Pharmacokinetics of FCE 22101 in man following different modes of administration

Twelve healthy volunteers received single iv doses of either 500 and 1000 mg or 750 and 1500 mg of the sodium salt of FCE 22101; in addition, five of the volunteers received a further dose of 2000 mg. In the second part of the study, 11 of the volunteers received 1000 mg doses of FCE 22101 in a four-way randomized fashion by iv bolus (1000 mg, with and without probenecid), im injection (1000 mg plus lignocaine) and a continuous infusion (280 mg/h) to steady state. All doses were well tolerated by the volunteers with no serious side effects and no significant haematological or biochemical changes following drug administration. Plasma and urine concentrations of FCE 22101, and in the cross-over study also its open ring metabolites P1 and P2, were determined by HPLC. Good linearity was observed between the peak plasma levels or AUC and the dose given. Plasma concentrations were fitted to a two-compartment model and the mean pharmacokinetic parameters determined after iv bolus were: Cmax 117 mg/l, T1/2 beta 36 min, Vss 181, AUC 2179 mg/min/l with urinary recoveries of FCE 22101 37%, P1 36% and P2 6%. With probenecid the values were Cmax 116 mg/l, T1/2 beta 47 min, Vss 141, AUC 4540 mg/min/l and urinary recoveries of FCE 22101 20%, P1 40% and P2 7%. Following im injection the mean values were Cmax 15 mg/l, Tmax 30 min, T1/2abs 14 min, T1/2 beta 61 min, AUC 2117 mg/min/l and urinary recoveries of FCE 22101 33%, P1 37% and P2 6%. At steady state during continuous infusion, mean values were Css 12.7 mg/l, Vss 131 and T1/2 beta after steady state was 22 min. Although urinary recoveries varied widely between volunteers there was a tendency towards consistency of recovery within individual volunteers. We conclude that FCE 22101 is a well tolerated penem with pharmacokinetic properties broadly similar to those of other penem and carbapenem antibiotics.