Yan Li (1), Maria Palmisano (1), Duxin Sun (2) and Simon Zhou (1)
(1) Celgene Cooperation, Summit, NJ, USA; (2) College of Pharmacy, University of Michigan, Ann Arbor, MI, USA
Objectives: In traditional pharmacology and modeling, oral absorption is approximated by a constant rate constant. It provides a reasonable description of overall PK profile, but rarely captures the kinetic oral absorption phase with particular problems for sustained or extended (Controlled CR) release formulations. Weibull functions have been successfully applied to characterize the in vitro drug dissolution from various IR and CR dosage forms. The aim of this analysis is to characterize the in vivo oral absorption profiles of IR and CR formulations of Losartan, Dexibuprofen, Methylphenidate and Tramadol using Weibull absorption function.
Methods: Human plasma concentration-time profiles of IR and CR formulations of Losartan, Dexibuporfen, Methylphenidate, and Tramadol were digitized from published manuscripts. The PK data were fitted by 1 or 2 compartment structural models with constant rate of absorption or time-varying Weibull absorption functions. The Weibull absorption functions was adopted to represent physiologic processes of drug release and absorption in vivo. The modeling and simulation were conducted using NONMEM 7.2.
Results: Data fitting with constant rate of absorption rate did not yield consistent PK parameters for IR and CR formulation of lorsartan, dexibuporfen, methylphenidate and tramadol, requiring separate sets of PK parameters of Ka, CL and V for IR and CR formulations and poor data fit of absorption phase of PK profiles. The models with single or dual Weibull absorption functions well-characterized the overall PK profile with consistent CL and V parameters and the early absorption phases for both IR and CR formulations. The analysis also provided a mechanistic link between the values of Weibull distribution parameters (λ and κ) and the diffusion mechanisms of the drug release in vivo. For all 4 drugs, oral absorption stopped between 6 and 8 hours, providing a new insight into the physiological limit of stretching oral absorption with modified release. Simulations further demonstrated the numerical stability and statistical rigor of Weibull absorption models to describe complex drug absorption.
Conclusions: Drug release from IR and CR formulations have mode and distribution that could not be adequately described with a first order process. Weibull functions with versatile time varying release/absorption rates are proper models to characterize drug absorption, and useful to compare and qualify CR formulations.
References:
[1] Pharmacokinetic Evaluation of Newly Developed Oral Immediate Release and Sustained Release Dosage Forms of Losartan Potassium. Basuvan Babu, Subramania Nainar Meyyanathan, Byran Gowramma, Selvadurai Muralidharan, Kannan Elangoand Bhojraj Suresh, 2012
[2] Pharmacokinetic-PharmacodynamicModel of Newly Developed Dexibuprofen Sustained Release Formulations. SelvaduraiMuralidharan, 2012
[3]
[4] Tramadol extended-release in the management of chronic pain. Bill McCarberg, 2007
Reference: PAGE 24 () Abstr 3416 [www.page-meeting.org/?abstract=3416]
Poster: Drug/Disease modeling - Absorption & PBPK