Half-life and steady state: why week 5 feels different than week 1

A compound with a seven-day half-life doesn't reach its full blood level until roughly week five — and after the last injection, it takes just as long to leave. That one fact explains most of the confusing timeline reports around weekly peptides: the underwhelming first week, the side effects that appear a month in on an unchanged dose, and the effects that linger long after stopping. This article walks through the arithmetic — first-order elimination, the five-half-lives rule, and accumulation — with real half-life figures across compound classes.

First-order elimination in plain language

Most peptides are cleared by first-order elimination: in any given stretch of time, the body removes a constant fraction of what's circulating, not a constant amount. When a lot of drug is on board, a lot gets cleared per day; as levels fall, absolute clearance falls with them. Plotted, the concentration traces a decaying exponential — steep at first, then a long shallow tail.

The half-life is the time it takes the concentration to fall by half, and under first-order kinetics it stays constant no matter where on the curve you are. So the ledger after a single dose reads:

• 1 half-life: 50% remains
• 2 half-lives: 25%
• 3 half-lives: 12.5%
• 4 half-lives: 6.25%
• 5 half-lives: ~3%

The standard working rule falls straight out of that table: after about five half-lives, a single dose is ~97% gone.

The rule works in both directions

The same arithmetic that drains a dose also fills a plateau. Dose repeatedly at a fixed interval and the level climbs toward steady state along the mirror image of the decay curve: 50% of the eventual plateau after one half-life of dosing, 75% after two, 87.5%, 93.8%, and ~97% after five.

Steady state is the point where rate in equals rate out — each dosing interval now clears exactly one dose's worth. The level stops climbing not because the body "adapted," but because first-order elimination scales with concentration until it catches up with the input.

Accumulation: why the trough roughly doubles

Make it concrete with a weekly injection of a compound whose half-life is seven days — the profile of semaglutide, whose FDA label puts the half-life at about one week.

• Just before dose 2, half of dose 1 remains: the trough is 0.5 dose-equivalents.
• Just before dose 3, half of (1 + 0.5) remains: 0.75.
• Then 0.875, 0.938, 0.969 — converging on exactly 1.0 full dose riding underneath every fresh injection.

Between week 1 and week 5, the trough roughly doubles — from 0.5 to 1.0 dose-equivalents — while the injected dose never changed. Peaks climb the same way, from 1.0 toward 2.0. When the dosing interval equals the half-life, the steady-state accumulation ratio is exactly 2.

Stretch the interval relative to the half-life and accumulation shrinks; compress it and accumulation grows. Tirzepatide (half-life ~5 days, injected every 7) accumulates about 1.6-fold, and the Mounjaro label reports steady state after 4 weeks of once-weekly dosing. Ozempic and Wegovy labeling puts semaglutide steady state at 4–5 weeks. Liraglutide, with a ~13-hour half-life dosed daily, plateaus within about three days.

Two classes, two clocks

The long-acting GLP-1 class is engineered for slow clearance — fatty-acid side chains and other modifications that bind albumin and resist degradation. Hence half-lives measured in days: semaglutide ~7, tirzepatide ~5, dulaglutide ~5, and — among investigational agents not yet approved anywhere — retatrutide at ~6 days and cagrilintide at ~7–8 days.

Growth-hormone secretagogues sit at the other extreme, and most are not approved for human use: ipamorelin and both forms of CJC-1295 are sold as research chemicals, while sermorelin was formerly an approved product (Geref, since discontinued) and tesamorelin remains FDA-approved as Egrifta. Their half-lives are measured in minutes to hours: sermorelin ~10–20 minutes, tesamorelin ~26–38 minutes, CJC-1295 (no DAC) ~30 minutes, ipamorelin ~2 hours (human pharmacokinetics modeled by Gobburu et al., 1999). The exception proves the engineering rule: CJC-1295 (DAC) adds a drug-affinity-complex modification that binds albumin and stretches the half-life to ~6–8 days (Teichman et al., 2006).

The two clocks produce opposite pharmacology. A compound with a ~2-hour half-life is ~97% gone about ten hours after injection: nothing carries over from one day to the next, each dose is a standalone pulse, and "steady state" isn't a meaningful target — the transient spike is the entire mechanism. For a weekly GLP-1, it's the reverse: the plateau is the mechanism, and any single injection matters less than the accumulated floor beneath it.

Representative compounds and time to steady state

Half-life figures below match the PeptideLab compound catalog; time to steady state assumes the ~5-half-lives rule under regular repeat dosing. MK-677 (Ibutamoren), ipamorelin, and both CJC-1295 forms are not approved pharmaceuticals.

Why experience reports sound the way they do

Read against the math, the three most common timeline reports stop being mysterious.

"Felt nothing in week 1." After one injection of a 7-day-half-life compound, exposure sits at roughly half the eventual plateau — and on the approved GLP-1 products, week 1 is also the lowest rung of the label's titration ladder. Both effects stack.

"Side effects ramped in week 3–4, same dose." By weeks 3–4 exposure has climbed to 88–94% of steady state. The dose didn't change; the concentration did. A trough that has doubled since week 1 is a real pharmacological difference, not a perception shift.

"Felt it for weeks after stopping." One week after the last dose of a 7-day-half-life compound, half is still circulating; at two weeks, a quarter; only around week 5 does it fall to ~3%. The Wegovy label acknowledges the tail directly: it instructs discontinuing at least two months before a planned pregnancy because of the long washout period.

Titration schedules encode the same math

The escalation rhythm on GLP-1 labels is pharmacokinetics made policy. STEP 1 (Wilding et al., NEJM 2021) escalated semaglutide every 4 weeks — 0.25, 0.5, 1.0, 1.7, then 2.4 mg weekly by week 16 — the schedule the Wegovy label adopted. SURMOUNT-1 (Jastreboff et al., NEJM 2022) started tirzepatide at 2.5 mg weekly and stepped up in 2.5 mg increments every 4 weeks; the Zepbound label requires at least 4 weeks on a dose before each increase.

Four weeks is roughly four to six half-lives for these molecules. Each rung is held until exposure is near its plateau, so tolerability gets judged at steady state rather than at first exposure — and the next step begins from a known floor instead of a moving one.

Washout, and what it means for self-experiments

The rule runs backwards at discontinuation: ~5 half-lives to ~97% cleared. For semaglutide that's about 5 weeks; tirzepatide, about 3.5; ipamorelin, about 10 hours.

For anyone running n=1 comparisons, two implications follow. First, an effect can't cleanly be attributed to a compound started one week after stopping a weekly GLP-1 — the previous compound is still at roughly half strength, so the "new" observation is really a crossover with contamination. Washout windows should be counted in half-lives, not calendar habit. Second, "stopped for two weeks and felt fine" says little about discontinuing a 7-day-half-life compound: exposure at day 14 is still around 25%.

This is also where honest modeling matters. An exposure curve can only be drawn from characterized pharmacokinetics. BPC-157 is the standard cautionary example — not approved for human use, sold as a research chemical, and without published human pharmacokinetics. Stability work suggests it survives only minutes in plasma, but there is no defensible human half-life to compute a steady state or washout window from. PeptideLab's modeled-exposure view builds these curves from logged doses and published half-lives for exactly this reason — where no characterized PK exists, it declines to draw a curve rather than invent one.

The practical summary: week 5 feels different than week 1 because it is different — roughly twice the trough on the same weekly dose. Any plan for starting, comparing, or stopping a compound that ignores its half-life is arguing with an exponential, and the exponential wins.

Sources

• Wegovy (semaglutide) Prescribing Information, Novo Nordisk — half-life, titration schedule, pre-pregnancy discontinuation guidance.
• Ozempic (semaglutide) Prescribing Information, Novo Nordisk — steady state after 4–5 weeks of once-weekly dosing.
• Zepbound and Mounjaro (tirzepatide) Prescribing Information, Eli Lilly — half-life ~5 days, steady state after 4 weeks, 4-week escalation steps.
• Victoza (liraglutide) Prescribing Information, Novo Nordisk — half-life ~13 hours.
• Egrifta (tesamorelin) Prescribing Information, Theratechnologies — half-life.
• Wilding JPH et al. Once-weekly semaglutide in adults with overweight or obesity (STEP 1). New England Journal of Medicine, 2021.
• Jastreboff AM et al. Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). New England Journal of Medicine, 2022.
• Teichman SL et al. Prolonged stimulation of growth hormone and insulin-like growth factor I secretion by CJC-1295, a long-acting analog of GH-releasing hormone, in healthy adults. Journal of Clinical Endocrinology & Metabolism, 2006.
• Gobburu JV et al. Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers. Pharmaceutical Research, 1999.
• Rowland M, Tozer TN. Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications — first-order kinetics, accumulation, time to steady state.