Pharmacokinetics of Faropenem
DESCRIPTION
Faropenem (C12H15NO5S, MW 285.32) is a penem-class oral b-lactam antimicrobial agent. Although faropenem is structurally similar to the carbapenems, it is distinguished by a sulphur atom at position 1. In Japan, faropenem has been available since 1997 as faropenem sodium hydrate (Faroms) (C12H14NNaO5S21/2H2O; molecular weight, 352.34), whereas in the USA, faropenem is in phase III clinical trials as the ester prodrug, faropenem medoxomil (also known as faropenem daloxate) (C17H19NO8S; molecular weight, 397.40). Faropenem is notable because it is one of the few carbapenem-like agents that can be given orally.
Faropenem is effective against common community-acquired pathogens, such as Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, methicillin-susceptible Staphylococcus aureus (MSSA), other streptococci, E. coli, and anaerobes. However, faropenem is not active against methicillin-resistant S. aureus (MRSA), Enterococcus faecium, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia, and it tends to show relatively high MICs to Enterococcus faecalis and some Enterobacteriaceae. Faropenem has bactericidal activity by way of its interaction with penicillin-binding proteins (PBPs) like all other b-lactam antibiotics.
MECHANISM OF DRUG ACTION
The activity of faropenem against bacteria is determined by its binding to PBPs as with other b-lactams. Dalhoff et al. (2003b) studied the affinity of faropenem to various PBPs in S. aureus, E. coli, P. vulgaris, P. aeruginosa, S. marcescens, S. pneumoniae, and E. faecalis. Faropenem exhibited higher affinity to the high molecular weight PBPs (PBP1, 2, and 3) than to the low molecular weight PBPs (PBP4, 5, and 6) in most bacteria, with the exception of P. vulgaris, S. marcescens, and E. faecalis.
PHARMACOKINETICS AND PHARMACODYNAMICS
Bioavailability
The bioavailability of faropenem sodium is proposed to be 20–30%. Faropenem is approximately 90–95% bound to serum proteins. The half-life of faropenem sodium is approximately 0.8 hours. Administration of faropenem sodium under fasting and postprandial conditions resulted in no significant difference in Cmax and AUC.
Orally administered faropenem medoxomil is readily absorbed. The addition of the medoxomil ester to the faropenem moiety improves bioavailability. The bioavailability of faropenem medoxomil is proposed to be 70–80%, which is approximately four times that of faropenem sodium. The half-life of faropenem medoxomil is estimated to be 0.9 hours. Administration of faropenem medoxomil under fasting and postprandial conditions resulted in no significant difference in Cmax and AUC.
Drug interactions
In more than ten years’ clinical experience of faropenem sodium, no drug interactions have been reported. Possible drug interactions with faropenem medoxomil have been investigated in human studies. Compounds investigated included probenecid, furosemide, digoxin, theophylline, warfarin, cholestyramine, ranitidine, aluminium–magnesium hydroxide, and hormonal contraceptives. None of those compounds, except probenecid, had significant interactions. Probenecid extends exposure to faropenem, but it remains within the limits deemed safe.
Excretion
Faropenem is eliminated mostly via active renal tubular secretion and
has an estimated renal clearance of 27–43 ml/min. Approximately 14–20% of faropenem doses have been recovered in urine. Renal dihydropeptidase-I (DHP-I) hydrolyzes some faropenem to the inactive metabolites, M-1 and M-2. However, the concentrations of these metabolites in plasma were significantly lower than faropenem (Schurek et al., 2007).
TOXICITY
Gastrointestinal adverse events
The most common adverse events during treatments by faropenem are gastrointestinal, such as diarrhea, nausea, and vomiting. However, the frequency of those events (15%) was similar to the comparators, including penicillin, amoxicillin, amoxicillin–clavulanate, cephalexin, cefuroxime axetil, cefpodoxime, clarithromycin, azithromycin, and TMP-SMX (Schurek et al., 2007). 6b.
Hypersensitivity reactions
The frequency of hypersensitivity reactions to faropenem medoxomil or faropenem sodium is not yet clear. Cross-reactivity of faropenem to other b-lactams, such as penicillin, is possible, but its frequency has not been defined. 6c.
Fetal toxicity
There are no data in humans regarding fetal toxicity, but animal experiments show no teratogenicity (Maruho, 2008).
