Pharmacokinetic/pharmacodynamic serum and urine profile of cefditoren following single-dose and multiple twice- and thrice-daily regimens in healthy volunteers: a phase I study.

The objectives of this randomized, double-blind study were to evaluate the pharmacokinetics, and the pharmacodynamic and gastrointestinal (GI) tolerance of cefditoren pivoxil in healthy adult male volunteers when it is administered three times a day. Twenty healthy volunteers were included in the study. On day 1, 10 subjects received a 200-mg single dose of cefditoren pivoxil and 10 received a 400-mg dose. After a washout period of 8 days, eight subjects received cefditoren pivoxil 400 mg b.i.d., eight received 400 mg t.i.d., and four received placebo for 10 days. Medication was taken 30 min after meals. Blood and urine collections were carried out on days 1, 9, 14 and 19. Volunteers were asked about any GI change, especially about bowel habits, nausea, vomiting and abdominal pain. The maximum cefditoren concentration (C(max)) had a mean value of 3.77+/-0.66 mg/l, and was reached between 1.5 and 3 h in the thrice-daily administration. In the twice-daily regimen, the C(max) was 3.27+/-0.64 mg/l. The mean time above breakpoint minumum inhibitory concentration (MIC), calculated with data from each pharmacokinetic profile, was always above 40%, in both the twice- and thrice-daily regimens. The half-life of cefditoren was 1.19+/-0.2 h and 1.36+/-0.2 h in the twice-daily and thrice-daily regimens, respectively. The C(max) of cefditoren in urine was reached between 2 and 4 h postadministration, with a mean value of 154.53 mg/l in the twice-daily regimen, and 186.59 mg/l in the thrice-daily administration. There were no differences between the groups in the incidence of GI adverse events. The present data show that the administration of cefditoren pivoxil 400 mg t.i.d. is possible because it is well tolerated, and it increases the probability of success when the MIC of the causative bacteria is close to the susceptibility breakpoint. The high concentrations of active drug in the urine enable cefditoren to be considered as a useful candidate for the treatment of uncomplicated urinary tract infections (UTIs).