Major circulating glucuronides of icenticaftor
This paper from scientists at Novartis describes the human ADME characteristics of icenticaftor and its major circulating glucuronides. Several interesting elements are discussed in the paper and highlighted here.
Icenticaftor is a potentiator of the CTFR protein and it is currently in clinical development for treatment of COPD and chronic bronchitis. It is extensively metabolised through N-glucuronidation and O-glucuronidation to major human metabolites M8 and M9 which are excreted renally. However, an additional major glucuronide M5 was found to be circulating in humans that was only observed as a minor metabolite in multi species hepatocyte incubations.
Points of interest:
- Species difference observed between rats and humans in elimination of icenticaftor.
- Non-linear PK observed after administration of single & multiple doses, proposed to be due to saturation of UGT1A9 in the intestine and liver.
- M8 & M9 evaluated in toxicity studies due to their abundance compared to parent drug in humans.
- The main N-glucuronide M8 is acid-labile, highlighting the importance of adjusting the pH of urine samples to neutral values.
- M5 is only observed as a minor metabolite in human/rat/mouse hepatocyte incubations but more prominently circulates in humans.
M5 is an indirect glucuronide derived from CYP1A2-mediated O-demethylation of icenticaftor to form M14, which is then glucuronidated at the exposed hydroxyl position. The UGT responsible for this is not mentioned. From being a minor metabolite in vitro, M5 constituted >10% of circulating radioactive material in the human ADME study. M5 was made by scientists at Hypha by first synthesising the intermediate metabolite M14, which was then glucuronidated in a two-step procedure.
Paper
Icenticaftor hADME and in vitro metabolite phenotyping.
