Inpharma 1289 - 26 May 2001
Faropenem – a new oral
antibacterial agent
A number of presentations on the effect of various
drugs on the clinical pharmacokinetics of the new
synthetic penem antibacterial agent faropenem were
presented at the 11th European Congress on
Microbiology and Infectious Diseases [Istanbul, Turkey;
April 2001]. These showed that no adjustment of dose is
required for the coadministration of the ester of
faropenem with probenecid, furosemide or an antacid.
Evidence was also presented showing that multiple
dosing with the ester did not result in any major changes
in the oral or faecal flora and that faropenem was well
tolerated.
The carbapenems, exemplified by imipenem and
meropenem, are synthetic antibacterials, most of which
are parenteral agents. They are characterised by a high
degree of stability to β-lactamases and thus have an
extremely broad spectrum of activity that includes a
range of Gram-positive and Gram-negative bacteria that
are resistant to many other agents. Faropenem differs
from these parenteral agents in that it is available as an
ester (faropenem daloxate) which is hydrolysed in the
gut and absorbed orally as the parent compound
faropenem. A number of posters on various aspects of
faropenem and faropenem daloxate were presented.
In vitro properties of faropenem
In an in vitro study, the activity of the parent
compound faropenem was compared with that of
penicillins (amoxicillin, amoxicillin/clavulanic acid and
benzylpenicillin), cephalosporins (cefaclor and
cefixime), a fluoroquinolone (levofloxacin), a macrolide
(clarithromycin) and imipenem.
Faropenem had excellent activity against penicillin-
sensitive strains of Streptococcus pneumoniae but, like
other β-lactams, had reduced activity against the strains
with reduced susceptibility to penicillins. A similar
picture was seen against Staphylococcus aureus strains.
Various other Gram-positive species were highly
susceptible to faropenem (Corynebacterium
diphtheriae, Arcanobacterium haemolyticum and
haemolytic and Lancefield serogroups A, B, C and G
streptococci). Activity against the respiratory Gram-
negative pathogens Haemophilus influenzae and
Moraxella catarrhalis was similar to that of imipenem and
the penicillins.
Against Enterobacteriaceae species, faropenem had a
spectrum of activity similar to that of imipenem and
superior to that of the other β-lactams, indicating good
stability to a range of β-lactamases. This was confirmed
by data in another poster, where faropenem was shown
to have good activity against a number of
Enterobacteriaceae species producing extended-
spectrum β-lactamases and AmpC β-lactamases. Unlike
imipenem though, the compound does not have good
activity against Pseudomonas aeruginosa. The spectrum
of activity displayed by faropenem indicates that it could
be of value for the treatment of respiratory tract
infections.
Tolerance of multiple oral doses
A double-blind, randomised study evaluated the
effects of multiple oral doses of faropenem daloxate and
placebo on the oral and faecal flora of healthy male
volunteers. The dosage of faropenem daloxate was 300
or 600mg twice daily for 8 days in subjects aged
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1
between 20 and 46 years, with a body mass index of
between 20.2 and 30 kg/m2. For each dosage group 6
volunteers received the prodrug and 2 received placebo.
Swabs of the oropharynx and faecal samples were
collected prior to administration of drug, at the end of
the treatment period and 1–2 weeks after the end of the
treatment.
The ester was well tolerated, with no serious adverse
events being reported and no subject having to
discontinue the dose. No more adverse events were
reported by the subjects receiving the drug than those
receiving placebo – there were 14 adverse events
reported in the placebo group, 14 in the 600mg ester
group and 9 in the 300mg ester group. Vital signs, ECGs
and laboratory parameters (clinical chemistry,
haematology and renal function tests) were recorded
and showed no clinically relevant changes associated
with the administration of faropenem daloxate.
Effects on normal faecal and oral flora
The effect of the drug on the oropharyngeal flora was
minor, with no overgrowth of resistant species being
observed. In the faecal samples, a slight increase in the
numbers of enterococci isolated was noted (in particular
Enterococcus faecium) at the end of treatment, but
numbers reverted to normal during the follow-up
period. No selection of Clostridium difficile was noted in
any of the volunteers receiving faropenem daloxate,
although a transient reduction in other Clostridium
species was seen in the subjects receiving 300mg doses
of the drug. No overgrowth of the yeast Candida or of P.
aeruginosa, or of any potentially multiresistant
Enterobacteriaceae species occurred.
Interactions with other drugs
Faropenem, the active component of faropenem
daloxate, is excreted via the kidneys by both glomerular
and tubular secretion. Two studies examined the effect
of concomitant dosing of other drugs handled by the
kidney, one with faropenem daloxate and furosemide, a
drug excreted via the kidney tubules, and the other with
faropenem daloxate and probenecid, an inhibitor of
tubular excretion.
The furosemide study involved 11 healthy male
subjects aged 21–45 years with a bodyweight of
75–90kg. A 3-way, crossover, single-dose design was
used, with a dose of faropenem daloxate corresponding
to faropenem 300mg and 40mg of furosemide being
given, either alone or in combination. Blood samples
were collected from the subjects before dosing and at
intervals up to 12 hours after dosing. Urine samples
were collected at intervals up to 24 hours after dosing.
Only one possible drug-related adverse event,
headache, was attributed to faropenem. The AUC and
maximum plasma concentration (Cmax) of faropenem
were slightly increased when it was given concomitantly
with furosemide (AUC 25 vs 27.2 mg × h/L; Cmax 13 vs
14.7 mg/L). The AUC and Cmax of furosemide were
slightly reduced in the presence of faropenem. The half-
life of faropenem was similar when the drug was given
alone and in combination with furosemide (0.92 and
1.03 hours, respectively). The half-life of furosemide
was slightly extended when administered with
faropenem (3.01 vs 3.87 hours). These effects are not
considered sufficient to require any adjustment in
dosage when the drugs are administered concomitantly.
A 2-way crossover design was used to investigate the
effect of probenecid on the pharmacokinetics of
Inpharma 26 May 2001 No. 1289
2 Single Article
faropenem. A single dose of faropenem daloxate, » Editorial comment: Faropenem has been launched in Japan
corresponding to faropenem 300mg, was given 1 hour by Yamanouchi for the treatment of bacterial infections and
faropenem daloxate is in phase III trials for bacterial infections in
after a single 500mg dose of probenecid. A further 2
Europe with Bayer.
doses of probenecid (500mg) were given at 3 and 5
hours after the prodrug. Blood samples were collected
from the subjects before dosing and at intervals up to 24
hours after dosing with the prodrug. Urine samples were
collected at intervals up to 24 hours after dosing.
A significant, but moderate, increase in the
bioavailability of faropenem was seen when the ester
was dosed concomitantly with probenecid. The Cmax
increased from 13.4 to 17 mg/L, the half-life was
approximately doubled (1.07 hours to 2.33 hours) and
the AUC increased from 22 to 54.6 mg × h/L. These
increases are as would be expected with such a high
dose of probenecid and would not lead to an
accumulation of faropenem when the ester is dosed
twice daily. It is not therefore thought necessary to
adjust the dosage of faropenem daloxate if it is given
concomitantly with probenecid.
Effect of antacids
As the conversion by hydrolysis of the prodrug
faropenem daloxate to free faropenem is pH-dependent,
the ester was administered with a drug that affects the
intragastric pH to determine whether the absorption of
faropenem would be affected. Aluminium hydroxide/
magnesium hydroxide [‘Maalox’] is an antacid and the
effect of coadministration with the ester was determined
in a 3-way, crossover study in healthy male volunteers
aged 25–43 years with a bodyweight of 70–88kg. The
ester was given as a single dose corresponding to
300mg of faropenem and ‘Maalox’ was given as a 10ml
suspension containing aluminium hydroxide 900mg and
magnesium hydroxide 600mg. Volunteers received a
single dose of the ester, a single dose of the antacid
followed 5 minutes later by the ester, and antacid 4
times a day for 3 days after meals plus a single dose of
ester on the third day (2 hours before the first daily dose
of antacid), in a crossover fashion. Blood samples were
collected from the subjects before dosing and at
intervals up to 24 hours after dosing. Urine samples
were collected at intervals up to 24 hours after dosing.
The half-life of faropenem was not altered significantly
by coadministration of the antacid, but an approximately
20% reduction in the AUC was seen when the antacid
was administered only 5 minutes before the ester. When
the ester was dosed 2 hours apart from the antacid, the
effect was far less. The Cmax of faropenem was also
reduced by coadministration of antacid, with the
greatest effect being seen when the 2 drugs were given
within 5 minutes. These effects are not great enough to
require any adjustment in dosage.
Start boxed text
Properties of faropenem
Prodrug, faropenem daloxate, absorbed orally
Prodrug hydrolyses to release faropenem
Broad spectrum of antibacterial activity
Good stability to β-lactamases
Has little effect on normal oral and faecal flora
Excreted via the kidneys
No interactions seen with furosemide
No adjustment of dose required when co-
administered with probenecid or ‘Maalox’
End boxed text
Hunter P. Faropenem - a new oral antibacterial agent. Inpharma 1289: 13-14, 26
May 2001 800840570

Inpharma 26 May 2001 No. 1289 1173-8324/10/1289-0002/$14.95 Adis © 2010 Springer International Publishing AG. All rights reserved