Safety and pharmacokinetics of CS-834, a new oral carbapenem antibiotic, in healthy volunteers.
CS-834, (+)-[pivaloyloxymethyl (4R,5S,6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(R)-5-oxopyrroli din-3-yl]thio]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate], is an ester-type oral carbapenem prodrug, and an active metabolite is R-95867, which has antibacterial activity. CS-834 was administered orally to healthy male volunteers at single doses of 50, 100, 200, and 400 mg and at a multiple dose of 150 mg three times a day for 7 days to investigate its safety and pharmacokinetic profiles. Other studies were conducted to examine the effect of food intake on the bioavailability of CS-834 and also the effect of the coadministration of probenecid on the pharmacokinetics of CS-834. In the fasting state, the concentration of R-95867 in plasma reached maximum levels from 1.1 to 1.7 h after the oral administration of CS-834, followed by a monoexponential decrease. The maximum concentrations of R-95867 in serum (C[max]s) after the administration of CS-834 at doses of 50, 100, 200, and 400 mg were 0.51, 0.97, 1.59, and 2.51 microg/ml, respectively. The half-lives (t1/2s) were almost constant, approximately 0.7 h. The areas under the concentration-time curves (AUCs) were proportional to the doses, ranging from 50 to 400 mg x h/ml. The cumulative recoveries in urine were approximately 30 to 35% until 24 h after drug administration. The C(max), AUC, t1/2, and recovery in urine were not affected by food intake. Probenecid coadministration prolonged the t1/2, and it increased the C(max) and AUC for R-95867 by approximately 1.5- and 2.1-fold, respectively. The multiple-dose study showed no change in the pharmacokinetics from those for the single doses and no drug accumulation in the body. A mild transient soft stool was observed in one volunteer in the study with a single dose of 400 mg. In the multiple-dose study, mild transient soft stools were observed in six volunteers, one volunteer had mild transient diarrhea, and one volunteer had elevated serum glutamic oxalacetic transaminase and serum glutamic pyruvic transaminase levels (1.4- and 2.8-fold compared with the upper limits of normal, respectively). There were no other abnormal findings for objective symptoms or laboratory findings, including blood pressure, heart rate, electrocardiogram, body temperature, hematology, blood chemistry, and urinalysis.