Page 881 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 49 Antiviral Agents 867

acyclovir and approximate those achieved with intravenous acy- DOCOSANOL
clovir. Oral bioavailability is 54–70%, and cerebrospinal fluid
levels are about 50% of those in serum. Elimination half-life is Docosanol is a saturated 22-carbon aliphatic alcohol that inhibits
2.5–3.3 hours. fusion between the host cell plasma membrane and the HSV
Valacyclovir is generally well tolerated, although nausea, envelope, thereby preventing viral entry into cells and subsequent
headache, vomiting, or rash may occur. At high doses, confu- viral replication. Topical docosanol 10% cream is available with-
sion, hallucinations, and seizures have been reported. AIDS out a prescription. When applied within 12 hours of the onset of
patients who received high-dosage valacyclovir chronically prodromal symptoms, five times daily, median healing time was
(ie, 8 g/d) had increased gastrointestinal intolerance as well as shortened by 18 hours compared with placebo in recurrent orola-
thrombotic thrombocytopenic purpura/hemolytic-uremic syn- bial herpes. Application site reactions occur in ~2%.
drome; this dose has also been associated with confusion and
hallucinations in transplant patients. There is no evidence of an
increased risk of birth defects in infants exposed to valacyclovir TRIFLURIDINE
during pregnancy.
Trifluridine (trifluorothymidine) is a fluorinated pyrimidine
FAMCICLOVIR nucleoside that inhibits viral DNA synthesis in HSV-1, HSV-2,
CMV, vaccinia, and some adenoviruses. It is phosphorylated intra-
Famciclovir is the diacetyl ester prodrug of 6-deoxypenciclovir, an cellularly by host cell enzymes, and then competes with thymidine
acyclic guanosine analog. After oral administration, famciclovir triphosphate for incorporation by the viral DNA polymerase
is rapidly deacetylated and oxidized by first-pass metabolism to (Figure 49–2). Incorporation of trifluridine triphosphate into
penciclovir. It is active in vitro against HSV-1, HSV-2, VZV, EBV, both viral and host DNA prevents its systemic use. Application
and HBV. As with acyclovir, activation by phosphorylation is of a 1% solution is effective in treating keratoconjunctivitis and
catalyzed by the virus-specified thymidine kinase in infected cells, recurrent epithelial keratitis due to HSV-1 or HSV-2. Cutaneous
followed by competitive inhibition of the viral DNA polymerase application of trifluridine solution, alone or in combination with
to block DNA synthesis. Unlike acyclovir, however, penciclovir interferon-alfa, has been used successfully in the treatment of
does not cause chain termination. Penciclovir triphosphate has acyclovir-resistant HSV infections.
lower affinity for the viral DNA polymerase than acyclovir tri-
phosphate, but it achieves higher intracellular concentrations. INVESTIGATIONAL AGENTS
The most commonly encountered clinical mutants of HSV are
thymidine kinase-deficient; these are cross-resistant to acyclovir Two compounds (pritelivir and amenamevir) belong to the new
and famciclovir. class of helicase-primase inhibitors and are under development
The bioavailability of penciclovir from orally administered for HSV infection. Valomaciclovir, an inhibitor of the viral
famciclovir is 70%. The intracellular half-life of penciclovir tri- DNA polymerase, is currently under clinical evaluation for the
phosphate is prolonged, at 7–20 hours. Penciclovir is excreted treatment of patients with acute zoster and acute EBV infection
primarily in the urine. (infectious mononucleosis).
Oral famciclovir is generally well tolerated, although headache,
nausea, or diarrhea may occur. As with acyclovir, testicular toxicity
has been demonstrated in animals receiving repeated doses. How- ■ AGENTS TO TREAT
ever, men receiving daily famciclovir (250 mg every 12 hours) for CYTOMEGALOVIRUS (CMV)
18 weeks had no changes in sperm morphology or motility. In one
study, there was no evidence of increased birth defects in infants INFECTIONS
exposed to famciclovir during the first trimester. The incidence of
mammary adenocarcinoma was increased in female rats receiving CMV infections occur primarily in the setting of advanced
famciclovir for 2 years. immunosuppression and are typically due to reactivation of latent
infection. Dissemination of infection results in end-organ disease,
including retinitis, colitis, esophagitis, central nervous system dis-
PENCICLOVIR ease, and pneumonitis. Although the incidence in HIV-infected
patients has markedly decreased with the advent of potent antiret-
The guanosine analog penciclovir, the active metabolite of roviral therapy, clinical reactivation of CMV infection after organ
famciclovir, is available for topical use. Penciclovir cream (1%) transplantation is still prevalent.
shortened the median duration of recurrent herpes labialis by The availability of oral valganciclovir has decreased the use of
~17 hours compared to placebo when applied within 1 hour of intravenous ganciclovir, intravenous foscarnet, and intravenous
the onset of prodromal symptoms and continued every 2 hours cidofovir for the prophylaxis and treatment of end-organ CMV
during waking hours for 4 days. Adverse effects are uncommon, disease (Table 49–2). Oral valganciclovir has replaced oral ganci-
other than application site reactions in ~1%. clovir because of its lower pill burden.