Purpose: Tigecycline is a novel glycylcycline antibiotic with expanded broad-spectrum in vitro activity, including emerging multidrug-resistant pathogens. The goal of this analysis was to develop a PPK model for tigecycline in patients with complicated skin and skin-structure infections (cSSSI) or complicated intra-abdominal infections (cIAI) in Phase 2 studies and generate steady-state AUC0-12 values for use in exposure-response analyses of safety and efficacy.
Methods: A population PK model was developed using pooled data from two Phase 2 studies in patients with cSSSI or cIAI. Tigecycline was infused over 1 hr as either a 100-mg or 50-mg loading dose followed by either 50 or 25 mg every 12 hr for up to 14 days. Serial blood samples were collected to determine steady-state serum tigecycline concentrations using LC/MS/MS. Both 2- and 3-CMT models were evaluated using NONMEM®. Patient covariates were evaluated to explain interindividual variability in PK using stepwise forward selection (α = 0.05) and backward elimination (α = 0.001). The final model was used to generate individual tigecycline steady-state AUC0-12 values, which were assessed for bias (PE%) and precision (|PE|%) relative to noncompartmental estimates.
Results: A 2-CMT model with zero-order input and first-order elimination best described the steady-state tigecycline concentration-time data. Tigecycline clearance was increased with creatinine clearance, weight, and for male gender. Mean (SD) steady-state AUC0-12 values for the 25-mg and 50-mg dose groups were 1.34 (0.5) and 2.70 (0.8) mg⋅hr/L, respectively. Creatinine clearance had the largest apparent impact on the PK of tigecycline; AUC0-12 values were 31% to 48% higher across dose groups in patients with moderate or severe renal impairment relative to normal values. AUC0-12 was unbiased (median PE% ± 2%) and acceptably precise (median |PE|% < 10%).
Conclusions: A population PK model was developed to characterize steady-state tigecycline concentration-time data and to determine the impact of various patient covariates on the PK of tigecycline. Steady-state tigecycline exposures were obtained in the current Phase 2 patient population, and the model is available to estimate steady-state AUC0-12 in future Phase 3 trials.
Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Washington, DC, December 2005
By Scott A. Van Wart, Joel S. Owen, Alison K. Meagher, and Brenda B. Cirincione