Serum and urine pharmacokinetics of tigecycline in obese class III and normal weight adults

Objectives: To compare the serum and urine pharmacokinetics (PK) of intravenous tigecycline in obese class III (obese-C-3) adults with those in normal weight (NW) adults. Patients and methods: Obese-C-3 (n = 8) and NW (n = 4) healthy adult volunteers received a single intravenous dose of 100 mg of tigecycline for 30 min. Serum (0-96 h) and urine (0-48 h) tigecycline concentrations were assayed by liquid chromatography with tandem mass spectrometry. Parametric population PK systems analyses were used to model the data and assess the effects of total body weight (TBW) on PK parameters. The area under the concentration-time curve extrapolated to infinity (AUC(0-infinity)) was simulated to estimate the probability of AUC(0-infinity): MIC target attainment and cumulative fraction of response (CFR) based on wild-type MIC distributions of select pathogens. Clinicaltrials.gov: NCT01560143. Results: The median (range) age, TBW and initial body mass index were 42 (20-50) years, 121 (61-160) kg and 43.8 (20.8-53.8) kg/m(2), respectively. The serum concentration-time profiles and exposures were similar in the obese-C-3 and NW adults, with a mean urine recovery of 15.8% and 13.4%, respectively. The median (range) AUC(0-infinity) was 8.19 (6.12, 11.2) and 7.50 (6.78, 9.13) mg.h/L in the obese-C-3 and NW groups, respectively. The clearance of tigecycline was not related to TBW. The CFR was calculated to be <90% against Acinetobacter baumannii, Enterobacter cloacae and Klebsiella pneumoniae for an AUC(0-infinity): MIC target >= 6.96. Conclusions: The serum and urine PK of tigecycline is similar in obese-C-3 and NW healthy adults. A lower CFR is predicted against certain Gram-negative pathogens with the current standard tigecycline dosing regimen, irrespective of TBW.