Empirical and Semi-Mechanistic Modelling of Double-Peaked Pharmacokinetic Profile Phenomenon Due to Gastric Emptying
Journal Title: The AAPS Journal - Year 2015, Vol 17, Issue 1
Abstract
Models have been developed to explain double-peaked plasma concentration-time profiles using mechanisms such as variable absorption and enterohepatic recirculation. Interruption of gastric emptying has also been shown to produce double-peaks, and this work proposes models for analysis of such data. In the presence of levodopa, gastric emptying is interrupted at times associated with double-peaks in pharmacokinetic profiles. Data from a simultaneous scintigraphy and paracetamol absorption study with levodopa was obtained, and models with compartments for stomach, intestine, central and peripheral tissue were developed to describe levodopa and paracetamol pharmacokinetics, including the double-peak phenomenon. The empirical model uses two gastric emptying parameter rates which are applied over separate time periods to describe the varying gastric emptying rate. The semi-mechanistic model uses a feedback mechanism acting via an effect compartment to link the plasma concentration of levodopa to the rate of gastric emptying, allowing levodopa pharmacokinetics to vary the rate of gastric emptying and give rise to a multiple-peaked plasma pharmacokinetic profile. The models were applied to plasma levodopa and paracetamol pharmacokinetic data with and without simultaneous analysis of scintigraphy data, in both cases giving a good fit and in the absence of scintigraphy data adequately predicting the stomach profile. For the semi-mechanistic model, the first-order constant governing gastric emptying was shown to switch between fast and slow values at a critical levodopa effect compartment concentration. New models have thus been proposed for analysis of plasma concentration profiles that exhibit double-peak phenomenon and applied successfully to levodopa data.
Authors and Affiliations
Kayode Ogungbenro, Henry Pertinez, Leon Aarons
Keywords
Related Articles
- EP ID EP680908
- DOI 10.1208/s12248-014-9693-5
- Views 54
- Downloads 0
What is the Likelihood of an Active Compound to Be Promiscuous? Systematic Assessment of Compound Promiscuity on the Basis of PubChem Confirmatory Bioassay Data
Compound promiscuity refers to the ability of small molecules to specifically interact with multiple targets, which represents the origin of polypharmacology. Promiscuity is thought to be a widespread characteristic of p...
Advancing Product Quality: a Summary of the Second FDA/PQRI Conference
The purpose of the Conference on Advancing Product Quality, under the sponsorship of the Food and Drug Administration (FDA) and Product Quality Research Institute (PQRI), is to bring regulators, industry professionals, a...
Linking human and veterinary health: Trends, directions and initiatives
The objective of this brief article is to provide an overview of some of the important harmonization efforts that are currently under way within the animal health community. Topics include: scientific networks and interd...
Biomaterials/Tissue Interactions: Possible Solutions to Overcome Foreign Body Response
In recent years, a variety of biomaterial implantable devices has been developed. Of particular significance to pharmaceutical sciences is the progress made on the development of drug/implantable device combination produ...
The Use of Betaine HCl to Enhance Dasatinib Absorption in Healthy Volunteers with Rabeprazole-Induced Hypochlorhydria
Many orally administered, small-molecule, targeted anticancer drugs, such as dasatinib, exhibit pH-dependent solubility and reduced drug exposure when given with acid-reducing agents. We previously demonstrated that beta...