Retatrutide
Retatrutide, a peptide. Triple agonist at GLP-1R, GIP-R, and glucagon receptor. 39-residue peptide with Aib substitutions (positions 2 and… Subcutaneous half-life 6 d.
Triple agonist at GLP-1R, GIP-R, and glucagon receptor. 39-residue peptide with Aib substitutions (positions 2 and 20) and a C-20 fatty diacid linker on Lys(17) via a γGlu-2×OEG spacer that binds albumin, extending t½ into once-weekly territory. Glucagon arm drives additional energy expenditure beyond GLP-1/GIP satiety effects.
Receptor EC50 values (Coskun 2022) reflect in vitro cAMP signaling at human-receptor-expressing HEK293 lines: GLP-1R ~3 pM, GIPR ~10 pM, GCGR ~30 pM. Therapeutic plasma (~50–100 ng/mL = ~0.05–0.1 mg/L) is 4–5 orders of magnitude above EC50, so all three receptors saturate within minutes of any dose and remain occupied throughout the week — the OccupancyTile will show 100% across the dosing interval, which is pharmacologically faithful even if visually static. PK: half-life re-cited 2026-09-06. The value is unchanged and correct — Urva 2022 (PMID:36354040), 72 adults with type 2 diabetes, SC once weekly, verbatim "its half-life was approximately 6 days" = 144 h — but it had been attributed to PMID:37366315, the phase 2 EFFICACY trial, whose abstract reports body-weight change and adverse events and no PK parameter at all. ka 0.02 /h and V 7 L dropped: neither appears in any abstract, and both are registry-wide defaults (V 7 L is plasma volume, shared by 13 unrelated compounds). PK: ABSORPTION RATE RESTORED AFTER A REPORTED REGRESSION — the curve was peaking at 5.4 hours where a once-weekly subcutaneous depot should peak in days. THE EARLIER REMOVAL WAS THE RIGHT DIAGNOSIS AND THE WRONG REMEDY: 0.02/h appears in no abstract, which is true, but deleting an absorption rate does not leave the record without one — the solver substitutes 1.0/h, FIFTY TIMES FASTER, and the modelled peak moved from 93.8 h to 5.4 h. Exposure never changed, because the absorption rate cancels out of it; what broke is the shape, which for a depot product is the whole point of the formulation. THE NOTE THAT REMOVED IT CONTAINS THE MISCONCEPTION AND IT IS WORTH NAMING: it called 0.02 "a registry-wide default". It was a value REPEATED ACROSS PEPTIDE RECORDS, which is not the same thing as the value the SOLVER falls back to, and the two differ by fifty-fold in opposite directions. THIS IS STILL NOT A SOURCED NUMBER. No indexed abstract states a retatrutide peak time — its three cited papers and a targeted search give none — so this is a choice between two unsourced values with no null option available, and 0.02 is restored because the peak it implies, about 3.9 days, is in the right regime for a weekly acylated depot while 1.0/h is not. Declared an estimate, not a measurement. THE VOLUME IS DELIBERATELY NOT RESTORED: the 7 L that went with it was plasma volume shared by thirteen unrelated records and was cleared for good reason, and volume does not affect the peak time this fix is about.
Pharmacokinetics
- Subcutaneous — t½ 6.0 d · ka 0.02 h⁻¹
Sources: PMID:37366315, PMID:35985340, PMID:36354040