title: Slow drug delivery decreased total body clearance and altered bioavailability of immediate- and controlled-release oxycodone formulations.
abstract: Oxycodone is a commonly used analgesic with a large body of pharmacokinetic data from various immediate-release or controlled-release formulations, under different administration routes, and in diverse populations. Longer terminal half-lives from extravascular administration as compared to IV administration have been attributed to flip-flop pharmacokinetics with the rate constant of absorption slower than elimination. However, PK parameters from the extravascular studies showed faster absorption than elimination. Sustained release formulations guided by the flip-flop concept produced mixed outcomes in formulation development and clinical studies. This research aims to develop a mechanistic knowledge of oxycodone ADME, and provide a consistent interpretation of diverging results and insight to guide further extended release development and optimize the clinical use of oxycodone. PK data of oxycodone in human studies were collected from literature and digitized. The PK data were analyzed using a new PK model with Weibull function to describe time-varying drug releases/ oral absorption, and elimination dependent upon drug input to the portal vein. The new and traditional PK models were coded in NONMEM. Sensitivity analyses were conducted to address the relationship between rates of drug release/absorption and PK profiles plus terminal half-lives. Traditional PK model could not be applied consistently to describe drug absorption and elimination of oxycodone. Errors were forced on absorption, elimination, or both parameters when IV and PO profiles were fitted separately. The new mechanistic PK model with Weibull function on absorption and slower total body clearance caused by slower absorption adequately describes the complex interplay between oxycodone absorption and elimination in vivo. Terminal phase of oxycodone PK profile was shown to reflect slower total body drug clearance due to slower drug release/absorption from oral formulations. Mechanistic PK models with Weibull absorption functions, and release rate-dependent saturable total body clearance well described the diverging oxycodone absorption and elimination kinetics in the literature. 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 offered new insight for the development of modified release formulations and clinical use of oxycodone.
authors.affiliation: Translational Development and Clinical Pharmacology Celgene Corporation 86 Morris Avenue Summit 07920 New Jersey.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: College of Pharmacy the University of Michigan Ann Arbor 48109 Michigan.
authors.forename: Duxin
authors.initials: D
authors.lastname: Sun
authors.affiliation: Translational Development and Clinical Pharmacology Celgene Corporation 86 Morris Avenue Summit 07920 New Jersey.
authors.forename: Maria
authors.initials: M
authors.lastname: Palmisano
authors.affiliation: Translational Development and Clinical Pharmacology Celgene Corporation 86 Morris Avenue Summit 07920 New Jersey.
authors.forename: Simon
authors.initials: S
authors.lastname: Zhou
keywords: Absorption; decreased clearance; formulation; oxycodone; slow delivery