Orforglipron
Orforglipron. A NON-PEPTIDE, orally administered agonist of the glucagon-like peptide-1 receptor, which is why it has genuine oral… Oral half-life 30 h.
A NON-PEPTIDE, orally administered agonist of the glucagon-like peptide-1 receptor, which is why it has genuine oral pharmacokinetics where the peptide GLP-1 agonists have none. PMID:39693407 verbatim (orforglipron the subject): "Competition binding experiments using either [125I]GLP-1(7-36)NH2 or [3H]orforglipron indicated that orforglipron is a high-affinity [inhibition constant (Ki) = 1 nM], selective ligand of the human GLP-1R." It is described there as a competitive ligand with low intrinsic efficacy for effector activation and negligible beta-arrestin recruitment. The Ki is printed to ONE significant figure and no effect-compartment rate constant is published, so it is recorded in prose and no occupancy row is authored.
PubChem CID 137319706 (C48H48F2N10O5, 883.0), re-queried 2026-09-26. ANALYTE IS THE PARENT, verbatim (PMID:40888509): "Orforglipron was the most abundant plasma component (93.3%) with minor oxidative metabolites M7 (3.3%) and M23 (1.6%)", and elimination is faecal: "The primary route of elimination for [14C]-orforglipron-related radioactivity was via the feces (87% +/- 2.8%) with minimal urinary excretion (0.2% +/- 0.02%)." WHAT THE STORED VALUES DO AND DO NOT REPRODUCE, checked per R15: they give the paper's AUC exactly and its t1/2 to within 0.1 h, but a one-compartment Cmax at the 3 mg dose comes out near 7 ng/mL against the measured 13.4 ng/mL. That is expected and is disclosed rather than tuned away: Vz is a TERMINAL-phase volume and this drug's profile is not mono-exponential, so the one-compartment approximation is right on exposure and low on peak. The paper also prints Vss/F 303 L; Vz was used because with CL/F it is the pair that reproduces the reported t1/2. RANGES NOT STORED: PMID:37344954 gives "the mean t1/2 was 24.6 to 35.3 hours after a single dose (0.3-6 mg)" and 48.1-67.5 h on day 28 — a clean single-dose versus steady-state contrast showing roughly twofold accumulation in apparent t1/2, which is why the single-dose 29.5 h is the value stored. PMID:41325139 reports 51.8-76.1 h at week 12, steady state, unusable for a volume. PRESENTATION MATTERS FOR DOSE: PMID:41994902 gives capsule doses of 1, 3, 6, 12, 24 and 36 mg against tablet doses of 0.8, 2.5, 5.5, 9, 14.5 and 17.2 mg, so tablet and capsule strengths are NOT interchangeable mg-for-mg; the stored range is the capsule/target-dose scale used in the phase 2 and 3 trials.
Pharmacokinetics
- Oral — t½ 29.5 h · F 79% · Vd 279.2 L
Sources: PMID:38402332, PMID:40888509, PMID:39693407, PMID:37344954, PMID:41325139