3 Clinical psychopharmacology3.2 Pharmacokinetics
3.2.6 Therapeutic drug monitoring
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Written by Resident Doctor Committee · Published
When a level is worth measuring
Therapeutic drug monitoring measures a drug or active metabolite level to judge exposure, response, toxicity or adherence.
A level helps most when dose predicts concentration poorly and concentration tracks response or toxicity.
Reasons to measure include suspected toxicity, poor response, doubtful adherence, interacting drugs, changing organ function and pregnancy.
Treat suspected serious toxicity at once rather than waiting for the result.
Therapeutic index
The therapeutic index is the ratio of the lowest toxic plasma level to the lowest therapeutic plasma level. It measures a drug's margin of safety.
Index | Meaning | Examples |
|---|---|---|
Narrow | Small changes in dose or level cause toxicity or loss of effect | Lithium, carbamazepine, phenytoin, digoxin, warfarin, theophylline |
Wide | Relatively safe in overdose, and dosed by response rather than by levels | Sertraline |
Lithium has the narrowest therapeutic index of the commonly prescribed psychotropics: toxicity begins at serum levels only a little above the target range.
Lithium monitoring
Point | Detail |
|---|---|
Sample time | 12 hours after the last dose, so the morning after a night-time dose |
After a dose change | About one week, then weekly until stable |
Long-term | Three-monthly in the first year, then every three to six months; renal and thyroid tests six-monthly |
Maintenance range | 0.6 to 0.8 mmol/L; up to 1.0 for poor response; 0.4 to 0.6 in older people |
Toxicity | Often above 1.5 mmol/L and severe above 2.0, but possible at lower levels |
The 12-hour rule exists because reference ranges were standardised on 12-hour samples. An earlier sample reads high and the pre-dose trough reads low.
One week is long enough because steady state takes about five half-lives and lithium's half-life is roughly 24 hours.
New gastrointestinal upset is an early sign of toxicity. Ataxia, dysarthria, coarse tremor and confusion mark established toxicity.
Fine tremor is expected at therapeutic levels, unlike coarse tremor.
Target ranges of other drugs
Relationship | Drugs |
|---|---|
Therapeutic window: response is poorer above and below the range | Nortriptyline, the best established |
Response threshold only | Clozapine, imipramine |
Toxicity ceiling only | Lithium |
No level-response relationship | Selective serotonin reuptake inhibitors |
Drug | What is measured | Target |
|---|---|---|
Nortriptyline | Parent drug | 50 to 150 micrograms/L |
Amitriptyline | Parent plus its metabolite nortriptyline | 100 to 200 micrograms/L |
Clozapine | Parent, with norclozapine reported alongside | 350 to 500 micrograms/L |
Olanzapine | Parent, sampled 12 hours after the dose | 20 to 40 micrograms/L |
Risperidone | Active moiety: parent plus 9-hydroxyrisperidone | 20 to 60 micrograms/L, also used for paliperidone alone |
Carbamazepine (bipolar disorder) | Parent drug | Above 7 mg/L |
Phenytoin | Parent drug | 10 to 20 mg/L |
Valproate | Total drug | 50 to 100 mg/L |
Norclozapine (N-desmethylclozapine) is clozapine's principal active metabolite. The parent to metabolite ratio helps judge sample timing and metabolism.
Clozapine's seizure risk rises above about 1,000 micrograms/L.
Smoking lowers olanzapine levels by inducing cytochrome P450 1A2 (CYP1A2).
Autoinduction lowers carbamazepine levels over the first few weeks, with clearance changing for three to five weeks.
Interpreting a level
Before acting on an unexpected level, check sample timing, steady state, missed doses, organ function, interactions and smoking.
Reference ranges are population probabilities: some people respond below the range and others are toxic within it.
Hypoalbuminaemia can lower total valproate while free drug stays normal, so raising the dose to correct the total risks toxicity.