Half-life

The definition that avoids the common mistake

Toutain and Bousquet-Mélou state the distinction in the first line of their 2004 paper. Terminal plasma half-life is the time required to divide the plasma concentration by two after pseudo-equilibrium has been reached. It is not the time required to eliminate half the administered dose. [1] PMID: 15601438

That second sentence is the one peptide pages usually skip. A molecule can leave plasma on one clock and still have most of an injected dose sitting in tissue, or already gone as metabolite. Half-life, used properly, is a plasma-concentration statement.

What controls it

When absorption is not the slow step, half-life is a hybrid. Clearance and the extent of distribution both set it. When absorption is the slow step, the terminal half-life reflects the rate and extent of absorption instead of elimination. The authors call that flip-flop pharmacokinetics. A long terminal half-life after a subcutaneous injection can be the injection site releasing the drug slowly, not the body failing to clear it. [2] PMID: 15601438

This is why half-life should not be copied from an intravenous study onto a subcutaneous product, or from a rat paper onto a human vial, without saying which phase and which route were measured. Richter and Jacobsen note that subcutaneous absorption of biotherapeutics is relatively slow. [3] PMID: 25100673 Slow absorption is exactly the condition under which flip-flop can make the terminal slope lie about elimination.

What half-life is not

It is not "how long it works." A hormone pulse can end while the peptide is still measurable, or a receptor effect can outlast the plasma peak. Bowers reported that after intravenous injection of an early growth-hormone-releasing hexapeptide, growth hormone rose within 2 minutes, peaked at 10 to 20 minutes, and had usually returned to normal by 2 hours. [4] PMID: 6714155 That time course is a hormone response. It is not the half-life of the hexapeptide, and the paper does not pretend it is.

Half-life is also the parameter that matters for repeated dosing, because it governs accumulation, how much the concentration swings, and how long it takes to reach equilibrium. [5] PMID: 15601438 A single-dose anecdote does not answer those questions.

How CompoundGuide should use the number

Dosing and administration guides on this site mention half-life because readers ask for it. The number is only meaningful with a matrix (plasma or not), a phase (terminal or not), a route, and a species. If a compound page quotes a half-life, this definition is the standard it has to meet. A bare "half-life of X minutes" with none of those qualifiers is not a pharmacokinetic result.