2011 - Athens - Greece

PAGE 2011: Absorption and physiology-based PK
Kayode Ogungbenro

A semi-mechanistic gastric emptying pharmacokinetic model for 13C-octanoic acid: an evaluation using simulation

K Ogungbenro(1) and Leon Aarons(2)

(1)Centre for Applied Pharmacokinetic Research, (2)School of Pharmacy and Pharmaceutical Sciences, The University of Manchester, Oxford Road, Manchester, M13 9PL, United Kingdom

Objectives: The 13C-octanoic acid breath test is widely used for indirect assessment of the rate of gastric emptying and it is yet to achieve universal acceptance due to inconsistencies when the results are compared with simultaneous and direct measurements using scintigraphy.  The main objective of this work was to propose a new semi-mechanistic model for analysing 13C-octanoic acid breath test data and to assess the performance of the new model using simulation studies. 

Methods: The new semi-mechanistic model has five separate compartments; stomach, intestine, central and peripheral body and breath.  A simulation study was performed based on two experiments i.e. two 13C-octanoic acid breath tests in each individual.  The first test is the baseline study and the second test is after treatment with a drug that increases the rate constant of gastric emptying by 50%.  Stomach and breath profiles were simulated for 50 individuals under four conditions: (1) variability on all parameters; (2) no variability on the rate constant of gastric emptying and the rate constant of absorption; (3) variability on the rate constant of gastric emptying and the rate constant of absorption only; and (4) no variability on all parameters.  A mono-exponential model was fitted to the stomach profile and the new semi-mechanistic model and three other widely used methods (Modified exponential model [1], Ghoos method [1],  and Wagner-Nelson method [2]) were fitted to the breath profiles.

Results: The gastric emptying half times from stomach profiles correlate better (R2=1,1,1,1 for the four conditions) with the half emptying times from the new semi-mechanistic model compared with half emptying times from the modified exponential model (R2=0.72,0.53,0.88,1), Ghoos method (R2=0.72,0.54,0.88,1) and Wagner-Nelson method (R2=0.79,0.68,0.89,1) for the four simulation studies.

Conclusions: The new semi-mechanistic model is very effective for the assessment of gastric emptying using the 13C-octanoic acid breath test and could be applied in the development of drugs that influence gastric emptying.  This semi-mechanistic model allows direct estimation of the rate of GE while modelling the rate of elimination of 13CO2 from the ingested 13C-octanoic acid meal, taking into account the absorption, distribution and elimination by other routes.

References:
[1] Ghoos et al, Gastroenterol, 104:1640-1647 (1993).
[2] Odunsi et al, Neurogastroenterol Motil, 21:706-738.




Reference: PAGE 20 (2011) Abstr 2211 [www.page-meeting.org/?abstract=2211]
Poster: Absorption and physiology-based PK
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