Modeling the two peak phenomenon in pharmacokinetics using a gut passage model with two absorption sites
Andreas Krause(1), Marc Lavielle(2), Kaelig Chatel(2), Christopher Kohl(3), Ruben de Kanter(3), Stephane de la Haye(3), Alison Mackie(1), Jochen Zisowsky(1), Jasper Dingemanse(1)
(1) Actelion Pharmaceuticals Ltd, Department of Clinical Pharmacology, Gewerbestr. 16, 4123 Allschwil, Switzerland, (2) Lixoft - Incuballiance, 84 rue de Paris, 91400 Orsay, France, (3) Actelion Pharmaceuticals Ltd, Drug Metabolism and Pharmacokinetics, Gewerbestr. 16, 4123 Allschwil, Switzerland
Objectives: Characterization of the pharmacokinetic (PK) two peak phenomenon with pronounced second peak in higher doses by a gut passage model with two absorption sites and an absorption limit on the first site of absorption.
Methods: The first study with a new compound in humans showed PK characteristics that can be characterized by single compartment models. Higher doses though exhibited a two peak phenomenon: after the drug concentration had almost returned to 0, a second peak occurred that became more pronounced with higher doses. Preclinical data suggested that the underlying mechanism could be a gut passage with two absorption sites, in the upper and lower intestinal tract, respectively.
A PK model with the desired properties was implemented in Monolix. It comprises two separate dose administration compartments with direct first order absorption and a set of transit compartments (with the number of transit compartments estimated). The last transit compartment transfers into the central compartment, thus causing a second peak in systemic concentration. The amount of drug absorbed from the first absorption compartment is limited, and the absorption limit is estimated.
Results: The gut passage model with two absorption sites with an absorption limit on the first captures the two peak PK phenomenon very well. It can capture very different shapes of concentration-time profiles, including large differences between subjects in the magnitude of the second peak relative to the first peak.
Conclusions: The gut passage model represents a viable alternative to enterohepatic recycling models for the PK two peak phenomenon ([1], [2], [3]).
References:
[1] Davies NM et al.: Multiple Peaking Phenomena in Pharmacokinetic Disposition. Clinical Pharmacokinetics 2010, 49(6), 351-377
[2] Funaki T: Enterohepatic circulation model for population pharmacokinetic analysis. PAGE 8 (1999) Abstr 150 [www.page-meeting.org/?abstract=150]
[3] Petricoul O et al.: Population Models for Drug Absorption and Enterohepatic Recycling. In: Ette E and Williams PJ (eds.): Pharmacometrics: The Science of Quantitative Pharmacology. Wiley 2007, 345-382
