Simon Zhou (1), Yan Li (1), Maria Palmisano (1) and Duxin Sun (2)
(1) Celgene Cooperation, Summit, NJ, USA, (2)College of Pharmacy, Univ. of Michigan, Ann Arbor, MI, USA
Objectives: Traditional PK model with first order absorption slower than elimination generates flip-flop plasma PK-time profile in which the terminal half-lives reflects slower rate of absorption. PK studies with IV and extravascular administration of drugs rarely produce pharmacokinetic profiles that can be entirely explained and accurately modeled by a slower first order absorption. The goal is to develop a mechanistic model to describe non-first order drug release and its impact on characterization of PK properties.
Methods: A new PK model with Weibull function for absorption and saturable elimination affected by slower drug input to portal vein was adopted to capture time varying drug releases/absorption in vivo and slower drug clearance caused by slower absorption. The new and traditional PK models were coded in NONMEM and applied to human PK data of oxycodone and two Celgene drug candidates following IV and PO administration including modified release formulations[1]. Sensitivity analyses was conducted to address the relationship between modes of drug release/absorption and PK profiles plus terminal half-lives.
Results: When drug release is varying with time and hepatic drug extraction ratio is high, traditional PK model could not be applied consistently to describe drug absorption and elimination. Errors were forced on absorption or elimination parameters or both parameters when IV and PO profiles were fitted separately or simultaneously. The new PK model with Weibull function on absorption and slower clearance with slower absorption adequately describes the complex interplay between absorption and elimination in vivo. The mode and distribution of Ka over time accounted for the slow drug release and absorption components following PO administration of oxycodone and two Celgene drugs. Terminal phase of PK profile was shown to reflect slower drug clearance due to slower drug absorption, resulting in a pseudo “flip-flop” that the terminal half-life is predominately driven by slower elimination with NO actual drug absorption.
Conclusions: PK models with Weibull absorption functions and release rate-dependent clearance capture the absorption and elimination kinetics for drug with high extraction ratios . It showed no actual drug absorption during the terminal phase but slower drug clearance caused by slower release/absorption producing the appearance of flip-flop and incorrect fraction of dose absorbed estimation by traditional PK model.
References:
[1] Mandema, J. et al. Characterization and validation of a pharmacokinetic model for controlled-release oxycodone. Br. J. Clin. Pharmacol. 1996, 42: 747-756.
Reference: PAGE 24 (2015) Abstr 3415 [www.page-meeting.org/?abstract=3415]
Poster: Drug/Disease modeling - Absorption & PBPK