Pharmacokinetics (PK) of Tigecycline (TG) in Healthy Adult Volunteers and in Subjects with Renal Impairment

Conference: ECCMID
Division: Cognigen


Background: TG is a novel glycylcycline antibiotic with an expanded spectrum of activity, which includes gram-positive, gram-negative, atypical, and anaerobic pathogens. TG has also shown activity against pathogens resistant to other antibiotics. The goal of this analysis is to summarize the PK of intravenous TG in healthy volunteers and subjects with renal impairment.

Methods: PK data have been collected and analyzed using noncompartmental methods for 174 subjects in 5 Phase I studies: 3 single intravenous dose (SD) and 2 multiple intravenous dose (MD) studies. This included 6 subjects with severe renal impairment (CrCl<30mL/min) and 8 subjects with end stage renal disease (ESRD) receiving hemodialysis (HD). Doses ranged from 12.5 mg to 300 mg in SD and 25 mg to 100 mg q12h in the MD studies. TG was given under both fasting and fed conditions. Plasma and urine samples were collected and analyzed using validated HPLC or LC/MS/MS methods. PK parameters, including maximum plasma concentration (Cmax), half-life (t1/2), area under the concentration-time curve (AUC), total clearance (CLt), and volume of distribution at steady state (Vss), were calculated.

Results: The plasma concentration-time profile was characterized by a steep decline in the distribution phase during the first 2 hours, followed by a slower terminal phase. Steady state was reached in ~3 days. Healthy volunteer PK values are listed in Table 1. With multiple doses, both Cmax and AUC increased roughly in proportion with dose. CLr accounted for ~20% of CLt and less than 13% of TG was excreted unchanged in urine. CLt was reported to be reduced by ~20% in subjects with severe renal impairment or ESRD. TG was not removed by HD. Results of an SD age and gender study concluded Cmax was lowest in young men and highest in elderly women (26% difference) and AUC was higher in young women than in young men (21% difference), with only a 4% difference between elderly women and men. At the target clinical dose of 100 mg load infused over 30-60 min followed by 50 mg q12h, Cmax and AUCss (mean ± stdev) were 621±93 ng/mL and 3069±381 ng.h/mL, respectively.

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 currently being developed for the treatment of complicated skin/soft tissue and intra-abdominal infections.

European Congress of Clinical Microbiology and Infectious Disease (ECCMID), Prague, Czech Republic, May 2004

By AK Meagher, BB Cirincione, KA Liolios, S Troy, and PG Ambrose