Noncompartmental Pharmacokinetics of Tigecycline in Phase 3 Studies of Patients with Complicated Skin and Skin-Structure and Intra-Abdominal Infections

Authors: Darling IM, Cirincione B, Owen JS
Conference: ICAAC
Keywords: anti-infectives, antibiotic, cIAI, cSSSI, dermatology, infectious disease, intravenous, IV, noncompartmental, steady state, WinNonlin
Division: Clinical Pharmacology and Pharmacometrics (CPP)

Abstract

Purpose: Tigecycline is the first glycylcycline to reach Phase 3 clinical trials and is active against multidrug-resistant organisms. Four Phase 3 studies have examined tigecycline for the treatment of complicated skin and skin-structure (cSSSI) and intra-abdominal infections (cIAI). Pharmacokinetics (PK) of multiple-dose tigecycline in subsets of patients with cSSSI and cIAI from three of these studies have been examined and compared.

Methods: cSSSI and cIAI were studied separately. Patients received a loading dose infusion of tigecycline (100 mg) followed by 50 mg every 12 hr for up to 14 days. Infusion durations were 0.5 hr (cIAI) or 1 hr (cSSSI). Four blood samples for PK analysis were obtained on the day of or the day before discharge from the hospital. Samples were collected before start of infusion, at the end of infusion, and 3 and 6 hr after start of infusion. Serum was analyzed by LC/MS/MS. Css,max, Css,min, AUCss, and clearance (CL) were calculated using noncompartmental methods.

Results: A total of 122 patients were included in the PK analysis of the three studies (107 cIAI and 15 cSSSI patients). All patients received at least six doses of tigecycline before PK sampling (steady-state). The mean AUC0-12 values from all studies correlated to a daily AUC greater than the target, 6 μg·hr/mL, determined from previous studies. Mean (± SD) values for Css,max, Css,min, AUCss and CL in one of the cIAI studies (n = 83) were 794 ng/mL (± 479), 152 ng/mL (± 72), 3.16 μg·hr/mL (± 1.46) and 18.3 L/hr (± 6.9), respectively. Mean AUCss and CL values in the cIAI and cSSSI patients were similar to those observed in healthy subjects and previously studied patients with cIAI and cSSSI. Css,max values were similar to those observed in previous studies with comparable infusion durations. AUCss and CL values between Phase 3 cSSSI and cIAI patients were in the same range.

Conclusions: These studies demonstrate no substantial differences in steady-state PK parameters of tigecycline between healthy subjects and patients with cSSSI and cIAI, suggesting similar exposures to tigecycline among all groups studied.

Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Washington, DC, December 2005

By Inger M. Darling, Brenda B. Cirincione, and Joel S. Owen