Progress in Pharmacokinetics and Pharmacodynamics - I
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274 Abstracts Progress in pharmacokinetics and pharmacodynamics - I P1022 Pharmacokinetics of telithromycin in plasma and was higher in young women than in young men (21% difference), soft tissue after single-dose administration in healthy volunteers with only a 4% difference between elderly women and men. At the target clinical dose of 100 mg load infused over 30–60 min fol- R. Gattringer, F. Traunmueller, E. Urbauer, M. Zeitlinger, lowed by 50 mg q12h, Cmax and AUCss (mean Æ SD) were M. Mueller, C. Joukhadar 621 Æ 93 ng/mL and 3069 Æ 381 ng h/mL, respectively. Vienna, A Objectives: Telithromycin was described to reach high concentra- Dose (mg), with MD given q 12h tions levels in inflammatory fluid, in bronchopulmonary tissues and in tonsillar tissue. Because of these data telithromycin is spe- Pk parameter 12.5 25 50 75 100 200 300 culated to be a new option in the therapy of skin and soft tissue infections. To determine the concentration of telithromycin in the SD CLt 0.29 Æ 0.20 0.20 Æ 0.10 0.28 Æ 0.04 0.29 Æ 0.04 0.30 Æ 0.08 0.23 Æ 0.04 0.25 Æ 0.03 interstitial space fluid, the pharmacokinetics of this new antibiotic (L/hr/kg) (n ¼ 6) (n ¼ 6) (n ¼ 6) (n ¼ 6) (n ¼ 57) (n ¼ 24) (n ¼ 12) were assessed after single dose administration in young healthy MD CLt ÁÁÁ 0.20 Æ 0.04 0.20 Æ 0.02 ÁÁÁ 0.24 Æ 0.045 ÁÁÁ ÁÁÁ (L/hr/kg) (n ¼ 5) (n ¼ 5) (n ¼ 3) volunteers by the use of microdialysis. SD AUCÒ 753 Æ 515 2255 Æ 1023 2558 Æ 534 3658 Æ 1003 4872 Æ 1405 1321 Æ 2796 17294 Æ 2176 Methods: Plasma- and extracellular samples (subcutaneous adi- (ng h/mL) (n ¼ 6) (n ¼ 6) (n ¼ 6) (n ¼ 6) (n ¼ 57) (n ¼ 24) (n ¼ 12) MD AUCÒ ÁÁÁ 1482 Æ 259 3069 Æ 381 ÁÁÁ 4980 Æ 925 ÁÁÁ ÁÁÁ pose tissue a. skeletal muscle) were taken from 10 healthy male (ng h/mL) (n ¼ 5) (n ¼ 5) (n ¼ 3) volunteers by a venous catheter (plasma) and by microdialysis SD t½(h) 11 Æ 10 32 Æ 20 18 Æ 3.6 22 Æ 5.3 22 Æ 10 52 Æ 12 44 Æ 7.8 (soft tissue) every 20 min over a period of 8 h after administration (n ¼ 6) (n ¼ 6) (n ¼ 6) (n ¼ 6) (n ¼ 57) (n ¼ 24) (n ¼ 12) MD t½(h) ÁÁÁ 49 Æ 35 37 Æ 12 ÁÁÁ 66 Æ 23 ÁÁÁ of 800 mg telithromycin. Telithromycin was analysed by a HPLC (n ¼ 5) (n ¼ 5) (n ¼ 3) method. SD Vss 2.8 Æ 0.95 6.4 Æ 1.3 6.5 Æ 2.0 7.5 Æ 0.77 6.8 Æ 2.5 13 Æ 3.3 12 Æ 2.4 (L/kg) (n ¼ 6) (n ¼ 6) (n ¼ 6) (n ¼ 6) (n ¼ 57) (n ¼ 24) (n ¼ 12) Results: The mean telithromycin AUC for plasma was MD Vss ÁÁÁ 4.0 Æ 1.2 2.4 Æ 0.66 ÁÁÁ 2.9 Æ 1.4 ÁÁÁ ÁÁÁ 247.8 mg h/L. For muscle tissue and subcutis a mean AUC of (L/kg) (n¼5) (n¼5) (n¼3) 34.97 and 52.35 mg h/L, respectively, could be found. The mean SD CmaxÒ 109 Æ 11 252 Æ 63 383 Æ 64 566 Æ 78 927 Æ 224 1787 Æ 525 2817 Æ 479 after 1 hr (n ¼ 6) (n ¼ 6) (n ¼ 6) (n ¼ 6) (n ¼ 57) (n ¼ 18) (n ¼ 6) Cmax of plasma, subcutis and muscle was 1.23, 0.18 and infusion 0.16 mg/L, respectively. (ng/mL) Conclusion: A once daily dose of 800 mg telithromycin achieves MD CmaxÒ ÁÁÁ 324 Æ 54 621 Æ 93 ÁÁÁ 1173 Æ 176 ÁÁÁ ÁÁÁ after 1 hr (n ¼ 5) (n ¼ 5) (n ¼ 3) concentrations in the interstitial space fluid which are sufficient to infusion eradicate highly sensible pathogens like S. pyogenes but the dosage (ng/mL) may lead to a therapeutic failure in treating infections caused by bacteria exceeding a MIC of 0.18 mg/L. Conclusions: TG exhibited approximate linear PK across all dose ranges evaluated in multiple-dose studies. TG has a long t1=2 with a high Vss, indicating extensive tissue distribution. PK parameters were not significantly affected by food, age, or gender. TG is cur- P1023 Pharmacokinetics of tigecycline in healthy adult rently being developed for the treatment of complicated skin/soft volunteers and in subjects with renal impairment tissue and intra-abdominal infections. A. Meagher, B. Cirincione, M. Piedmonte, S. Troy, P.G. Ambrose Buffalo, Phildelphia, USA Background: TG is a novel glycylcycline antibiotic with an expan- P1024 Comparative pharmacodynamics of ABT492 and ded spectrum of activity, including Gram-positive, Gram-negative, ciprofloxacin (CIP) with Escherichia coli and Pseudomonas atypical and anaerobic pathogens. TG has also shown activity aeruginosa in an in vitro dynamic model against pathogens resistant to other antibiotics. The goal of this analysis is to summarise the PK of TG in healthy volunteers and I. Lubenko, A. Firsov, S. Vostrov, I. Alferova, Y. Portnoy, subjects with renal impairment. S. Zinner Methods: PK data have been collected and analysed using non- Moscow, RUS; Cambridge, USA compartmental methods for 144 subjects in four Phase 1 studies: three single IV dose (SD) and one multiple IV dose (MD) studies. Objective: To compare the pharmacodynamics of ABT492 relative This included six subjects with severe renal impairment to CIP, the kinetics of killing of Gram-negative organisms were (CrCl < 30 mL/min) and eight subjects with end stage renal dis- studied using a dynamic model that simulates human pharmaco- ease (ESRD) receiving haemodialysis (HD). Doses ranged from kinetics of the fluoroquinolones. 12.5 to 300 mg in SD and from 25 to 100 mg q12h in the MD Methods: Clinical isolates of E. coli and P. aeruginosa (MICABTs study. TG was given under both fasting and fed conditions. 0.01 and 0.12; MICCIPs 0.01 and 0.19 mg/L, respectively) were Plasma and urine samples were collected and analysed using vali- exposed to bi-exponentially decreasing concentrations of ABT492 dated HPLC or LC/MS/MS methods. PK parameters, including (T1/2, alpha 2.1 h, T1/2, beta 23 h) and mono-exponentially maximum plasma concentration (Cmax), half-life (t1=2), area under decreasing concentrations of CIP (T1/2 4 h). Single dose simula- the concentration-time curve (AUC), total clearance (CLt), renal tions were performed with ABT492 vs. two 12-h doses CIP at dif- clearance (CLr), and volume of distribution (Vss), were calculated. ferent ratios of the area under the curve (AUC) to MIC, which Results: The plasma concentration-time profile was characterised varied from 60 to 480 h. Both E. coli and P. aeruginosa were also by a steep decline in the distribution phase during the first 2 h, exposed to the clinically achievable AUC/MIC ratios of ABT492 followed by a slower terminal phase. Steady state was reached in (1740 and 140 h, respectively) and CIP (2200 and 120 h, respect- 3 days. Healthy volunteer PK values listed in the table below ively) that correspond to a 400-mg dose of ABT492 and two are mean Æ SD. With multiple doses, both Cmax and AUC 500-mg doses of CIP. In addition, an 800-mg dose of ABT492 was increased roughly in proportion with dose. CLr accounted for simulated against P. aeruginosa as a single dose (AUC/MIC 280 h) 20% of CLt and less than 13% of TG was excreted unchanged and as two 400-mg doses given with a 12-h interval (AUC/MIC in urine. CLt was reduced by 20% in subjects with severe renal 2 Â 140 h). impairment or ESRD. TG was not removed by HD. Results of an Results: The maximal reductions in the starting inoculum of anti- SD age and gender study concluded Cmax was lowest in young biotic-exposed E. coli and P. aeruginosa were greater with ABT492 men and highest in elderly women (26% difference) and AUC than with CIP at most of the simulated AUC/MICs, but the times Clinical Microbiology and Infection, Volume 10, Supplement 3, 2004 275 to regrowth were shorter with ABT492. Species-independent the treatment of ‘difficult-to-treat‘ nosocomial infections. The pur- AUC/MIC relationships of the intensity of the antimicrobial effect pose of this study was to assess the pharmacodynamic activity of (IE – area between the control growth and the time-kill/regrowth Iclaprim using an in vitro pharmacodynamic model (IVPM) curves) were specific for ABT492 and CIP. Despite greater IEs against S. pneumoniae collected from across Canada. produced by CIP at a given AUC/MIC ratio (from 120 to 480 h), Methods: Six S. pneumoniae isolates with varying susceptibilities to the effect of the clinically achievable AUC/MIC of ABT492 penicillin, erythromycin, levofloxacin, trimethoprim/sulfameth- (1740 h) on E. coli was more pronounced than the respective oxazole and Iclaprim. The IVPM was inoculated with AUC/MIC of CIP (2200 h). With P. aeruginosa, a 140-h AUC/MIC 1 Â 106 CFU/ml and Iclaprim was dosed at 0 and 12 h to simu- of ABT492 (400 mg as a single dose) provided an 1.8-fold smaller late a Cpmax of 3.5 lg/mL and t1=2 of 3 h. Sampling was per- IE than a 120-h AUC/MIC of CIP. However, two 12-h doses of formed over 24 h to assess viable growth.