Resource Center

Oct 30, 2004
  |  Poster

Population Pharmacokinetics of Tigecycline in Phase 1 Subjects

Abstract

Background: TGC is the first glycylcycline antimicrobial agent in development and has potent in vitro activity against many multi-drug resistant organisms. Given observed differences in the PK profiles after single doses (SD) & multiple doses (MD) of TGC, separate PPK models were developed for SD & MD data pooled from 5 Phase 1 studies.

Methods: TGC (12.5 to 300 mg) was infused over 1 hour twice daily for 9 to 10 days. Serial blood samples were collected after a SD (2030 samples, 174 subjects) and on Day 9 or 10 (203 samples, 13 subjects). Both 2- and 3-compartment (CMT) models were fit to the serum
TGC data using NONMEM®. The models that best described the full-profile SD & MD data were evaluated on a PH 1 dataset reduced to the Phase 2/3 sparse sampling scheme and dose range (25 to 100 mg)

Results: 3-CMT models with 1st-order elimination best described the SD & MD data. Intersubject variability (IIV) of CL, distribution CL (Q1 & Q2), and volume (Vp1 & Vp2) for each peripheral CMT were described using an exponential error model. However, the IIV of Q2 & Vp2 could not be estimated for MD data and were removed from the MD model. A log error model best described residual variability (RV) for both the SD & MD models. The elimination half-life was longer following MD of TGC (115 hr) than a SD (51 hr). The MD Bayesian PK parameters were also used to predict SD data (reverse superpositioning), revealing that the SD AUC0-12 was underpredicted for most subjects. Thus, the full-profile SD & MD data were not pooled and fit with a single model. The reduced Phase 1 data collected out 12 hr for both SD & MD of TGC were adequately described using a 2-CMT model. The predicted SD & MD AUC0-12 values were unbiased relative to observed values; median prediction error (PE) and absolute PE were similar for both models and were ±1% and 3%, respectively.

Conclusions: A 3-CMT model best described the serial TGC data following a SD or MD, however, an empiric 2-CMT model provides unbiased estimates of AUC0-12 using the PK sampling strategy implemented in Phase 2/3.

Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Washington, DC, October 2004

By Van Wart, S., Cirincione, B., Hirankarn, S., Luann Phillips, Meagher, A., Troy, S., Joel S. Owen

Contact Us About This Poster