Page 883 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 49 Antiviral Agents 869

of CMV disease in high-risk solid organ and bone marrow trans- therapy may be due to high levels of ionized drug in the urine.
plant recipients. Adverse effects, drug interactions, and resistance Nausea, vomiting, anemia, elevation of liver enzymes, and fatigue
patterns are the same as those associated with ganciclovir. have been reported; the risk of anemia may be additive in patients
receiving concurrent zidovudine. Central nervous system toxicity
includes headache, hallucinations, and seizures; the risk of seizures
FOSCARNET may be increased with concurrent use of imipenem. Foscarnet
caused chromosomal damage in preclinical studies.
Foscarnet (phosphonoformic acid) is an inorganic pyrophosphate
analog that inhibits herpesvirus DNA polymerase, RNA poly-
merase, and HIV reverse transcriptase directly without requiring CIDOFOVIR
activation by phosphorylation. Foscarnet blocks the pyrophos-
phate binding site of these enzymes and inhibits cleavage of Cidofovir is a cytosine nucleotide analog with in vitro activity
pyrophosphate from deoxynucleotide triphosphates. It has in vitro against CMV, HSV-1, HSV-2, VZV, EBV, HHV-6, HHV-8,
activity against HSV, VZV, CMV, EBV, HHV-6, HHV-8, HIV-1, adenovirus, poxviruses, polyomaviruses, and human papillomavi-
and HIV-2. rus. In contrast to ganciclovir, phosphorylation of cidofovir to the
Foscarnet is available in an intravenous formulation only; poor active diphosphate is independent of viral enzymes (Figure 49–2);
oral bioavailability and gastrointestinal intolerance preclude oral thus activity is maintained against thymidine kinase-deficient or
use. Cerebrospinal fluid concentrations are 43–67% of steady- altered strains of CMV or HSV. Cidofovir diphosphate acts both
state serum concentrations. Although the mean plasma half-life is as a potent inhibitor of and as an alternative substrate for viral
3–7 hours, up to 30% of foscarnet may be deposited in bone, with DNA polymerase, competitively inhibiting DNA synthesis and
a half-life of several months. The clinical repercussions of this are becoming incorporated into the viral DNA chain. Cidofovir-
unknown. Clearance of foscarnet is primarily renal and is directly resistant isolates tend to be cross-resistant with ganciclovir but
proportional to creatinine clearance. Serum drug concentrations retain susceptibility to foscarnet.
are reduced ~50% by hemodialysis. Although the terminal half-life of cidofovir is approximately
Foscarnet is effective in the treatment of end-organ CMV dis- 2.6 hours, the active metabolite cidofovir diphosphate has a pro-
ease (ie, retinitis, colitis, and esophagitis), including ganciclovir- longed intracellular half-life of 17–65 hours, thus allowing infre-
resistant disease; it is also effective against acyclovir-resistant HSV quent dosing. A separate metabolite, cidofovir phosphocholine,
and VZV infections. The dosage of foscarnet must be titrated has a half-life of at least 87 hours and may serve as an intracellular
according to the patient’s calculated creatinine clearance before reservoir of active drug. Cerebrospinal fluid penetration is poor.
each infusion. Use of an infusion pump to control the rate of infu- Elimination is by active renal tubular secretion. High-flux hemo-
sion is important to prevent toxicity, and large volumes of fluid are dialysis reduces serum levels of cidofovir by approximately 75%.
required because of the drug’s poor solubility. The combination of Intravenous cidofovir is effective for the treatment of CMV
ganciclovir and foscarnet is synergistic in vitro against CMV and retinitis and is used experimentally to treat adenovirus, human pap-
has been shown to be superior to either agent alone in delaying illomavirus, BK polyomavirus, vaccinia, and poxvirus infections.
progression of retinitis; however, toxicity is also increased when Intravenous cidofovir must be administered with high-dose pro-
these agents are administered concurrently. As with ganciclovir, a benecid (2 g at 3 hours before the infusion and 1 g at 2 and 8 hours
decrease in the incidence of Kaposi’s sarcoma has been observed in after), which blocks active tubular secretion and decreases nephro-
patients who have received long-term foscarnet. toxicity. Before each infusion, cidofovir dosage must be adjusted for
Foscarnet has been administered intravitreally for the treat- alterations in the calculated creatinine clearance or for the presence
ment of CMV retinitis in patients with AIDS, but data regarding of urine protein, and aggressive adjunctive hydration is required.
efficacy and safety are incomplete. Initiation of cidofovir therapy is contraindicated in patients with
Resistance to foscarnet in HSV and CMV isolates is due to existing renal insufficiency. Direct intravitreal administration of
point mutations in the DNA polymerase gene and is typically cidofovir is not recommended because of ocular toxicity.
associated with prolonged or repeated exposure to the drug. The primary adverse effect of intravenous cidofovir is a dose-
Mutations in the HIV-1 reverse transcriptase gene have also been dependent proximal tubular nephrotoxicity, which may be reduced
described. Although foscarnet-resistant CMV isolates are typically with prehydration using normal saline. Proteinuria, azotemia,
cross-resistant to ganciclovir, foscarnet activity is usually main- metabolic acidosis, and Fanconi’s syndrome may occur. Concurrent
tained against ganciclovir- and cidofovir-resistant isolates of CMV. administration of other potentially nephrotoxic agents (eg, ampho-
Potential adverse effects of foscarnet include renal impairment, tericin B, aminoglycosides, nonsteroidal anti-inflammatory drugs,
hypo- or hypercalcemia, hypo- or hyperphosphatemia, hypo- pentamidine, foscarnet) should be avoided. Prior administration of
kalemia, and hypomagnesemia. Saline preloading helps prevent foscarnet may increase the risk of nephrotoxicity. Other potential
nephrotoxicity, as does avoidance of concomitant administration adverse effects include uveitis, ocular hypotony, and neutropenia
of drugs with nephrotoxic potential (eg, amphotericin B, pentami- (15–24%). Concurrent probenecid use may result in other toxicities
dine, aminoglycosides). The risk of severe hypocalcemia, caused or drug-drug interactions (see Chapter 36). Cidofovir is mutagenic,
by chelation of divalent cations, is increased with concomitant gonadotoxic, and embryotoxic, and causes hypospermia and mam-
use of pentamidine. Genital ulcerations associated with foscarnet mary adenocarcinomas in animals.