De invloed van gevorderde leeftijd op de absorptie van geneesmiddelen

Background: Globally, the population aged 65 and older is rapidly increasing. In contrast to these trends, inclusion of this population in clinical trials is scarce. This, in turn, led to a lack of physiological and pharmacokinetic reference data specific to this population. A recent gap analysis conducted within the Horizon 2020 AGePOP ITN identified critical gaps relevant to oral drug absorption. Specifically, heterogeneous results in the literature regarding gastric emptying, gastrointestinal pH, and drug metabolising enzymes and transporters were identified. Since these processes are determinants of oral absorption, further research in this area is warranted. Objectives: This work aimed to contribute to a broader understanding of gastrointestinal processes relevant to oral drug absorption and how advanced age influences gastrointestinal pH, intestinal drug transporters and drug metabolising enzymes. More specifically, the dynamic pH environment in the upper gastrointestinal tract, the abundance of drug-metabolising enzymes in the duodenum and colon, and the abundance of drug transporters were explored. In addition, the pharmacokinetics of paracetamol, a compound susceptible to changes in gastric emptying, were assessed, and the influence of sparkling water as a potentially absorption-modifying beverage was explored. Methods: Dynamic trends in gastrointestinal pH were assessed in a pooled analysis of previously collected data in the Drug Delivery and Disposition Laboratory, utilising generalised additive models for location, scale and shape. Age-related trends were analysed using Kendall's tau correlation. The abundance of drug metabolising enzymes and drug transporters was explored in biopsies from 58 volunteers aged 19-85 using targeted absolute proteomics. Age-related trends were quantified using multiple regression analysis of scaled and centred abundance data. Paracetamol pharmacokinetics were explored in a small-scale, randomised, controlled clinical trial with a cross-over design. Fourteen volunteers, with a median age of 72.5, were enrolled. One tablet containing 500 mg paracetamol was administered with either still or sparkling water. The results were examined for age-related changes in pharmacokinetics, compared with the reference literature. The impact of sparkling water was analysed for changes in absorption as measured by the partial AUC0-30min . Results: Gastrointestinal pH changes dynamically depending on co-administration of water, food and proton-pump-inhibitor medication. Fed state profiles showed different temporal pH profiles compared to the fasted state post-water ingestion in the stomach and duodenum. An exploratory analysis using an FDA-standard high-fat breakfast yielded pH profiles similar in shape to those with a liquid meal, Ensure Plus, though with a trend towards lower median pH values. Co-administration of esomeprazole resulted in pH increases not only in the stomach but also in the duodenum and jejunum, compared to the fasted state. No advanced age-related trends in gastrointestinal pH were observed. However, available data were limited. The abundance of twenty-five drug-metabolising enzymes and drug transporters was quantified in intestinal biopsies collected from fifty-eight volunteers. This analysis revealed significant age-related changes in duodenal protein abundance, with scaled and centred age coefficients ranging from -0.36 to 0.51. Specifically, a decrease in duodenal abundance with age was observed for carboxylesterase 2 (CES2), peptide transporter 1 (PEPT1), and villin-1. Additionally, a significant age-dependent increase in the abundance of breast cancer resistance protein (BCRP), multidrug resistance-associated proteins 1, 3, 4 (MRP1, MRP3, MRP4) and permeability-glycoprotein (P-gp) was observed. No significant impact of sex or sex-specific age effects was detected. Paracetamol pharmacokinetics in fourteen older adults were comparable to those reported in the reference literature for young adults. Reduced variability of absorption-related parameters and a trend towards higher early exposure were observed in the sparkling water group, as demonstrated by a 1.6-fold increased AUC0-30min, a 2-fold reduced geometric coefficient of variation (GCV) for AUC0-30min, and a reduced median [interquartile range] Tmax of 25.0 [20.0-30.0] min compared to 30.0 [25.0-45.0] min. Conclusion: These findings provide detailed insight into the dynamic luminal environment of the ageing GI tract, potentially relevant to the design, optimisation, and evaluation of oral dosage forms. The results may be utilised in physiologically based pharmacokinetic modelling and inform future research in this area. However, functional verification of the observed trends is clearly needed.