Qadir Faqe1, Enoche Oga1, Abdullah Isreb2, Omar Sarheed1, Asa Auta3, Robert Forbes1
1University of Central Lancashire, 2Liverpool John Moores University, 3Edge Hill University
Introduction/Objectives Although metformin remains the first line of diabetes treatment as monotherapy, there may be the need for combination with the other antidiabetic agents to adequately control hyperglycaemia [1]. Utilising dual or triple therapies with metformin such as combining metformin with saxagliptin or dapagliflozin or all three together could be an effective strategy, with saxagliptin and dapagliflozin demonstrating high efficacy and low risk to those patients whose blood sugar is not adequately controlled by metformin alone [2, 3]. The study aimed to construct a physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics of saxagliptin, dapagliflozin and metformin in different special populations towards enhancing treatment strategies for diabetes [4,5]. The influence of the presence and absence of food while on these medicines was also explored. Methods The study utilised relevant physicochemical and physiological base data for input to a PBPK model to predict clinical outcomes of these antidiabetics in paediatrics, geriatrics and pregnant women, comparing this to normal age adults. This was carried out in simulated healthy, renal or hepatically impaired patients in fasted or fed situations. PBPK modeling and simulations were conducted using the advanced compartmental absorption & transit model in GastroPlus® [6]. Modeling of single and population simulations were used to predict the pharmacokinetic modelling of oral, immediate release dosage forms (metformin 500mg, saxagliptin 5mg and dapagliflozin 10mg). Clinical data was obtained from clinical studies and clinical trial reports. Other data such as physicochemical properties for input into the PBPK models, data for human physiology in fed and fasted state, ratio of blood-to-plasma and fraction unbound in plasma were obtained from the literature or predicted. This PBPK model considered the entire body, predicting the drug amount distributed to each tissue and provides important information about their safety and efficacy and likelihood of drug-disease interaction. Results Simulations revealed that age significantly influenced the pharmacokinetics of metformin, saxagliptin and dapagliflozin in both fed and fasted states. The presence or absence of food also influenced the pharmacokinetics of these medicines, related to food being able to alter several physiological characteristics e.g. gastric pH, gastric emptying time, bile secretion and hepatic blood flow. Fed conditions delayed Tmax possibly due to slower gastric emptying time. Following single simulations of these drugs in paediatric and geriatric populations with different stages of renal impairment and cirrhosis, steatosis, hepatitis, the results demonstrated that severe renal impairment and end stage renal failure (ESRF) have a significant effect on the AUC0-24 of metformin. In addition, severe hepatic impairment (Cirrhosis C) significantly increased the AUC0-8 and AUC0-24. It is known that physiological alterations like glomerular filtration reduces by ~1% per year after 40 years leading to a decline in renal function due to slower drug elimination thus increasing drug exposure in geriatrics. For saxagliptin, severe renal impairment and ESRF significantly increased AUC0-8 and AUC0-24. Cirrhosis A, B, C and simple steatosis significantly increased the AUC0-8 and AUC0-24. For dapagliflozin, mild, moderate and severe renal impairment also significantly increased the Cmax and AUC0-24. Likewise, cirrhosis A, B, C, simple steatosis and non-alcoholic hepatitis significantly increased its AUC0-8 and AUC0-24 Conclusions These findings suggest that there were some significant differences in fasted and fed conditions following oral administration of these drugs. Drug specific physiochemical and physiological properties of antidiabetic drugs including solubility, permeability, changing gastric pH, gastric emptying time and bile secretion can influence the bioavailability of orally administered drug in the presence or absence of food. The mechanism through which food can impact the pharmacokinetics of drugs is not fully understood especially in the paediatrics population and may require further study. Findings of compartmental absorption demonstrated that cirrhosis A, B, C, simple steatosis, and non-alcoholic conditions had no significant effect on the compartmental absorption of these drugs. In addition, fed and fasted conditions had no significant effect on the compartmental absorption for the different populations, however the regional absorption along the gastrointestinal tract for metformin show significant absorption in the jejunum in comparison to other gastrointestinal regions. References [1] Schwartz S S and A. Katz (2016). Diabetes Metab Syndr Obe 9: 71-82. [2] Del Prato S et al. (2018) Diabetes Obes Metab 20(6): 1542-1546. [3] Kim N H et al. (2024). Diabetes, Obesity and Metabolism 26(9): 3642-3652. [4] Butrovich M A et al. (2022). J Clin Pharmacol 62(8): 1018-1029. [5] Mori, K. et al. (2016). Biopharmaceutics & drug disposition, 37(8) 491–506. [6] Le Merdy M et al (2024). Pharmaceutics, 16(1), 96.
Reference: PAGE 33 (2025) Abstr 11602 [www.page-meeting.org/?abstract=11602]
Poster: Drug/Disease Modelling - Absorption & PBPK