Semi-mechanistic PK/PD modeling of Paracetamol and Sulfapyridine to characterize effects on gastric emptying and small intestinal transit
Martin Bergstrand (1), Sandra Visser (2), Catharina Alm (1), Ahmad Al-Saffar (3), Mats O Karlsson (1)
(1) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. (2) DMPK, AstraZeneca R&D, Södertälje, Sweden. (3) Safety Pharmacology, Safety Assessment, AstraZeneca R&D, Södertälje, Sweden.
Objectives: Drug-induced changes in gastric emptying (GE) and small intestinal transit time (SITT) can cause altered absorption of other drugs as well as constipation and diarrhoea. As a consequence, it is desirable to identify if drug substances alter these processes in an early stage of drug development. The paracetamol (PCM) and sulfapyridine (SP) double marker technique (1) is based on combined gastric administration of PCM and sulfasalazine followed by plasma concentration measurements for PCM and SP. Paracetamol is rapidly absorbed from duodenum and can be regarded as marker for GE. Sulfasalazine is poorly absorbed in the small intestine and is in colon extensively metabolized by bacteria into SP. As SP is absorbed from colon only it serves as a marker for SITT. Present explorative modeling of studies with the double marker technique aims to increase mechanistic understanding and develop a new standard study design and modelling approach.
Methods: Two similar double marker studies, one under fed and one under fasting conditions, each included 6 dogs each receiving, atropine (0.06 mg/kg), erythromycin (1 mg/kg), and vehicle treatment in a cross-over design. In addition, a study with two dogs receiving intragastric and intravenous infusions of PCM was included in the analysis. A semi-mechanistic compartmental population model was applied for simultaneous analysis of PCM and SP plasma concentrations. The influence of drug treatment and concomitant food intake was investigated for GE and SITT.
Results: Gastric emptying was described by a combination of an active and a passive process, both governed by first order rate constants. The active part of the GE was stimulated by erythromycin and potently inhibited by atropine treatment. For atropine, a concentration-effect relationship was identified based on a priori information on t½ for atropine (~2 hr). The estimated IC50 corresponds to atropine concentrations four t½ post dose. A chain of five transit compartments was found to best describe small intestinal transit. Erythromycin treatment significantly prolonged SITT whereas no effect of atropine was seen for this parameter. Food intake was identified to influence both GE and SITT in a complex manner, possibly corresponding to an initial transient increase in motility followed by a decreased motility for a longer duration.
Conclusion: Simultaneous modelling of PCM and SP is feasible and can increase mechanistic understanding of effects on GE and SITT.
References:
[1] Mizuta H, Kawazoe Y, Ogawa K. Gastrointestinal absorption of chlorothiazide: evaluation of a method using salicylazosulfapyridine and acetaminophen as the marker compounds for determination of the gastrointestinal transit time in the dog. Chem Pharm Bull (Tokyo). 1990 Oct;38(10):2810-3.
