Heino Stass

Novel Pharmacokinetic-Pharmacodynamic Model for Prediction of Outcomes with an Extended-Release Formulation of Ciprofloxacin

ABSTRACT The pharmacokinetics of an extended-release (XR) formulation of ciprofloxacin has been compared to that of the immediate-release (IR) product in healthy volunteers. The only significant difference in pharmacokinetic parameters between the two formulations was seen in the rate constant of absorption, which was approximately 50% greater with the IR formulation. The geometric mean plasma ciprofloxacin concentrations were applied to an in vitro pharmacokinetic-pharmacodynamic model exposing three different clinical strains of Escherichia coli (MICs, 0.03, 0.5, and 2.0 mg/liter) to 24 h of simulated concentrations in plasma. A novel mathematical model was derived to describe the time course of bacterial CFU, including capacity-limited replication and first-order rate of bacterial clearance, and to model the effects of ciprofloxacin concentrations on these processes. A “mixture model” was employed which allowed as many as three bacterial subpopulations to describe the total bacterial load at any moment. Comparing the two formulations at equivalent daily doses, the rates and extents of bacterial killing were similar with the IR and XR formulations at MICs of 0.03 and 2.0 mg/liter. At an MIC of 0.5 mg/liter, however, the 1,000-mg/day XR formulation showed a moderate advantage in antibacterial effect: the area under the CFU-time curve was 45% higher for the IR regimen; the nadir log CFU and 24-h log CFU values for the IR regimen were 3.75 and 2.49, respectively; and those for XR were 4.54 and 3.13, respectively. The mathematical model explained the differences in bacterial killing rate for two regimens with identical AUC/MIC ratios.

Single- and Multiple-dose Pharmacokinetics of Oral Moxifloxacin and Clarithromycin, and Concentrations in Serum, Saliva and Faeces

Moxifloxacin and clarithromycin are important antibacterial drugs in the treatment of community-acquired respiratory tract infections. In a double-blind, randomized, 2-period cross-over study the pharmacokinetics of moxifloxacin versus clarithromycin were determined after single and multiple doses in 12 healthy male volunteers. The concentrations of the antibiotics in serum, saliva and faeces were measured by validated high-performance liquid chromatographic methods. In serum, moxifloxacin exhibited a mean peak concentration of 3.1 ± 0.6 mg/l after a time to peak concentration of 1.67 ± 0.96 h on day 1, with a significant increase to 3.98 ± 1.10 mg/l on day 7 (p < 0.05). The area under the curve-12 revealed a highly significant increase from 28.2 ± 4.1 mg*h/l on day 1 to 39.5 ± 6.6 mg*h/l on day 7 (p < 0.01). There were also significant differences in terminal half-life between day 1 and day 7 [10.6 h (range 9.0-12.8) vs 14.9 h (range 12.6-28.1); p < 0.01] and in mean residence time (15.1 ± 1.9 vs 18.2 ± 2.4 h; p < 0.01). The concentrations of moxifloxacin in saliva were well equilibrated with serum at a relatively constant saliva-serum ratio of about 0.8. Pharmacokinetic parameters of clarithromycin and its metabolite, 14-hydroxy-clarithromycin, were similar to previously published data. Accumulation was found. No serious adverse events were observed with either study drug.

Pharmacokinetics and Tissue Penetration of Moxifloxacin in Intervention Therapy for Intra-Abdominal Abscess

AbstractBackground and objective: Intra-abdominal abscesses are usually polymicrobial and involve a variety of aerobic and anaerobic organisms. Thus, in addition to adequate drainage, empirical coverage with broad-spectrum antimicrobials is central to the management of such abscesses and an understanding of pharmacokinetic properties can be valuable when selecting antimicrobial agents. The present study examined the penetration of the fluoroquinolone antimicrobial moxifloxacin into abdominal abscess fluid in patients with an intra-abdominal abscess. Methods: This was a non-randomized, open-label, single-centre trial. Eight patients with CT or ultrasound evidence of a localized intra-abdominal abscess requiring interventional drainage without signs of generalized peritonitis were considered suitable candidates for pharmacokinetic analysis. Each patient received a single dose of moxifloxacin 400 mg by intravenous infusion. Paired samples of blood and abscess fluid were collected over 24 hours for pharmacokinetic analysis. Results: Following intravenous infusion, moxifloxacin penetrated and accumulated in intra-abdominal abscess fluid. The abscess fluid/plasma concentration ratio increased continuously from 0.083 (95% CI 0.047, 0.147) at 2 hours after administration to 1.66 (95% CI 0.935, 2.946) at 24 hours; concentrations in abscess fluid tended to exceed those in plasma after 12–24 hours. Half-life and mean residence time were longer in abscess fluid than in plasma, suggesting that moxifloxacin accumulates in abscess fluid. The abscess fluid/plasma concentration ratio continued to increase throughout the 24-hour sampling period, indicating that equilibrium between plasma and abscess fluid was not reached during this time. High intersubject variability for total moxifloxacin concentrations in intra-abdominal abscess fluid was noted, suggesting that abscess wall permeability is likely to be the parameter most strongly influencing moxifloxacin pharmacokinetics in abscess fluid. Comparison of the study results with data obtained from other in vitro studies suggested that abscess fluid concentrations above the minimum inhibitory concentrations for pathogens commonly isolated in intra-abdominal infections were maintained for approximately 8 hours after administration in this study. Conclusions: Moxifloxacin penetrates intra-abdominal abscesses after interventional drainage. Based on the pharmacokinetic data, moxifloxacin is a good candidate therapy for use in patients with intra-abdominal abscesses undergoing CT-guided percutaneous drainage and may also prove valuable in the general systemic management of intra-abdominal abscesses in the future.

Effects of Enteral Feeding on the Oral Bioavailability of Moxifloxacin in Healthy Volunteers

AbstractBackground and objective: Moxifloxacin is a new generation fluoroquinolone antimicrobial agent used worldwide. In clinical practice in intensive care units, moxifloxacin may be frequently administered through a nasogastric feeding tube. In the absence of an oral liquid formulation and since the multivalent cations contained in enterai feeds may potentially impair absorption of moxifloxacin administered via this route, we studied the effect of concomitant enterai feeding on the pharmacokinetics and tolerability of moxifloxacin administered as a crushed tablet through the nasogastric tube. Participants and methods: This was a single-centre, open-label, randomised, controlled, nonblinded, three-way crossover study. Twelve young healthy volunteers (nine females and three males) aged 20–42 years were included in the study. Each participant received three separate treatment regimens in a randomised fashion: an intact moxifloxacin 400mg tablet (regimen A, reference treatment), a crushed moxifloxacin 400mg tablet as a suspension through a nasogastric tube with water (regimen B) and a crushed moxifloxacin 400mg tablet as a suspension through a nasogastric tube with enterai feeding (regimen C). A washout period of 1-week followed each treatment. Concentrations of moxifloxacin in serum were measured by a validated high-performance liquid chromatography method. Pharmacokinetic parameters were calculated by noncompartmental methods. Additionally, the primary parameters indicative for changes in absorption (area under the serum concentration-time curve from time zero to infinity [AUC∞] and peak serum concentration [Cmax]), were tested for bioequivalence, assuming log-normally distributed data using ANOVA. Results: All moxifloxacin treatment regimens were well tolerated. The AUC∞ was slightly, but not statistically significantly, decreased in treatments with regimens B and C. AUC∞ (geometric means 39.6 [regimen A] vs 36.1 [regimen B] vs 36.1 mg · h/L [regimen C] and point estimates 91% for B: A and C: A) indicated bioequivalence of the treatments. Bioequivalence criteria of AUC∞ and Cmax were met upon retrospective statistical analysis. Likewise Cmax after moxifloxacin administration through nasogastric tube with water (regimen B) and with tube feed (regimen C) were slightly decreased (geometric means 3.20 [regimen A] vs 3.05 [regimen B] vs 2.83 mg/L [regimen C]; point estimates 88% for B: A, and 95% for C: A). They were within the range seen in other studies conducted with oral administration of the drug. No statistically significant differences were observed in time to reach Cmax (tmax; median 1.75 [regimen A] vs 1.00 [regimen B] vs 1.75 hours [regimen C]). Thus, the rate of absorption of moxifloxacin was not affected by administration through a nasogastric tube. This route of ingestion seems to be associated with a slight loss of bioavailability independent of the carrier medium used (water vs enterai feed); no clinically relevant interaction with the multivalent cations contained in the enterai feed was observed, indicating that moxifloxacin and enterai nutrition can be administered concomitantly. Conclusion: There was no clinically relevant effect of enterai feeding on the pharmacokinetics of oral moxifloxacin in healthy volunteers. This result has to be evaluated in patients, particularly those from the intensive care unit, who are characterised by severe infectious and/or concomitant diseases that might influence absorption of moxifloxacin.

Penetration and accumulation of moxifloxacin in uterine tissue

To determine whether moxifloxacin penetrates the uterine tissue and accumulates at levels sufficient to eradicate the major pathogens causing pelvic inflammatory disease (PID).

Determination of moxifloxacin anaerobic susceptibility breakpoints according to the Clinical and Laboratory Standards Institute guidelines

A summary of the key data presented to Clinical and Laboratory Standards Institute (CLSI, formerly National Committee for Clinical and Laboratory Standards) in determination of moxifloxacin anaerobic breakpoints is presented. The breakpoint analysis required review of a variety of data, including bacteriologic and clinical outcomes by MIC of anaerobic isolates from prospective clinical trials in patients with complicated intra-abdominal infections, human and animal pharmacokinetic/pharmacodynamic (PK/PD) information and in vitro models, MIC distributions of indicated organisms, and animal model efficacy data for strains with MIC values around prospective breakpoints. The compilation of the various components of this breakpoint analysis supports the US Food and Drug Administration (FDA) and CLSI moxifloxacin anaerobic breakpoints of < or =2 mg/L (susceptible), 4 mg/L (intermediate), and > or =8 mg/L (resistant), and provides information to European investigators for interpretation of MICs prior to establishment of the European Committee on Antimicrobial Susceptibility Testing breakpoints.