“Clinical Pharmacokinetics of Oral Semaglutide: Analyses of Data from Clinical Pharmacology Trials”, 2021-05-10 (; backlinks):
This population pharmacokinetic model for semaglutide provides a general characterisation of semaglutide pharmacokinetics across oral, subcutaneous and intravenous administration in healthy subjects and subjects with type 2 diabetes.
Dosing conditions (post-dose fasting time and water volume) of oral semaglutide influence semaglutide exposure and bioavailability.
The variability of exposure for oral semaglutide was accurately characterised, and demonstrated how the long half-life and daily dosing result in reduced variability at steady state.
Objective: The absorption, distribution and elimination of oral semaglutide, the first oral glucagon-like peptide-1 receptor agonist for treating type 2 diabetes, was investigated using a population pharmacokinetic model based on data from clinical pharmacology trials.
Method: A previously developed, 2-compartment pharmacokinetic model, based on subcutaneous and intravenous semaglutide, was extended to include data from 6 oral semaglutide trials conducted in either healthy volunteers or subjects with renal or hepatic impairment. 5 trials employed multiple doses of oral semaglutide (5–10 mg) and one was a single-dose (10 mg) trial. In a separate analysis, the model was re-estimated using data from a trial in subjects with type 2 diabetes.
Results: The model accurately described concentration profiles across trials. Post-dose fasting time, co-ingestion of a large water volume, and body weight were the most important covariates affecting semaglutide exposure. Bioavailability was 0.8% when oral semaglutide was dosed using the recommended dosing conditions (30 min post-dose fasting time, administered with 120 mL of water), increasing with a longer post-dose fasting time and decreasing with higher water volume. Within-subject variability in bioavailability was 137%, which with once-daily dosing and a long half-life translates into 33% within-subject variability in steady-state exposure. There was no statistically-significant difference in oral bioavailability of semaglutide in healthy subjects and subjects with type 2 diabetes.
Conclusion: The updated model provided a general characterisation of semaglutide pharmacokinetics following oral, subcutaneous and intravenous administration in healthy subjects and subjects with type 2 diabetes. Within-individual variation of oral bioavailability was relatively high, but reduced considerably at steady state.
ClinicalTrials.gov identifiers: NCT01572753, NCT01619345, NCT02014259, NCT02016911, NCT02249871, NCT02172313, NCT02877355.