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Semi-mechanistic PK/PD modeling of Paracetamol and Sulfapyridine to characterize pharmacological effects on gastric emptying and small intestinal transit.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Pharmacometrics Research Group)
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

The paracetamol (PCM) and sulfapyridine (SP) double marker technique is based on combined gastric administration of PCM and sulfasalazine followed by plasma concentration measurements for PCM and SP. PCM is rapidly absorbed from the duodenum and can be regarded as a marker for gastric emptying (GE). Sulfasalazine is poorly absorbed from the small intestine but is extensively metabolized in the colon by bacteria into SP. As SP is only absorbed from the colon it serves as a marker for small intestinal transit time (SITT). The double marker method is used to identify and characterize effects on GE and SITT. The aim of the present investigation was to demonstrate how semi-mechanistic modeling of PCM and SP could facilitate characterization and the understanding of pharmacologically induced changes in GI transit under fed and fasting conditions. Two double marker validation studies were performed in dogs with erythromycin (1 mg/kg) and atropine (0.06 mg/kg), both of which have been described to affect GE and SITT. A semi-mechanistic nonlinear mixed-effects model was applied for simultaneous analysis of PCM and SP plasma concentrations. The model featured a compartment representing the stomach linked to a colon compartment via a series of four transit compartments representing the small intestine. Disposition of PCM and SP was described with standard 2- and 1-compartment models respectively. An essential part of the model was the inclusion of saturable first pass metabolism of PCM. This has been described before, but never taken into account when using PCM as a marker for GE. The effect of concomitant food intake on GE and SITT was found to be time dependent. Atropine and erythromycin were found to have time/concentration dependent effects on GE and SITT. As expected, erythromycin stimulated and atropine inhibited GE in the fasting state. Given the saturable first pass metabolism this resulted in almost twice as high bioavailability for PCM in erythromycin treated dogs (90%) as in atropine treated dogs (50%). Atropine treatment was primarily found to counteract the stimulatory effect of food intake on SITT, whereas erythromycin prolonged SITT under both fed and fasting conditions. Simultaneous modeling of PCM and SP was found to increase mechanistic understanding and result in plausible estimates of GE and SITT.

Keyword [en]
gastric emptying, small intestinal transit, mechanistic modeling, NONMEM
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
URN: urn:nbn:se:uu:diva-149313OAI: oai:DiVA.org:uu-149313DiVA: diva2:404477
Available from: 2011-03-17 Created: 2011-03-17 Last updated: 2011-05-04
In thesis
1. Application of Mixed-Effect Modeling to Improve Mechanistic Understanding and Predictability of Oral Absorption
Open this publication in new window or tab >>Application of Mixed-Effect Modeling to Improve Mechanistic Understanding and Predictability of Oral Absorption
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Several sophisticated techniques to study in vivo GI transit and regional absorption of pharmaceuticals are available and increasingly used. Examples of such methods are Magnetic Marker Monitoring (MMM) and local drug administration with remotely operated capsules. Another approach is the paracetamol and sulfapyridine double marker method which utilizes observed plasma concentrations of the two substances as markers for GI transit. Common for all of these methods is that they generate multiple types of observations e.g. tablet GI position, drug release and plasma concentrations of one or more substances. This thesis is based on the hypothesis that application of mechanistic nonlinear mixed-effect models could facilitate a better understanding of the interrelationship between such variables and result improved predictions of the processes involved in oral absorption.

Mechanistic modeling approaches have been developed for application to data from MMM studies, paracetamol and sulfapyridine double marker studies and for linking in vitro and in vivo drug release. Models for integrating information about tablet GI transit, in vivo drug release and drug plasma concentrations measured in MMM studies was outlined and utilized to describe drug release and absorption properties along the GI tract for felodipine and the investigational drug AZD0837. A mechanistic link between in vitro and in vivo drug release was established by estimation of the mechanical stress in different regions of the GI tract in a unit equivalent to rotation speed in the in vitro experimental setup. The effect of atropine and erythromycin on gastric emptying and small intestinal transit was characterized with a semi-mechanistic model applied to double marker studies in fed and fasting dogs.

The work with modeling of in vivo drug absorption has highlighted the need for, and led to, further development of mixed-effect modeling methodology with respect to model diagnostics and the handling of censored observations.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 89 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 142
Keyword
Absorption, magnetic marker monitoring, drug release, IVIVC, pharmacometrics, NONMEM, model diagnostics, pcVPC, pvcVPC, visual predictive check, VPC, BQL, paracetamol, sulfapyridine.
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-149314 (URN)978-91-554-8030-1 (ISBN)
Public defence
2011-04-29, B41, Uppsala Biomedicinska Centrum (BMC), Husargatan 3, Uppsala, Sweden, 09:15 (English)
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Supervisors
Available from: 2011-04-07 Created: 2011-03-17 Last updated: 2011-05-04Bibliographically approved

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Bergstrand, Martin

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