Pharmacokinetics of FCE 22891, a new oral penem

Abstract

FCE 22891 is the oral prodrug of FCE 22101, a new broad-spectrum penem. The pharmacokinetics of FCE 22891 after single-dose administration, its absolute bioavailability, and the effect of food intake on its absorption were investigated in three different randomized crossover studies in healthy volunteers. Drug levels in blood and urine were measured by high-pressure liquid chromatography and bioassay. For optimal comparison of the results of all studies, and since there was good agreement of both methods, only the high-pressure liquid chromatography results are included. The pharmacokinetics of the penem were linear, and its bioavailability after oral administration was 42 ± 11%. Food intake increased the total area under the curve from 0 h to infinity from 11.9 ± 3.5 to 14.1 ± 2.4 mg. h/liter. A specffic side effect, i.e., bladder complaints, was registered in some volunteers taking FCE 22891 at doses -1.0 g.

Pharmacokinetics of [14C]FCE 22891, a penem antibiotic, following oral administration to healthy volunteers

“…The pharmacokinetic parameters of FCE 22101 obtained in the present study after oral administration of its prodrug FCE 22891 are in good agreement with those reported previously (7,9,13). Recovery of radioactivity in this study was almost complete, because about 90 to 95% of the dose (3a).…”

“…This is in agreement with the limited intersubject variabilities in AUCs observed after intravenous administration of FCE 22101 (7,9,13). The variabilities in CLR and urinary excretion of FCE 22101 observed after intravenous administration reflect intersubject differences in the metabolic activity of renal DHP-I.…”

“…Its absolute bioavailability as FCE 22101 is about 30 to 40% (7,9,13). FCE 22891 is rapidly hydrolyzed to FCE 22101 in vivo; no detectable unchanged FCE 22891 is found in human plasma or urine, even when samples are collected over potassium fluoride to inhibit ex vivo hydrolysis (12).…”

“…The pharmacokinetics of FCE 22891 in humans have been studied following different single doses ranging from 500 mg to 2 g (7,9,12,13), following repeated administration of 500 mg to 1 g (1), and after food intake (9). Its absolute bioavailability as FCE 22101 is about 30 to 40% (7,9,13).…”

Clinical and bacteriological efficacy and tolerability of FCE 22891 in patients with exacerbations of chronic obstructive pulmonary disease

“…This was the maximum dosage which was tolerated well when given to healthy individuals in multiple administrations. Moreover, pharmacokinetic studies showed an acceptable bioavailability after a single oral administration of 1 g of FCE 22891 (20).Symptoms were assessed before, during (days 4 and 8), and after (day 11) treatment and during follow-up (day 18) by the same investigator (S.P.). The severity of symptoms (dyspnea, cough, rales, signs of bronchial obstruction, and sputum production) was scaled from 0 to 2 (absent, mild, and severe).…”