
|HSV-DNA polymerase mutants||5-443|
|*Mean = 269μM|
Statistically significant decreases in positive CMV cultures from blood and urine have been demonstrated in two studies (FOS-03 and ACTG-015/915) of patients treated with FOSCAVIR. Although median time to progression of CMV retinitis was increased in patients treated with FOSCAVIR, reductions in positive blood or urine cultures have not been shown to correlate with clinical efficacy in individual patients.
TABLE 2: Blood and Urine Culture Results From CMV
|End of Induction†||1||60|
|End of Induction†||21||37|
|*A total of 77 patients were treated with FOSCAVIR in two
clinical trials (FOS-03 and ACTG-015/915). Not all patients had blood or urine
cultures done and some patients had results from both cultures.
†(6 0 mg/kg FOSCAVIR TID for 2 -3 weeks).
Strains of both HSV and CMV that are resistant to FOSCAVIR can be readily selected in vitro by passage of wild type virus in the presence of increasing concentrations of the drug. All FOSCAVIR resistant mutants are known to be generated through mutation in the viral DNA polymerase gene. CMV strains with double mutations conferring resistance to both FOSCAVIR and ganciclovir have been isolated from patients with AIDS. The possibility of viral resistance should be considered in patients who show poor clinical response or experience persistent viral excretion during therapy.
The pharmacokinetics of foscarnet has been determined after administration as an intermittent intravenous infusion during induction therapy in AIDS patients with CMV retinitis. Observed plasma foscarnet concentrations in four studies (FOS-01, ACTG- 015, FP48PK, FP49PK) are summarized in Table 3:
TABLE 3: Foscarnet Pharmacokinetic Characteristics*
|Parameter||60 mg/kg Q8h||90 mg/kg Q12h|
|Cmax at steady-state (μM)||589 ± 192 (24)||623 ± 132 (19)|
|Ctrough at steady-state (μM)||114 ± 91 (24)||63 ± 57 (17)|
|Volume of distribution (L/kg)||0.41 ± 0.13 (12)||0.52 ± 0.20 (18)|
|Plasma half-life (hr)||4.0 ± 2.0 (24)||3.3 ± 1.4 (18)|
|Systemic clearance (L/hr)||6.2 ± 2.1 (24)||7.1 ± 2.7 (18)|
|Renal clearance (L/hr)||5.6 ± 1.9 (5)||6.4 ± 2.5 (13)|
|CSF: plasma ratio||0.69 ± 0.19 (9) †||0.66± 0.11(5) ‡|
|*Values expressed as mean S.D. (number of subjects
studied) for each parameter
†5 0 mg/kg Q8h for 28 days, samples taken 3 hrs after end of 1 hr infusion (Astra Report 815-04 AC025-1)
‡90 mg/kg Q12hr for 28 days, samples taken 1 hr after end of 2 hr infusion (Hengge et al., 1993)
In vitro studies have shown that 14 - 17% of foscarnet is protein bound at plasma drug concentrations of 1 - 1000μM.
The foscarnet terminal half-life determined by urinary excretion was 87.5 ± 41.8 hours, possibly due to release of foscarnet from bone. Postmortem data on several patients in European clinical trials provide evidence that foscarnet does accumulate in bone in humans; however, the extent to which this occurs has not been determined. In animal studies (mice), 40% of an intravenous dose of FOSCAVIR was deposited in bone in young animals and 7% was deposited in adult animals.
Adults with impaired Renal Function: The pharmacokinetic properties of foscarnet have been determined in a small group of adult subjects with normal and impaired renal function, as summarized in Table 4:
TABLE 4: Pharmacokinetic Parameters (mean ± S.D.)
After a Single 60 mg/kg Dose of FOSCAVIR in 4 Groups* of Adults with Varying
Degrees of Renal Function
|Creatinine clearance (mL/min)||108 ± 16||68 ± 8||34 ± 9||20 ± 4|
|Foscarnet CL (mL/min/kg)||2.13 ± 0.71||1.33 ± 0.43||0.46 ± 0.14||0.43 ± 0.26|
|Foscarnet half-life (hr)||1.93 ± 0.12||3.35 ± 0.87||13.0 ± 4.05||25.3 ± 18.7|
|* Group 1 patients had normal renal function defined as a creatinine clearance (CrCI) of >80 mL/min, Group 2 CrCl was 50 - 80 mL/min, Group 3 CrCl was 25 - 49 mL/min and Group 4 CrCl was 10 - 24 mL/min.|
Total systemic clearance (CL) of foscarnet decreased and halflife increased with diminishing renal function (as expressed by creatinine clearance). Based on these observations, it is necessary to modify the dosage of foscarnet in patients with renal impairment (see DOSAGE AND ADMINISTRATION).
A prospective, randomized, controlled clinical trial (F0S-03) was conducted in 24 patients with AIDS and CMV retinitis comparing treatment with FOSCAVIR to no treatment. Patients received induction treatment of FOSCAVIR, 60 mg/kg every 8 hours for 3 weeks, followed by maintenance treatment with 90 mg/kg/day until retinitis progression (appearance of a new lesion or advancement of the border of a posterior lesion greater than 750 microns in diameter). All diagnoses and determinations of retinitis progression were made from masked reading of retinal photographs. The 13 patients randomized to treatment with FOSCAVIR had a significant delay in progression of CMV retinitis compared to untreated controls. Median times to retinitis progression from study entry were 93 days (range 21 - >364) and 22 days (range 7 - 42), respectively.
In another prospective clinical trial of CMV retinitis in patients with AIDS (ACTG-915), 33 patients were treated with two to three weeks of FOSCAVIR induction (60 mg/kg TID) and then randomized to either 90 mg/kg/day or 120 mg/kg/day maintenance therapy. The median times from study entry to retinitis progression were not significantly different between the treatment groups, 96 (range 14 - >176) days and 140 (range 16 - >233) days, respectively.
In study ACTG 129/FGCRT SOCA study 107 patients with newly diagnosed CMV retinitis were randomized to treatment with FOSCAVIR (induction: 60 mg/kg TID for 2 weeks; maintenance: 90 mg/kg QD) and 127 were randomized to treatment with ganciclovir (induction: 5 mg/kg BID; maintenance: 5 mg/kg QD). The median time to progression on the two drugs was similar (Fos=59 and Gcv=56 days).
Relapsed CMV Retinitis
The CMV Retinitis Retreatment Trial (ACTG 228/SOCA CRRT) was a randomized, open-label comparison of FOSCAVIR or ganciclovir monotherapy to the combination of both drugs for the treatment of persistently active or relapsed CMV retinitis in patients with AIDS. Subjects were randomized to one of the three treatments: FOSCAVIR 90 mg/kg BID induction followed by 120 mg/kg QD maintenance (Fos); ganciclovir 5 mg/kg BID induction followed by 10 mg/kg QD maintenance (Gcv); or the combination of the two drugs, consisting of continuation of the subject's current therapy and induction dosing of the other drug (as above), followed by maintenance with FOSCAVIR 90 mg/kg QD plus ganciclovir 5 mg/kg QD (Cmb). Assessment of retinitis progression was performed by masked evaluation of retinal photographs. The median times to retinitis progression or death were 39 days for the FOSCAVIR group, 61 days for the ganciclovir group and 105 days for the combination group. For the alternative endpoint of retinitis progression (censoring on death), the median times were 39 days for the FOSCAVIR group, 61 days for the ganciclovir group and 132 days for the combination group. Due to censoring on death, the latter analysis may overestimate the treatment effect. Treatment modifications due to toxicity were more common in the combination group than in the FOSCAVIR or ganciclovir monotherapy groups (see ADVERSE REACTIONS section).
Mucocutaneous Acyclovir Resistant HSV Infections
In a controlled trial, patients with AIDS and mucocutaneous, acyclovir-resistant HSV infection were randomized to either FOSCAVIR (N=8) at a dose of 40 mg/kg TID or vidarabine (N=6) at a dose of 15 mg/kg per day. Eleven patients were nonrandomly assigned to receive treatment with FOSCAVIR because of prior intolerance to vidarabine. Lesions in the eight patients randomized to FOSCAVIR healed after 11 to 25 days; seven of the 11 patients nonrandomly treated with FOSCAVIR healed their lesions in 10 to 30 days. Vidarabine was discontinued because of intolerance (N=4) or poor therapeutic response (N=2). In a second trial, forty AIDS patients and three bone marrow transplant recipients with mucocutaneous, acyclovir-resistant HSV infections were randomized to receive FOSCAVIR at a dose of either 40 mg/kg BID or 40 mg/kg TID. Fifteen of the 43 patients had healing of their lesions in 11 to 72 days with no difference in response between the two treatment groups.
Last reviewed on RxList: 7/13/2016
This monograph has been modified to include the generic and brand name in many instances.
Additional Foscavir Information
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