Therapeutic Drug Monitoring

Clare Ford Clinical Chemistry Royal Wolverhampton Hospitals NHS Trust

Applied Pharmacokinetics

Processes involved in drug handling

Dose Prescribed
concordance

Concordance (compliance)
Often poor. Improved by simplifying regimes Assessment:

Other tissues
distribution

Dose taken

absorption

Drug in blood
Metabolism/ elimination

Active site

EFFECT

Was Rx dispensed? Tablet counts Direct observation/ interview Drug/metabolite levels Effect

Excreted/ inactivated drug pharmacokinetics pharmacodynamics

Bioavailability

First-pass metabolism
Metabolism en route from gut to systemic circulation in the LIVER

Bioavailability,

F = Dose absorbed Dose administered

(IV dosing, bioavailability = 1)

Drugs with extensive first-pass metabolism: Analgesics (aspirin, morphine, paracetamol, pethidine) CNS-active drugs (chlormethiazole, chlorpromazine) Cardiovascular (glyceryl trinitrate, nifedipine) Respiratory (salbutamol, terbutaline) Oral contraceptives

First-pass metabolism
One reason for apparent variations in drug absorption between individuals Reduced in severe liver disease
Greatly increased delivery of drug to active site

Salt-conversion factor (S)

Factor relating to the actual concentration of active drug in the preparation being used
e.g. 108 mg phenytoin sodium = 100 mg phenytoin e.g. 200 mg aminophylline = 160 mg theophylline
(aminophylline is the EDTA salt of theophylline, S = 0.8) So, DRUG ABSORBED = S x F x DOSE ADMINISTERED

Distribution
We define:
Volume of Distribution, Vd = Amount of drug in body Plasma concentration

Volume of distribution
For example:
Amiodarone Digoxin Phenytoin Aspirin Vd is LOW if Vd (L/kg) 1.3 7.3 0.65 0.14

Volume of distribution is the THEORETICAL VOLUME that would contain all the drug in the body if it were present everywhere at the same concentration that is found in plasma

low lipid solubility - high plasma protein binding - low tissue binding (and vice versa)

Metabolism and Excretion

Metabolism usually hepatic Excretion - via kidneys into the urine - via liver into the bile Both these processes are encompassed in the pharmacokinetic parameter CLEARANCE

Plasma protein binding

Primarily to ALBUMIN and 1 acid glycoprotein % plasma protein binding
Lithium Gentamicin Digoxin Theophylline Carbamazepine Phenytoin 0% <10% 20% 60% 70-80% 90-94%

Reduced plasma protein binding

Reduced protein binding (more free drug)
Low protein (liver disease, pregnancy, nephrotic syndrome) Displacement (renal failure, other drugs) Abnormal binding proteins

Decreased protein binding

Free fraction Free conc. Total conc.

Initially

New steady state

First-order kinetics
Rate of elimination
Amount of drug in = body at time t

Peak and trough concentrations

C

A0e-kt

Conc

where A0 is the amount at time 0 and k is the elimination rate constant - the percentage elimination per unit time

Time

Non-linear (saturation) kinetics

150 GW

Non-linear (saturation) kinetics

Michaelis-Menten equation
Rate of elimination =
PHe

100 Plasma conc. umol/L 50

Vmax x C Km + C Vmax x C Km FIRST ORDER = Vmax ZERO ORDER

If
PHo

C << Km

Rate =

If

C>> Km

Rate =

Vmax x C C

0 0 100 200 300 400 500 600 700 Dose mg/day

Therapeutic Drug Monitoring

Anticonvulsant prescribing without TDM

Measuring drug or metabolite concentrations in body fluids as an aid to optimising therapy

1. Prescribe drug in standard dosage 2. If no effect, add another drug (also in standard dosage) 3. Add third or fourth drug 4. If fits continue, tell patient to learn to live with them .

Patient

Reduction in polypharmacy
Drug

40 adult OPs with chronic epilepsy. Reduction to single drug possible in 29 (72%). Of these, 1 year later, seizure control:
Better in 55% Same in 28% Worse in 17%
(Shorvon & Reynolds, 1979)

Initial dose

Revise dose

Plasma concentration Measure Interpret

Effect

Measure

Dose prescribed compliance Dose taken pharmacokinetics

absorption distribution metabolism excretion

Criteria for valid TDM

Drug has reversible action at receptor site Dose has poor correlation with effect Plasma concentration correlates well with effect Narrow therapeutic ratio Well-established therapeutic range

Serum concentration
diffusion transport

Concentration at receptor pharmacodynamics

tissue responsiveness other drugs

Pharmacological effect

Drugs for routine measurement

Established value
Aminoglycosides Carbamazepine Ciclosporin Digoxin Lithium Methotrexate Mycophenolate Phenytoin Tacrolimus Theophylline Vancomycin

Drugs for routine measurement

Less well -established Amiodarone Anti-retrovirals Caffeine Chloramphenicol Clozapine Disopyramide Flecainide Flucytosine Haloperidol Lamotrigine Olanzapine Phenobarbital Procainamide Quinidine Sirolimus Tricyclics Valproate

Aminoglycosides
Poor oral absorption give parenterally No metabolism or protein binding renal excretion Half-life 2-4h (much longer in renal failure) Toxicity nephrotoxicity and ototoxicity Monitoring essential for control/toxicity (low therapeutic index) Extended dose interval
High peaks, low troughs 7 mg/kg gentamicin

Extended interval aminoglycosides: dosing (Hartford nomogram)

35 30 25

Conc. (mg/L)

20 15 10 5 0

Every 48h Every 36h Every 24h

6 10
Time post dose (h) 14.00

Use TDM to determine interval, not dose (e.g. Hartford nomogram)

Not applicable to children (?), pregnancy, ascites, endocarditis, CF, burns, neutropenia, CrCl < 20 mL/min

6.00

14

Digoxin post-dose

Digoxin
Samples must be at least 6h post-dose Used in management of some types of chronic cardiac failure and arrhythmia Other factors (e.g. K+) influence response/toxicity.
Toxicity exacerbated by hypokalaemia

(Nicholson, 1980)
2.5

1.5

C/Css
1

Monitoring not indicated in most patients Monitor if:

Response poor ? Toxic (GI, neurotoxicity) ? Stop drug

0.5

0 0 5 10 15 20 25

Hours post dose

Lithium
Half-life 10-35 h (longer in elderly/poor renal function) Not protein bound Excreted in urine Side effects thirst, polyuria, hypothyroidism, renal impairment, coma Monitor at 12h post-dose Target range @ 12h 0.4-0.8 mmol/L (up to 1.2 in acute Rx) Individualise frequency of monitoring Interactions dec clearance: thiazides, NSAIDs Monitoring essential at start of Rx, advisable at intervals thereafter, especially if ill/pregnant or if other drugs changed (especially diuretics)

Theophylline
Bronchodilator Short half-life (3-13h: 4h in smokers, 24-30 h in neonates) trough measurements Hepatic metabolism Protein binding 50-65% (less in babies) Side effects: CNS, GI, cardiac Target range 10-20 mg/L (55-110 umol/L) (lower in babies) Interactions: erythromycin dec clearance, enzyme inducers (phenytoin, CBZ) inc clearance Monitoring useful to identify undertreated patients, adjust dosage and confirm toxicity Compliance often erratic

Epilepsy
Commonest neurological disorder Highest therapeutic potential 0.5-1% of population 50 million worldwide 20-30% still have fits despite Rx

Antiepileptic drugs (UK)

Bromide Phenobarbitone Phenytoin Ethosuximide Carbamazepine Valproate Clonazepam Clobazam 1857 1912 1938 1960 1972 1972 1974 1978

Vigabatrin Lamotrigine Gabapentin Topiramate Tiagabine Oxcarbazepine Levatiracetam Pregbalin

1989 1991 1993 1996 1998 2000 2000 2004

Epilepsy - Rx
There is scarcely a substance in the world capable of passing through the gullet of man that has not, from time to time, enjoyed the reputation of being an antiepileptic
Sieveking, 1858

Inhibit excitation Enhance inhibition Modify cell excitability

Phenytoin
(Richens and Dunlop. 1975)

Phenytoin
Long half-life (20 40 h, up to 100h at high concs)
timing unimportant

150 GW

Saturation kinetics Metabolism hepatic oxidation

Faster in infants/children, slower in preterm Inc by ethanol and carbamazepine, dec by enzyme inhibitors (e.g. cimetidine)

100 Plasma conc. umol/L 50

PHe

90-93% protein-bound Side effects neurotoxicity (nausea, ataxia, drowsiness) cosmetic Target range 10-20 mg/L (40-80 umol/L)
Only a guide wide variation

PHo

Very strong case for routine monitoring

0 0 100 200 300 400 500 600 700 Dose mg/day

Carbamazepine
Short half-life (8-24h) Trough samples preferable Target range 4-10 mg/L (17-42 umol/L) Protein binding 22-30% Side effects rash (5%), haematological (rare), neurotoxicity (mild), ADH stimulation (hyponatraemia) Induces own metabolism (hepatic oxidation) Clearance inc by phenytoin/phenobarbitone, dec by enzyme inhibitors Monitor if control difficult Active metabolite (CBZ 10,11 epoxide)

Valproate
Half-life 8-15h Wide diurnal variation (rapid absorption and elimination) Hepatic metabolism (CBZ, phenytoin increase clearance) Very poor evidence for target range
Clinical effect may take weeks to develop Antiepileptic effect persists after dose stopped Poor correlation between conc and effect

Protein binding 90-95%

Dose dependent (free fraction varies with concentration) Displaced from protein by fatty acids (meals), aspirin

Side effects: GI, drowsiness, tremor, hepatotoxicity (in young children), haematological. teratogenic Monitoring generally unnecessary

Vigabatrin
Gamma-vinyl GABA Structural analogue of the inhibitory neurotransmitter GABA Suicide inhibitor of GABA transaminase Irreversible - long pharmacodynamic halflife Monitoring not helpful

GABA + -ketoglutarate
GABA transaminase

Succinic semialdehyde + glutamate

Transplantation & Immunosuppressants

1887 1954 1962 1964 1967 1983 1985 1994 1995 First corneal transplant First kidney transplant Azathioprine First liver transplant First heart transplant Cyclosporin OKT3 Tacrolimus Mycophenolate mofetil

Goals for immunosuppressive Rx

Prevent acute and chronic rejection Minimise side effects of Rx Avoid over-immunosuppression resulting in opportunistic infection Minimise use of anti-rejection medication
(and associated cost)

Targets for immunosuppressants

Allograft or Autoreactive cell

Applications of immunosuppressants
macrophage Class II antigens
V V

IL- 1

steroids
V

prevention of rejection in allotransplantation treatment of autoimmune disease

azathioprine/MTX in RhA MTX in psoriasis CsA in RhA (early onset IDDM) etc cyclophosphamide in autoimmune nephrotic conditions

CD3

DNA

Helper T cell

OKT-3
CD3 complement

Ciclosporin, tacrolimus

TC

B
proliferation differentiation

TNF, lymphotoxin etc. .

azathioprine methotrexate mycophenolate steroids

sirolimus
activated T cells plasma cells

ANTIBODY

Immunosuppressants
Increasing range of drugs Trend to:
drug combinations lower doses reduced toxicity for same/improved effect

Ciclosporin A
Cyclic undecapeptide ex Tolypocladium inflatum Gams Very hydrophobic/lipophilic Highly selective inhibitor of T cell activation (inhibits IL2 synth by helper T cells) No myelosuppression

Ciclosporin monitoring
Whole blood assay (drug concentrated in red cells) Use of concentration at 2h (C2)
Better correlation with AUC (exposure)

Tacrolimus (FK-506)
Similar mechanism of action to CsA, but 10 to 100 x more potent Measure trough level Can reverse acute allograft rejection Same TDM problems as CsA
Specificity requires MS Metabolites (not a problem if LCMSMS)

Essentials for effective TDM

Rational indication for assay Appropriate sample Accurate analysis Correct interpretation Necessary action taken

TDM - questions
Patient not responding to therapy Could this be due to inadequate plasma concentration? Why is plasma concentration inadequate?
Poor compliance? Inappropriate dosage? Rapid metabolism? Malabsorption?

Could patients symptoms be caused by drug toxicity?

Sample
Has steady-state been reached?
(>4 to 5 half-lives after dose change)

Interpretation
Concept of the Therapeutic Range
a guide to aim at!

? Appropriate timing after last dose

Therapeutic decisions should never be based solely on the drug concentration in the serum
(Koch-Weser, 1972)