A. Mullie

Piperacillin: Human Pharmacokinetics After Intravenous and Intramuscular Administration

The pharmacokinetics of piperacillin were studied in a total of 26 Caucasian normal male volunteers. Single intramuscular doses of 0.5, 1.0, and 2.0 g were given to three groups, each containing eight volunteers. Mean peak serum concentrations of 4.9, 13.3, and 30.2 μg/ml were assayed at 30 to 50 min, and measurable levels were present up to 4, 6, and 8 h, respectively, after dosing. Single intravenous bolus doses of 1.0, 2.0, 4.0, and 6.0 g were given to four groups of five subjects, and mean serum concentrations of 70.7, 199.5, 330.7, and 451.8 μg/ml were measured at the end of the injections. The antibiotic had a mean terminal serum half-life of 60 to 80 min after the intramuscular doses and 36 to 63 min after intravenous administrations, depending on the dose. The apparent distribution volume was 20 to 24 liters/1.73 m2, and distribution volume at steady state was 16 to 19 liters/1.73 m2. Mean urinary recovery in 24 h was 74 to 89% for the intravenous doses and 57 to 59% for the intramuscular doses. The piperacillin-creatinine clearance ratios indicated that the proportion of renal excretion of piperacillin through tubular secretion was 56 to 73%, and this was confirmed by the renal clearance data from eight volunteers receiving probenecid treatment before the piperacillin dose. Probenecid (1 g given orally before administration of piperacillin) increased peak serum concentration by 30%, terminal serum half-life by 30%, and the area under the plasma concentration curve by 60%, and it decreased the apparent distribution volume by 20% and the renal clearance of the intramuscularly administered (1 g) antibiotic by 40%. Injections of piperacillin by both parenteral routes were well tolerated.

Comparative pharmacokinetics of ceftazidime and moxalactam.

The pharmacokinetics of ceftazidime and moxalactam were compared after intravenous and intramuscular administration of single 1-g doses to eight healthy volunteers in a crossover study. The bioavailability of the antibiotics after administration by either route was almost complete. Both drugs had similar areas under the serum curves. Significant differences between ceftazidime and moxalactam were observed with respect to the apparent volume of distribution (18.4 and 24.1 liters, respectively), to the terminal half-life (1.6 versus 2.0 h), and to urinary recovery of the active compound (96 versus 79%). Ceftazidime was almost completely eliminated by renal excretion (greater than 96%), whereas about 20% of the moxalactam was eliminated by nonrenal mechanisms. The concentrations of ceftazidime and moxalactam in serum after a 1-g dose exceeded the concentrations required to inhibit 90% of the Enterobacteriaceae for about 8 and 10 h, respectively. The levels of ceftazidime and moxalactam in serum exceeded the 90% minimal inhibitory concentration of Pseudomonas aeruginosa for about 6 and 1 h, respectively.

Comparative Multiple Dose Kinetics of two Formulations of Indomethacin

SummaryThe kinetics of a controlled release (CR) formulation of indomethacin 75 mg (Indocid-Retard®) given once daily was compared with a conventional 25 mg indomethacin capsule (Indocid®) given 3 times daily for 7 days, to 14 healthy volunteers, using a randomized, cross-over, multiple-dose study design. The following differences in plasma indomethacin profiles after the 2 treatments were observed: average peak concentrations (Cmax) for the CR regimen were higher and the time to peak (Tmax) was significantly delayed. Trough (pre-morning dose) plasma concentrations (Cmin) on Days 2, 5, 6 and 7 were significantly lower after the CR-formulation. No statistically significant differences between preparations for area under the plasma concentration time curve (AUC0–24h) or for renal clearance were observed. Average steady-state plasma concentrations (Cpss) on Day 7 of the multiple dose regimens averaged 0.477 and 0.427 µg/ml for the 75 mg CR once daily and the conventional 25 mg t.i.d. treatments, respectively. These results show that the bioavailability of the CR and conventional indomethacin formulations under these multiple-dose conditions was not significantly different.

Relative Bioavailability of Enteric Coated Pellets, Stearate and Ethylsuccinate Formulations of Erythromycin

In a randomized three-phase crossover study, 12 healthy male volunteers were given three 12-hourly 500-mg doses of erythromycin base, as enteric coated pellets in capsules (2 X 250 mg), erythromycin stearate tablet (1 X 500 mg), or erythromycin ethylsuccinate sachet (1 X 500 mg). The reaction time after administration of the pellets is significantly longer than after the stearate or ethylsuccinate formulations. The peak serum concentrations are higher for the pellets after both the 1st and 3rd dose. The time to reach peak concentrations is significantly longer for the pellets than for the stearate and ethylsuccinate formulations. The area under the serum concentration/time curve during 0-8 h after both doses is highest for the pellets. In conclusion, these findings indicate that despite the longer lag (1.8-1.2 h), the extent of gastrointestinal absorption and bioavailability of erythromycin is apparently greater for the base pellets than for the stearate and ethylsuccinate formulations.

Comparative study of in vitro antimicrobial activity and human pharmacokinetics of dibekacin and tobramycin.

SummaryThe in vitro activity of dibekacin, a new aminoglycoside, has been compared to that of tobramycin and other antibiotics, against over 500 clinical isolates of Enterobacteriaceae, Pseudomonas and staphylococci. The activity of dibekacin was similar to that of tobramycin. About 40 % of the gentamicinresistant Enterobacteriaceae remained susceptible to dibekacin.A pharmacokinetic cross-over study of dibekacin and tobramycin was conducted in 6 healthy volunteers. After IV bolus injection and IM administration of single doses of 75 mg the pharmacokinetic parameters of both aminoglycosides appeared to be very similar: half-life times between 1.9 and 2.0 h, mean peak serum levels of 2.5 and 2.3 ug/ml after IM administration with a bio-availability of 100%, and a mean urinary recovery in 24 h between 72 % and 84 % of the dose.