Evaluation of tigecycline penetration into colon wall tissue and epithelial lining fluid using a population pharmacokinetic model and Monte Carlo simulation

Abstract number: o360

Rubino  C.M., Ma  L., Bhavnani  S.M., Korth-Bradley  J., Speth  J., Ellis-Grosse  E.J., Ambrose  P.G., Drusano  G.L.

Objectives: 

To assess the penetration of tigecycline into colon wall tissue and epithelial lining fluid (ELF).

Methods: 

These analyses included data from patients without infection (Phase 1) and those with intra-abdominal infections (Phase 2/3).All patients received a 100 mg loading dose, followed by 50 mg every 12 hours of intravenous tigecycline in ELF and Phase 2/3 patients only.Steady-state serum samples were collected from all patients (n = 577), while colon wall and ELF specimens were obtained from patients without infection (n = 23 and n = 30, respectively). Separate models were created for ELF and colon wall tissue. For both models, tissue and serum data were simultaneously co-modelled using BigNPAG, and distinct three-compartment, open models with zero-order IV input and first-order elimination was employed. To examine the full range of tissue penetration and their associated probabilities, two 9,999 subject Monte Carlo simulations were performed, one for ELF and one for colon wall.

Results: 

Data were well fit using models described above with all r2 values above 0.94. Results of the Monte Carlo simulations, tigecycline exposure and penetration into serum, colon wall tissue, and ELF stratified by infection status, are presented in the table below. For patients without infection, the median colon wall and ELF penetration ratios were 1.3 and 0.43, respectively (see Table). Estimates of colon wall penetration were higher, 2.6, in patients with intra-abdominal infection, most likely due to tissue inflammation.

Conclusion: 

Simulation results indicate that tissue penetration varies considerably by patient, and likely explains unexpected clinical outcomes for those patients infected with strains at margins of the minimum inhibitory concentration (MIC) distribution.