A Textbook of Clinical Pharmacology and Therapeutics

FOSCARNET (TRISODIUM PHOSPHONOFORMATE)

Uses

Foscarnetis active against several important viruses, notably
HIV-1 and all human herpes viruses, including aciclovir-
resistant herpes viruses and cytomegalovirus (CMV). It is used
to treat CMV infections (retinitis, pneumonitis, colitis and
oesophagitis) and aciclovir-resistant herpes simplex virus
(HSV) infections in immunocompetent and immunosup-
pressed hosts. Foscarnetis given intravenously as loading dose
followed by infusions. Dose reduction is required in patients
with renal failure.

Mechanism of action

Foscarnet is a nucleotide analogue that acts as a non-
competitive inhibitor of viral DNA polymerase and inhibits the
reverse transcriptase from several retroviruses. It is inactive
against eukaryotic DNA polymerases at concentrations that
inhibit viral DNA replication.

Adverse effects

These include the following:

• nephrotoxicity: minimized by adequate hydration and
  dose reduction if the serum creatinine rises; monitoring of
  renal function is mandatory;


• central nervous system effects include irritability, anxiety
  and fits;


• nausea, vomiting and headache;


• thrombophlebitis;


• hypocalcaemia and hypomagnaesemia;


• hypoglycaemia (rare).

Pharmacokinetics

Foscarnetis poorly absorbed (2–5%) after oral administration.
Plasma concentrations decay in a triphasic manner and the
terminalt1/2is 18 hours. Foscarnetis excreted renally by
glomerular filtration and tubular excretion. Approximately
20% remains in the body bound in bone.

Drug interactions

The nephrotoxicity of foscarnetis potentiated in the presence of

other nephrotoxins, e.g. pentamidine,gentamicin,ciclosporin

andamphotericin B. Administration with pentamidinecan

cause marked hypocalcaemia.

GANCICLOVIR (DIHYDROXYPROPOXYMETHYL-

GUANINE, DHPG)

Uses

Ganciclovir, a guanine analogue, is used to treat sight- or life-

threatening CMV infections (e.g. retinitis, pneumonitis, colitis

and oesophagitis) in immunocompromised hosts. It also has

potent activity against herpes viruses 1 and 2 and is used to treat

aciclovir-resistant herpes. A loading dose is administered intra-

venously followed by maintenance infusions. Oral ganciclovir

is available for therapy despite its poor bioavailability and is

only slightly less effective than intravenous therapy in CMV

retinitis in AIDS patients. It is easier for the patients and less

expensive. Intravitreal ganciclovir implants are effective in

treating CMV retinitis and are more effective at suppressing pro-

gression of disease than systemic ganciclovir.

Valgancicloviris the L-valyl ester prodrug of ganciclovir. It

can be used orally on a twice daily schedule for initial control

and suppression of CMV retinitis.

Mechanism of action

Gancicloviris metabolized intracellularly to its monophos-

phate in herpes-infected cells by the virally encoded thymi-

dine kinase. It undergoes further phosphorylation by host

kinases to its triphosphate anabolite which competitively

inhibits the CMV (or HSV) DNA polymerase. If it is incorp-

orated into nascent viral DNA, it causes chain termination.

Gancicloviris concentrated ten-fold in infected cells com-

pared to uninfected cells.

Adverse effects

These include:

• neutropenia and bone marrow suppression
  (thrombocytopenia and less often anaemia); cell counts
  usually return to normal within two to five days of
  discontinuing the drug;


• temporary or possibly permanent inhibition of
  spermatogenesis or oogenesis;


• phlebitis and pain at intravenous infusion site;


• rashes and fever;


• gastro-intestinal upsets;


• transient increases in liver enzymes and serum creatinine
  in underhydrated patients.

Contraindications

Gancicloviris contraindicated in pregnancy (it is teratogenic

in animals) and in breast-feeding women.

Pharmacokinetics

Only 4–7.5% of an oral dose of ganciclovir is absorbed.

Valgancicloviris well absorbed orally and is converted to

346 FUNGAL AND NON-HIVVIRAL INFECTIONS

Key points

Aciclovir and its analogues

• Aciclovir is an acyclic guanosine analogue that is active
  against the herpes virus.


• Aciclovir and its analogues are initially phosphorylated
  by virally coded thymidine kinase and further
  phosphorylated intracellularly to their triphosphate
  form, which inhibits the viral DNA polymerase.


• They are used to treat oral herpes simplex (topical),
  genital herpes simplex (oral therapy) and herpes
  encephalitis (intravenous therapy).


• Aciclovir has low oral bioavailability.


• Famciclovir (prodrug of penciclovir) and valaciclovir
  (an aciclovir prodrug) have much greater bioavailability
  than aciclovir.


• Aciclovir side-effects are mild: increased creatinine
  levels, rashes, hepatitis and gastro-intestinal
  disturbances.


• Viral resistance to aciclovir is an increasing problem.