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Mechanism Of Action
Foscarnet 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. Foscarnet does not require activation (phosphorylation) by thymidine kinase or other kinases.
Antiviral Activity In Cell Culture
The quantitative relationship between the cell culture susceptibility of human cytomegalovirus (CMV) or herpes simplex virus 1 and 2 (HSV-1 and HSV-2) to foscarnet 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 (EC50), vary greatly depending on the assay method used, cell type employed and the laboratory performing the test. A number of sensitive viruses and their EC50 values are listed below (Table 1). The combination antiviral activity of foscarnet and ganciclovir or acyclovir are not antagonistic in cell culture.
Foscarnet Inhibition of Virus Replication in Cell Culture
|Virus||EC50 value (μM)|
|Ganciclovir resistant CMV||190|
|HSV-TK negative mutant||67|
|HSV-DNA polymerase mutants||5-443|
|*Mean = 269 μM|
Antiviral Activity In Vivo
Statistically significant decreases in positive CMV cultures from blood and urine have been demonstrated in two studies (FOS-03 and ACTG-015/915) of subjects treated with FOSCAVIR. Although median time to progression of CMV retinitis was increased in subjects treated with FOSCAVIR, reductions in positive blood or urine cultures have not been shown to correlate with clinical efficacy in individual subjects (Table 2).
Blood and Urine Culture Results from CMV Retinitis Patients*
|End of Induction†||1||60|
|End of Induction†||21||37|
|*A total of 77 subjects were treated with FOSCAVIR in two clinical trials (FOS-03 and ACTG-015/915). Not all subjects had blood or urine cultures done and some subjects had results from both cultures.
†(60 mg/kg FOSCAVIR TID for 2–3 weeks).
CMV and HSV isolates with reduced susceptibility to foscarnet have been selected in cell culture by passage of wild type virus in the presence of increasing concentrations of the drug. All foscarnet resistant isolates are known to be generated through amino acid substitutions in the viral DNA polymerase pUL54 (CMV) or pUL30 (HSV) (Table 3).
Summary of Foscarnet Resistance-associated DNA Polymerase Amino Acid
Substitutions in Cell Culture
|CMV pUL54||T419M, T552N, S585A, F595I, Q807A, M844T/V, V946L|
|HSV-1 pUL30||Y577H, E597D, A605V, L702H, V714M, L774F, L788M, D780N, L782I, P797T, L802F, V813M, V817M, Y818C, T821M, R842S, S889A, F891C, V892M, D907V, A910V, SRA914-916LCV, V958L, R959H|
Limited clinical data are available on the development of clinical resistance to foscarnet and many pathways to resistance likely exist. Substitutions documented in the literature in treated patients as associated with foscarnet resistance, are listed in Table 4.
Summary of Foscarnet Resistance-associated Amino Acid Substitutions
Observed in Treated Patients
|CMV pUL54||N495K, Q578H/L, D588E/N, T700A, V715M, E756D/K/Q, L773V, L776M, V781I, V787L, L802M, A809V, V812L, T813S, T821I, A834P, T838A, G841A/S, del 981-982|
|HSV-1 pUL30||S599L, D672N, R700G, V715G, A719T/V, S724N, E798K, G841C/S, A910T, Y941H|
|HSV-2 pUL30||A724T, S725G, S729N, Q732R, L783M, D785N, T844I, L850I, D912V|
|Note: Many additional pathways to foscarnet resistance likely exist|
The possibility of viral resistance should be considered in patients who show poor clinical response or experience persistent viral excretion during therapy.
Cross-Resistance: The amino acid substitutions that resulted in reduced susceptibility to foscarnet and either ganciclovir, acyclovir and/or cidofovir are summarized in Tables 5 and 6.
Summary of CMV DNA polymerase Amino Acid Substitutions Conferring
Foscarnet Resistance with Cross-Resistance to Ganciclovir and/or Cidofovir
|Cross-resistant to ganciclovir||CMV pUL54||Q578H, D588N, E756K, L773V, L776M, V781I, V787L, L802M, A809V, V812L, T813S, T821I, A834P, G841A/S, del 981-982|
|Cross-resistant to cidofovir||CMV pUL54||Q578H, D588N, E756K, L773V, V812L, T813S, A834P, G841A, del 981-982|
TABLE 6 Summary of HSV DNA polymerase Amino Acid Substitutions Conferring Foscarnet Resistance with Cross-Resistance to Acyclovir and/or Cidofovir
|Cross-resistant to acyclovir||HSV-1 pUL30||E597D, S599L, A605V, D672N, R700G, L702H, V714M, V715G, A719T/V, S724N, L774F, L778M, D780N, L782I, P797T, E798K, L802F, V813M, V817M, Y818C, T821M, G841C/S, R842S, S889A, F891C/Y, V892M, D907V, A910V/T, SRA914-916LCV, Y941H, V958L, V959H|
|HSV-2 pUL30||A724T, S725G, S729N, Q732R, L783M, D785N, T844I, D912V|
|Marginally cross-resistant to cidofovir||HSV-1 pUL30||V714M, A719V, S724N, L778M, L802F, Y818C, T821M, G841S|
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 7:
Foscarnet Pharmacokinetic Characteristics*
|Parameter||60 mg/kg Q8h||90 mg/kg Q12h|
|C max at steady-state (μM)||589 ± 192 (24)||623 ± 132 (19)|
|C trough 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
†50 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 – 1000 μM.
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.
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 8:
TABLE 8 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
|108 ± 16||68 ± 8||34 ± 9||20 ± 4|
|2.13 ± 0.71||1.33 ± 0.43||0.46 ± 0.14||0.43 ± 0.26|
|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 (CrCl) 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 half-life 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).
The pharmacokinetics of foscarnet and ganciclovir were not altered in 13 patients receiving either concomitant therapy or daily alternating therapy for maintenance of CMV disease.
There is no clinically significant interaction with zidovudine (AZT), or probenecid.
A prospective, randomized, controlled clinical trial (FOS-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).
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: 11/28/2016
This monograph has been modified to include the generic and brand name in many instances.
Additional Foscavir Information
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