Foscarnet

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Abstract
The pyrophosphate analogue, foscarnet, selectively inhibits the DNA polymerase of human herpes viruses, including cytomegalovirus, and the reverse transcriptase of HIV. Viral replication is therefore prevented, but resumes when the drug is cleared from infected cells. In vitro, the combination of foscarnet and zidovudine (azidothymidine) has an additive effect against cytomegalovirus and acts synergistically against HIV An improvement in cytomegalovirus retinitis is obtained in over 85% of affected AIDS patients during foscarnet induction therapy, but relapse usually occurs within a month of ceasing treatment. There is a similar duration of remission during maintenance therapy given for 5 days each week, but this can be extended 4- to 5-fold with daily administration of higher doses. In allograft recipients, progression of retinitis can be halted by foscarnet until immune function recovers and eradicates the virus. The incidence of acute renal failure, which is common during foscarnet therapy, may be reduced by dosage adjustment and adequate prehydration. Anaemia, phlebitis, nausea and vomiting, and disturbances in serum calcium and phosphate levels, perhaps resulting from uptake of foscarnet into bone or chelation with ionised calcium, have also been associated with admin- istration of the drug Cytomegalovirus retinitis is difficult to treat, with few therapeutic options available. Although treatment with foscarnet produces some severe adverse effects, with care these can be minimised, and the drug produces clinical improvement in a large proportion of patients; this is a highly encouraging finding at this stage in its development. Preliminary comparative data indicate that foscarnet and ganciclovir are similarly effective, but foscarnet may have some theoretical advan- tages in AIDS patients since it can be used in combination with zidovudine without potentiating myelosuppression Foscarnet is a pyrophosphate analogue which prevents replication of herpesviruses, including cytomegalovirus, by inhibiting viral DNA polymerases. 50% inhibition of cytomegalovirus DNA polymerase is achieved by foscarnet 0.3 μmol/L; other herpesvirus enzymes are similarly sensitive. Foscarnet also inhibits HIV reverse transcriptase, causing 50% reduction in activity at concentrations of 0.1 to 0.5 μmol/L. In contrast, inhibition of mammalian DNA polymerase by foscarnet is negligible, with 50% inhibition achieved at a concentration of 40 or 50 μmol/L. Exposure for at least 18 hours to foscarnet 1000 μmol/L was required to inhibit DNA synthesis and division of human cell lines by 50% Human cytomegalovirus plaque formation was inhibited by 50% by foscarnet concentrations between 25 and 34 μmol/L; clinical isolates were about 3 to 8 times less sensitive. Late antigen expression, a marker of cell death, was prevented by foscarnet 500 μmol/L only if human fibroblasts were exposed to the drug within 24 hours of cytomegalovirus infection. The virustatic activity of foscarnet is reversible, with antigens to cytomegalovirus expressed 3 to 9 days after foscarnet was removed from cell culture. In vivo, intraperitoneal administration of foscarnet reduced the mortality rate of cytomegalovirus-infected mice by 40%, but was ineffective in guineapigs. Foscarnet 10 to 25 μmol/L inhibited in vitro HIV replication by 50%, and 132 μmol/L caused 98% inhibition of the virus. Inhibition of cytomegalovirus replication in human cell lines is additive when foscarnet is combined with zidovudine and synergistic with trifluridine (trifluorothymidine). Synergistic inhibition of HIV replication occurred with the combination of foscarnet and zidovudine, particularly at higher ratios of foscarnet Although resistance of cytomegalovirus to foscarnet has not been reported either in vitro or clinically, resistant mutants of herpes simplex are readily produced. The lack of susceptibility to foscarnet is conferred by changes in the viral DNA polymerase; at least 3 different drug-resistant variants have been identified In summary, foscarnet reversibly inhibits cytomegalovirus and HIV replication by blocking DNA polymerase and reverse transcriptase, respectively, at concentrations relatively harmless to host cellular enzymes and division Mean steady-state plasma concentrations of foscarnet, achieved after 6 to 21 days’ continuous intravenous infusion of foscarnet 0.09 to 0.19 mg/kg/min, were between 228 and 261 μmol/L in AIDS patients, although there was substantial variation between individuals. With 2-hour infusions of foscarnet 60 mg/kg given every 8 hours, mean peak and trough plasma concentrations of 495 and 126 μmol/L were reached after 14 days. The mean apparent volume of distribution of foscarnet in 13 patients with HIV infection was 5.1 L/kg, indicating extensive distribution out of the plasma No metabolites of foscarnet have been detected. In HIV-infected patients, 83% of a cumulative intravenous dose of foscarnet was recovered unchanged in the urine during the first 36 hours of stopping the infusion, with 88% recovered within a week. The remainder was accounted for by deposition into bone, assuming that excretion of foscarnet is exclusively through the kidneys. Glomerular filtration and tubular secretion contribute almost equally to renal clearance which accounts for 82 to 86% of total plasma clearance of foscarnet. Uptake into bone matrix appears to be responsible for the balance Sequestration into bone may be responsible for the long terminal phase half-life of foscarnet which was up to a mean of 88 hours. Of more practical value in terms of a dosage schedule are the first and second phase elimination half-lives of foscarnet which were 0.5 to 1.4 hours and 3.3 to 6.8 hours, respectively. Based on in vitro activity of foscarnet against cytomegalovirus, most investigators have aimed at keeping drug plasma concentrations between 333 and 500 μmol/L to ensure that virustatic levels are maintained In common with other agents used in this condition, clinical experience with foscarnet in the management of patients with cytomegalovirus retinitis is largely limited to noncomparative studies involving AIDS patients, and to isolated case reports Both continuous and intermittent intravenous infusions have been investigated as induction therapy, with the latter approach now preferred because of apparently greater efficacy, convenience and reduced toxicity. Induction therapy commencing with an intravenous bolus injection of foscarnet 20 or 30 mg/kg followed by a continuous infusion of 230 mg/kg/day for 2 to 4 weeks elicits a complete response in 50 to 75% of patients, and a partial response in about 10 to 50%. The overall response rate is over 85% Continuous infusions have now largely been superseded by the alternative induction regimen of infusion of foscarnet 60 mg/kg every 8 hours or 100 mg/kg every 12 hours for 2 to 4 weeks, resulting in an overall response rate of over 88%, with partial responses predominating Because relapse occurs in approximately 66% of surviving patients within a month of stopping induction therapy, subsequent maintenance treatment is given. Over 60% of patients receiving maintenance schedules of 2-hour intravenous infusions of foscarnet 60 to 90 mg/kg/day for 5 days each week relapsed within 2 to 4 weeks. In contrast, administration of foscarnet 100 or 120 mg/kg each day delayed retinitis progression for 17 to 23 weeks on average, with no increase in toxicity The clinical response is clearly related to the virological outcome. Cytomegalovirus was eliminated from over 83% of buffy coat, blood and urine samples during induction treament, a rate which corresponded to clinical response In published case reports, maintenance foscarnet therapy was given at home to 2 AIDS patients, and coadministration of zidovudine, discontinued during previous ganciclovir therapy, was recommenced. Furthermore, foscarnet prevented retinitis progression until immunological status recovered sufficiently to eradicate the virus in a bone marrow transplant recipient Limited comparative data suggest that the efficacy of foscarnet is similar to that of ganciclovir in managing AIDS-related cytomegalovirus retinitis The most frequent dose-limiting adverse effect of foscarnet therapy is a 2- to 3-fold increase in serum creatinine in about 45% of patients. Loin pain has been reported and haemodialysis may be required in severe cases of renal impairment. The cause appears to be acute tubular necrosis, which tends to be reversible on foscarnet withdrawal, even in renal allograft recipients. The incidence and severity of renal dysfunction is reduced by adjusting the dosage of foscarnet depending on the serum creatinine level, using intermittent rather than continuous infusions, providing adequate prehydration and avoiding other potentially nephrotoxic drugs. Nausea and vomiting, which occurs in 20 to 30% of patients, could precipitate renal damage. Reversible hypercalcaemia and hyperphosphataemia occur in over 66% of foscarnet recipients, although symptomatic hypocalcaemia has also been observed. These disturbances are possibly due to foscarnet deposition in bone, chelation with ionised calcium, or to the drug inhibiting renal phosphate excretion Foscarnet causes anaemia in 20 to 50% of patients, but does not appear to be associated with neutropenia. Penile ulceration, resembling fixed drug eruption, associated with foscarnet use is increasingly being reported. It appears to be due to local irritation from unchanged drug in the urine, and therefore thorough personal hygiene is advised Thrombophlebitis of peripheral veins during continuous infusion, mild elevations in liver function, transient neurological disturbances, diarrhoea and headache have occasionally been reported The concomitant use of foscarnet and intravenous pentamidine appears to be contraindicated because of additive renal toxicity and severe hypocalcaemia The recommended dosage of foscarnet in the management of patients with cytomegalovirus retinitis is a bolus infusion of 20 to 30 mg/kg over 30 minutes followed by infusion of 180 to 200 mg/kg/day, adjusted according to renal function. Intermittent 2-hour infusions of 60 mg/kg every 8 hours or 100 mg/kg every 12 hours are preferred over continuous infusion. Induction treatment can last for up to 4 weeks Maintenance therapy is usually necessary to prevent relapse. Daily 2-hour intravenous infusions of foscarnet 90 to 120 mg/kg are currently considered to be more effective in prolonging remission than 60 to 90 mg/kg/day administered for 5 days each week Serum creatinine and calcium levels should be closely monitored, and saline or dextrose hydration given before and during treatment to minimise the risk of acute renal damage. Foscarnet (24 mg/ml) stock solution can be diluted by 50% and administered centrally rather than peripherally to reduce the risk of thrombophlebitis