3 Clinical psychopharmacology3.2 Pharmacokinetics

3.2.1.4 Half life, Tmax, Cmax, volume of distribution and AUC

Creator: Resident Doctor Committee
Published: 2026-10-14T21:05:16.259Z

4 min read3 figures

Written by Resident Doctor Committee · Published 14 October 2026

Half-life and clearance

Half-life (t1/2) is the time it takes for plasma concentration to halve.
Under first-order kinetics a constant fraction of drug is removed per unit time, so half-life stays constant and concentration falls exponentially.
Clearance (CL) is a drug-specific constant, and under first-order kinetics it does not change with dose.
In a one-compartment model t1/2 = 0.693 x Vd / CL, where Vd is volume of distribution, so wider distribution or lower clearance lengthens half-life.
A long half-life allows infrequent dosing, while a short half-life needs divided doses or a modified-release form.

Half-lives elapsed	Drug eliminated after stopping, or share of steady-state plateau reached
1	50%
2	75%
3	87.5%
4	94%
5	97%

Steady state under regular dosing is reached after about four to five half-lives, because each half-life closes half the remaining gap to the plateau.
Half-life alone sets the time to steady state; dose and dosing frequency do not change it, though dose sets the height of the plateau.
When a drug has a long-lived active metabolite, that component sets the time to steady state, so the drug takes longer to reach it.
A drug is treated as eliminated after four to five half-lives; lithium, with a half-life of about 24 hours, is about 97% gone after five days.

Apparent volume of distribution (Vd) is the amount of drug in the body divided by its plasma concentration, and it can exceed body size.
After a known intravenous dose, Vd = dose / plasma concentration at time zero, with the units made consistent.
Rearranged, the amount in the body = Vd x plasma concentration, which equals the dose given when bioavailability is complete and no drug has yet been eliminated.
A 70 kg adult with Vd 0.7 L/kg has a Vd of 49 L, so a concentration of 10 mg/L means about 490 mg is in the body.
A large Vd means extensive tissue binding, so amitriptyline and fluoxetine are poorly removed by dialysis, whereas lithium is dialysable.
The loading dose = target plasma concentration x Vd, divided by bioavailability (F) when the drug is given orally.
Vd sizes the loading dose, whereas clearance sets the maintenance dose.

Parameter	What it describes	With a slower-release formulation
Tmax	Time of the peak concentration, reflecting absorption rate	Later
Cmax	Height of the peak concentration	Lower
AUC	Area under the plasma concentration-time curve: cumulative systemic exposure	Usually unchanged

AUC measures total exposure over time, whereas Cmax, Tmax and half-life each describe one feature of the curve.
Under linear kinetics AUC = F x dose / CL, so doubling the dose doubles AUC unless absorption or metabolism saturates.
Absolute bioavailability is the dose-normalised oral AUC divided by the dose-normalised intravenous AUC.
Identical AUC does not guarantee identical peaks or tolerability, so bioequivalence testing compares both AUC and Cmax.
Immediate-release quetiapine peaks at about 1 to 1.5 hours, sooner than other common oral antipsychotics, which peak at 2 to 8 hours.

Drug	Half-life	Consequence
Quetiapine	About 6 to 7 hours, the shortest of the common second-generation antipsychotics	Immediate-release form is taken in divided doses
Clozapine, amisulpride	About 12 hours	Longer than quetiapine
Aripiprazole	About 75 hours (3 days); active metabolite longer still	Slow accumulation
Cariprazine	2 to 4 days; its main circulating active moiety, didesmethylcariprazine, 1 to 3 weeks	Akathisia and other effects may not appear for several weeks
Paliperidone palmitate depot	About 25 to 49 days, the longest of the common depots	Persistence is limited by release from the injection site
Decanoate ester depots	About 2 to 3 weeks
Risperidone microspheres	A few days

Drug	Half-life	Consequence
Fluoxetine	2 to 4 days, the longest of the selective serotonin reuptake inhibitors (SSRIs); norfluoxetine 1 to 2 weeks	Steady state takes weeks; allow at least 5 weeks before starting an irreversible monoamine oxidase inhibitor (MAOI)
Fluvoxamine	About 15 hours, the shortest SSRI	Other SSRIs run 21 hours or more
Duloxetine	About 12 hours (range 8 to 17)
Vortioxetine	About 66 hours (3 days)	Steady state takes about 2 weeks
Agomelatine	Mean 1 to 2 hours	Mostly cleared by cytochrome P450 1A2
Tranylcypromine	About 2 hours	Effect lasts until monoamine oxidase is resynthesised

Norfluoxetine is cleared far more slowly than any other antidepressant metabolite.
Irreversible non-selective MAOIs all have plasma half-lives of hours, so their half-life does not predict how long their effect lasts.

Drug	Half-life	Consequence
Donepezil	About 70 hours	Once-daily dosing
Buspirone	Short, about 2 to 11 hours	Divided daily doses

Drug	Half-life	Consequence
Midazolam	Shortest of the oral benzodiazepines	Short-acting
Triazolo- and imidazo-benzodiazepines, such as triazolam	About 2 hours	Short-acting
Lorazepam	About 10 to 20 hours	Intermediate; rebound and withdrawal possible
Nitrazepam	About 24 hours, near 40 hours in older adults	Long-acting; residual sedation and falls
Zaleplon	About 1 hour, one of the shortest hypnotics	Suits sleep-onset insomnia
Zolpidem	About 2 to 3 hours	Shortest of the common hypnotics and anxiolytics
Zopiclone	About 5 hours	Relatively short hypnotic action

Z-drug hypnotics have half-lives of about 2 to 6 hours, shorter than every benzodiazepine, so they leave the least drug on board by morning.

Revision material for the MRCPsych examinations. Not clinical guidance, and not for use in patient care.