A Population PK model to evaluate variability in oral absorption using gamma scintigraphy
L. Iavarone(1), G. Ghibellini(2), S. Carson(2), A. Parr(3), E. Sandefer (4),G. Nucci (1), R. Gomeni(1),
(1) CPK&MS, GSK, Verona, Italy; (2) CPDM, GSK, RTP, US; (3) Pharmaceutical Development, GSK, RTP, US; (4) Scintipharma, Lexington, US
Objectives: GSKX is a compound in development for CNS disorders showing high PK variability when orally administered in fasted conditions. This could be related to a variety of factors as gastric emptying patterns or formulation performance1. In phase I, variability was successfully limited by food. A study in human volunteers was carried out to assess the relationship(s) between GSKX absorption and gastric emptying time for a solution (fasted) and a tablet formulation (fasted and fed) in order to guide in the formulation development process. Gamma scintigraphy was used to evaluate formulation performance by visualizing the disintegration process and by measuring the gastric emptying time in relation to the use of food or of different formulations. A population PK modelling was developed to assess the relationship(s) between gastric emptying profiles (by gamma scintigraphy) and GSKX plasma disposition after administration of a solution or a tablet formulation in fasted and fed states.
Methods: A GI-transit-absorption kinetics model was developed using sequential compartmentimental approach to account for the stomach and the jejunum2. GI transit process from the stomach to the jejunum was described by a rate-limited process:
Ka=Rate_Max*Timeh/( Timeh+ T50h)
where Rate_Max is the fastest transit rate, T50 is the time at which rate is the 50% maximum rate and h is the sigmoidicity factor. The disposition PK model connected to this GI absorption model was a three compartment model with first order elimination rate constant from the central compartment.
Results: The transit of radioactivity from the stomach to the jejunum was found to be formulation and food dependent. When a solution was administered, T50 was estimated to be minimum and the equation describing Ka simplified to Ka=Rate_Max, whereas when a tablet was administered T50 was estimated to be higher in fed than in fasted conditions.
Conclusions: Absorption of GSKX resulted to be controlled substantially by the residence time in the stomach. Fed conditions generally decreased the rate of transit from the stomach into the jejunum. Simulations of plasma PK time-course associated with different GI-transit-absorption patterns were performed to support optimal formulation development.
References:
[1] Kilian K. et al, Comparison of the Rates of Disintegration, Gastric Emptying, and Drug Absorption Following Administration of a New and a Conventional Paracetamol Formulation, Using Gamma Scintigraphy, Pharm. Res., 20, 1668-1673, 2003
[2] Honghui Z., Pharmacokinetic Strategies in Deciphering Atypical Drug Absorption Profiles, J. Clin. Pharmacol. 43 211-227, 2003
