Development of a PBPK model to describe late colonic absorption after oral administration
Donato Teutonico (1), Maud Beneton (1), Magali Amiel (1), Marylore Chenel (1)
(1) Clinical Pharmacokinetics and Pharmacometrics division, Servier, France
Objectives: The compound S is a drug under development at Servier. It has poor water solubility and its PK profile in blood shows a second peak at about 15-24 h after fasted oral administration in human. Since such late absorption is not likely related to enterohepatic circulation (EHC), it is believed that this second peak could be explained by a colonic absorption of this compound, mainly driven by the solubility. A PBPK model in human was developed in order to test this hypothesis.
Methods: The PBPK model was built in PK-Sim 6.3. Since the colon in the gastrointestinal (GI) model implemented in this software is divided in 6 sub-compartments [1], it is well suited to test the hypothesis of a late colonic absorption. The distribution model as well as the clearance and drug lipophilicity were estimated from PK in 2 intravenous (IV) microdose studies. Intestinal permeability was estimated from PK data with 50 µg oral solution. Drug dissolution, solubility and parameters defining colonic absorption (solubility and permeability) were estimated from PK data after single oral administration of immediate release tablet with doses ranging from 5 to 800 mg.
Results: The PK-Sim standard distribution model and an unspecified total liver clearance were used to describe the drug disposition and metabolism. Weibull dissolution functions were used to describe the drug release from the dosage forms. The late portion of the colon in the PBPK model, sigmoid colon, was identified as the compartment able to explain the late phase absorption. In order to describe the second peak of the PK profile, drug solubility in the sigmoid colon had to be adjusted.
Conclusions: The PBPK model developed was able to describe the concentrations in blood of compound S after IV and oral administration for the tested dose range, in particular with respect to the hypothesis of a late phase absorption. The late portion of the colon, the sigmoid colon, was identified as the segment likely responsible for such late absorption.
References:
[1] Thelen, K. et al. Evolution of a detailed physiological model to simulate the gastrointestinal transit and absorption process in humans, part 1: oral solutions. J. Pharm. Sci. 100, 5324–5345 (2011)