Orforglipron — pharmacology
Molecular targets, mechanism of action, pharmacokinetics and interactions as characterised in humans.
§2Pharmacology
§2.1Molecular targets
Table 2. Molecular targets recorded for Orforglipron, with the character of the interaction and the potency where the Institute holds it.
| Target | Interaction | Note |
|---|---|---|
| GLP-1 receptor (GLP1R) | Biased partial agonist | Partial cyclic-AMP efficacy with minimal beta-arrestin recruitment; the bias is proposed to limit receptor internalisation and desensitisation |
§2.2Mechanism of action
Orforglipron activates the GLP-1 receptor from a non-peptide scaffold, producing the insulinotropic, glucagonostatic and central appetite effects of the class from an orally bioavailable molecule that does not require an absorption enhancer. Its partial agonism and signalling bias mean the maximum achievable receptor activation is below that of the injectable peptides, yet clinical weight effects approach those of subcutaneous semaglutide, which the Institute records as an important and not fully explained observation.[1,2]
§2.3Pharmacokinetics
- Terminal half-life
- ≈29–49 h
- Time to maximum concentration
- 4–6 h
- Volume of distribution
- not published
- Plasma protein binding
- high
- Clearance
- not published
- Bioavailability
- sufficient for once-daily oral dosing without a permeation enhancer
Hepatic metabolism with CYP3A4 involvement reported in early characterisation. No food or water restriction is required, which distinguishes it operationally from oral semaglutide.
§2.4Interactions
- Potential for interaction with CYP3A4 inhibitors and inducers, unlike the peptide GLP-1 receptor agonists which have no meaningful cytochrome interaction
References cited on this page
References are numbered in order of first citation in this document. Each superscript in the text links to its entry below.
- Wharton S, Blevins T, Connery L, Rosenstock J, Raha S, Liu R, Ma X, Mather KJ, Haupt A, Robins D, Pratt E, Kazda C, Konig M. Daily oral GLP-1 receptor agonist orforglipron for adults with obesity. New England Journal of Medicine 2023;389(10):877–888. doi:10.1056/NEJMoa2302392 · PMID 37342922
- Frías JP, Hsia S, Eyde S, Liu R, Ma X, Konig M, Kazda C, Mather KJ, Haupt A, Pratt E, Robins D. Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study. The Lancet 2023;402(10400):472–483. doi:10.1016/S0140-6736(23)01302-8 · PMID 37369232
Identifiers are reproduced only where the Institute holds them. Where a digital object identifier or PubMed identifier is not shown, the Institute has recorded the journal and year and has not constructed an identifier.