Semaglutide
Semaglutide, a peptide. GLP-1(7-37) analog with three modifications: Aib at position 2 (blocks DPP-4), Arg-34 (resists degradation), and… Subcutaneous half-life 7 d.
GLP-1(7-37) analog with three modifications: Aib at position 2 (blocks DPP-4), Arg-34 (resists degradation), and C-18 fatty-acid acylation on Lys-26 via γGlu + 2 short PEGs → albumin binding → 7-day t½. Activates GLP-1R on pancreatic β-cells (insulin release), α-cells (glucagon suppression), hypothalamus (satiety), and gut (slowed emptying). STEP trials showed ~15% weight loss at 68 weeks (2.4 mg). SELECT showed MACE reduction in CV-risk population.
PK: volume re-sourced 2026-09-06. Overgaard 2019 (PMID:30788808), 353 subjects across nine trials with both SC and IV data, verbatim "the central and peripheral volumes were estimated to be 3.59 L ... and 4.10 L ... (i.e. a total volume of distribution of 7.7 L)" — a true volume, not apparent. The stored 7 L was the registry default and happened to land near it; the approval document's 12.5 L is an apparent V/F and does not contradict this. Half-life 168 h stands on Ikushima 2018 (PMID:29536338), verbatim "the half-life (t1/2, ~ 1 week)", though note Enebo 2021 measured 145-165 h, so 168 h sits just outside a measured interval. ka 0.02 /h and F 0.89 dropped: neither appears in any human abstract, and the only verbatim bioavailability is 76.65-82.85% in RAT (PMID:36989942), not imported because species-mixing an otherwise-human record would degrade it. PK: ABSORPTION RATE AUTHORED FROM A VERBATIM PEAK TIME. This row carried no ka, so the solver substituted 1.0/h and the modelled peak landed at 5.5 h — for a slowly-absorbed subcutaneous product that is wrong by design, not by a little. Source: "Semaglutide 2.4 mg had a half-life of 145-165 h, with a median tmax of 12-24 h". RANGE: shorter endpoint taken. THE SAME PASSAGE REPORTS CAGRILINTIDE at "a median tmax of 24-72 h" — that figure belongs to the other drug and taking it would be a shared-sentence transplant. With the stored half-life fixing ke, Tmax solves uniquely for ka by inverting the model own definition, ln(ka/ke)/(ka-ke) = Tmax — ARITHMETIC, NOT AN ESTIMATE — giving 0.3813/h, which reproduces 12 h on substitution. EXPOSURE IS UNCHANGED: the absorption rate cancels out of AUC entirely, so only the shape moves.
Pharmacokinetics
- Subcutaneous — t½ 7.0 d · ka 0.3813 h⁻¹ · Vd 7.7 L
Related compounds
- Empagliflozin — synergistic
- Sitagliptin — caution
- Cagrilintide — synergistic
Sources: PMID:26308095, PMID:31031702, PMID:29536338, PMID:30788808, PMID:33894838