Foscarnet toxicity

Foscarnet, cidofovir, and trifuridine have been administered in acyclovir-resistant patients.30 These agents are usually reserved for use after other agents have failed because of their associated toxicities. 

Renal function Impairment The major toxicity of foscarnet is renal impairment, which occurs to some degree in most patients. Approximately 33% of 189 patients with AIDS and CMV retinitis who received IV foscarnet in clinical studies developed significant impairment of renal function, manifested by a rise in serum creatinine concentration to 2 mg/dL or more. 

The most clinically significant adverse effect of foscarnet is renal impairment. Nephrotoxicity is most likely to occur during the second week of induction therapy but may occur at any time during induction or maintenance therapy. Serum creatinine levels may be elevated in up to 33 to 50% of patients this effect is usually reversible upon drug discontinuation. Dehydration, previous renal impairment, and concurrent administration of other nephrotoxic drugs increase the risk of renal toxicity. Infusion of fluids along with foscarnet decreases the likelihood of renal impairment to about 12%. Dosage adjustment is required for patients with renal insufficiency. 

Foscarnet should not be used in combination with drugs that cause renal toxicity (e.g., acyclovir, aminoglycosides, amphotericin B, NSAIDs). Abnormal renal function has been noted when foscarnet is used with ritonavir or ritonavir and saquinavir. Pentamidine may increase the risk of nephrotoxicity, hypocalcemia, and... 

Renal impairment is the major toxicity of foscarnet and it occurs to some degree in most patients... 

Yoshizumi, M.O., et al. 1995. Ocular toxicity of iontophoretic foscarnet in rabbits. J Ocul Pharmacol Ther 11 183. 

Adverse Effects. The primary problem associated with foscarnet is impaired renal function, including acute tubular necrosis. Hematologic disorders (anemia, granulocytopenia, leukopenia), gastrointestinal disturbances (cramps, nausea, vomiting), and CNS toxicity (confusion, dizziness) may also occur during foscarnet treatment. 

LAMIVUDINE, TENOFOVIR, ZALCITABINE FOSCARNET SODIUM t adverse effects with tenofovir and possibly lamivudine and zalcitabine Uncertain possibly additive toxicity via competition for renal excretion Avoid if possible otherwise monitor FBC and renal function weekly... 

Foscarnet Intravenous administration Intravitreal injection Primary toxicity = nephrotoxicity... 

Cidofovir is an acyclic nucleotide analogue of the monophosphate of cytosine. When phosphoiylated by host cellular enzymes, the active compound cidofovir diphosphate has broad activity against the herpes viruses, including CMV, HSV 1 and 2, VZV, Epstein-Barr virus, and the BK polyomavirus. Cidofovir has primarily been used in the treatment of CMV retinitis in patients who have failed treatment with ganciclovir or foscarnet and in acyclovir-resistant herpes simplex infections. More recently, there is also a growing experience with the use of this medication in kidney transplant patients who have BK virus-associated nephropathy [31], although this interest has been dampened by significant toxicity and only modest clinical activity [32]... 

Acute kidney injury can be severe with foscarnet. Some degree of kidney injury has been reported to occur in as many as two-thirds of patients treated with foscarnet and has been a dose-limiting toxicity in 10-20% of cases [51-56]. Despite dose reduction or discontinuation of foscarnet, azotemia typically progresses for at least a few days before resolving. It may be possible to continue foscarnet at reduced doses in some patients with mild azotemia. Foscarnet-induced AKI is usually reversible, although temporary dialysis may be required [57]. Recovery may be slow, particularly in patients with preexisting kidney insufficiency. Elevated serum creatinine concentrations may persist for several months after discontinuation of foscarnet. Foscarnet nephrotoxicity may be also associated with mild proteinuria. Volume expansion with isotonic saline was effective in reducing the incidence of foscarnet nephrotoxicity to 13%, compared to 66% in non-hydrated historical controls, and allowed patients with prior kidney insufficiency to receive foscarnet without further reduction of kidney function [54, 58]. Intermittent, rather than continuous, infusion of foscarnet may also reduce the incidence of nephrotoxicity [52]. 

Clinically important, potentially hazardous interactions with amikacin, amphotericin B, delavirdine, drugs causing kidney toxicity, foscarnet, gentamicin, hydroxyurea, pentamidine, tobramycin... 

Acyclovir is the drug of choice for herpes simplex encephalitis. In patients with normal renal function, acyclovir is usually administered as 10 mg/kg intravenously every 8 hours for 2 to 3 weeks. Herpes virus resistance to acyclovir has been reported with increasing incidence, particularly from immunocompromised patients with prior or chronic exposures to acyclovir. The alternative treatment for acyclovir-resistant herpes simplex virus is foscarnet. The major toxicity of foscarnet is renal impairment, and doses must be individualized for renal function. The dose for patients with normal renal function is 40 mg/kg infused over 1 hour every 8 to 12 hours for 2 to 3 weeks. Ensuring adequate hydration is imperative. In addition, patients receiving foscarnet should be monitored for seizures related to alterations in plasma electrolyte levels. 

Yoshizumi MO, Dessouki A, Lee DA, Lee G. Determination of ocular toxicity in multiple applications of foscarnet iontophoresis. J Ocul Pharmacol Ther 1997 13 529-536. 

Clinical uses and toxicity The drug is used for prophylaxis and treatment of cytomegalovirus (CMV) infections (including CMV retinitis) and has activity against ganciclovir-resistant strains of this virus (Table 49-1). Foscarnet inhibits herpes DNA polymerase in acyclovir-resistant strains that are thymidine kinase-deficient and may suppress such resistant herpetic infections in patients with AIDS. Adverse effects include nephrotoxicity (30% incidence) with disturbances in electrolyte balance (especially hypocalcemia), genitourinary ulceration, and CNS effects (headache, hallucinations, seizures). 

These two compounds may possess some clinical advantage over ara-A due to their low systemic toxicity. The antiviral effects of phosphonoformic acid (PFA, foscarnet sodium), which is presently in Phase III clinical trials in Europe, 3 have been discussed in a recent review.91 The synthesis and structural requirements for antiherpes activity of a series of PFA esters have also been reported.92... 

Intravenous foscarnet 90 mg/kg every 12 hours and oral zalcitabine 750 micrograms every 8 hours were given to 12 HIV-positive subjects for 2 days. There were no clinically significant alterations in the pharmacokinetics of either drug. However, the manufacturers of zalcitabine suggested that the concurrent use of zalcitabine and foscarnet should be well monitored, because foscarnet may possibly decrease the renal elearanee of the zalcitabine, thereby increasing its serum levels and its toxicity, particularly peripheral neuropathy. The antiretroviral effects of foscarnet and zalcitabine were synergistic. ... 

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