TDM

Question 1

What is therapeutic drug monitoring?

Answer 1

The measurement of blood drug concentrations for the purpose of ensuring adequate and effective treatment while avoiding potential toxicity.

Question 2

What is the therapeutic and toxic response to a drug directly related to?

Answer 2

The therapeutic (and toxic) response to a drug is directly related to its concentration at some specific “receptor”
AND
The blood concentration of the drug reflects the concentration at the target receptor.

We can’t sample the receptor.

Question 3

What is the concept of the therapeutic range?

Answer 3

A range of serum drug concentrations associated with effective therapy but w/o significant toxicity or side effects

Analogous to reference interval

Derived from clinical studies (drug trials)

Question 4

Why do TDM?

Answer 4

Optimize dose and therapeutic response
—Undertreatment may be dangerous

Avoid toxicity
—-Overtreatment may be dangerous

Detect changes or variability in pharmacokinetics

Monitor compliance
—Is the patient taking the drug as prescribed?

Question 5

What is pharmacokinetics?

Answer 5

What the body does to a drug

Question 6

ADME stands for?

Answer 6

Absorption
Distribution
Metabolism
Elimination

Question 7

What is pharmacodynamics?

Answer 7

What the drug does to the body

effects and mechanism of action

Question 8

A single drug dose does ____result in the same ________dose in everyone.

Answer 8

NOT,

DOSE CONCENTRATION

Question 9

Pharmacological response is caused by ?

Answer 9

free drug bound to receptor site

Question 10

What are three ways to administer drugs? Describe the absorption and variability for each.

Answer 10

Intravenous administration

• –“instantaneous” and complete – not a variable
• –requires professional administration = cost

Intramuscular or subcutaneous
—-slower

Oral

Question 11

What is meant by distribution of a drug? What can it be affected by?

Answer 11

Delivery of a drug to various compartments
central – blood (and interstitial fluid) = ECF
peripheral – other tissues/organs

Distribution is affected by:

• —binding to blood proteins
• —lipophilicity (high distribution by depositing in fat)
• —specific binding in tissues (ie: digoxin bound up in heart and muscle/specific receptors bind tightly

Question 12

Why do we not draw drug levels during distribution phase?

Answer 12

Because blood levels overestimate how much drug is actually taken up by tissues.
Drug levels should be drawn AFTER distribution is complete.

Question 13

What are two proteins that bind drugs?

Answer 13

Albumin

• –binds acid & neutral drugs
• ——–phenytoin, carbamazepine, VPA

α1-acid glycoprotein (AAG, orosomucoid)
—binds basic drugs
——lidocaine, tricyclic antidepressants
acute phase reactant (increases during acute reaction)
—Drugs bound ≥90% may be appropriate for free drug measurement (don’t do often)

Question 14

How are drugs eliminated?

Answer 14

Hepatic Metabolism
—hepatic disease may alter dosing for drugs —–cleared primarily by metabolism

Renal Elimination
—decreased creatinine clearance (eGFR) may alter dosing for drugs cleared by excretion

Question 15

During drug metabolism how does the body’s reaction affect metabolism?

Answer 15

Reactions are designed to “de-toxify” the drug and/or increase its polarity for urinary excretion

Reactions may also form active drug (prodrug) or a toxin

Hepatic cytochrome P450 (CYP) system
18 CYP families, 43 sub-families, involved in:
drugs & other (3 families: CYP1, CYP2, CYP3)
genetic variability – pharmacogenetics (-omics)
warfarin –
VKORC1 – warfarin target
CYP2C9 – warfarin metabolism

Question 16

Michaelis-Menton kinetiics relationship to drug metabolism?

Answer 16

Michaelis-Menten kinetics (1st order to drug)

• –metabolizing enzymes are in excess of drug concentration
• –doubling dose approximately doubles drug concentration
• –True for most drugs at typical therapeutic concentrations

Saturation kinetics (zero order to drug)
---therapeutic concentrations overload metabolic enzymes
----inc. dose has a disproportionate increase in drug level
-----phenytoin (therapeutic range  ~ sat’n)
ethanol (sat’n at >0.02%) – legally drunk  = 0.08%

Question 17

In first order kinetics (exponential) elimination rate depends on ? (most drugs eliminated by first order kin)

Answer 17

drug concentration

Question 18

What is a drug half-life?

Answer 18

Half-life (T½): the time for the blood drug concentration to decrease by 50%

Question 19

What is the peak?

Answer 19

Peak – time at which the concentration (at the site of action) is highest

• –draw after distribution phase complete
• –not commonly used (Antibiotics only?)

Question 20

What is trough? JBND?

Answer 20

Trough – time of the lowest concentration

JBND – just before next dose
appropriate draw time for most drugs

Question 21

What is steady state in repetitive dosing?

DEFINITE TEST QUESTION

Answer 21

Steady-state – net equilibrium between drug intake and elimination

Time to reach steady-state is solely a function of half-life

Don’t draw levels before 4-5 half-lives from initiation or after change in dosing

Question 22

When do we use TDM?

Answer 22

• Drugs with narrow (low) therapeutic index
• Treatment failure – distinguish compliance vs. unusual pharmacokinetics
• Assess adequacy when clinical indicators evasive
• –prevent seizures, don’t titrate
• —prevent rejection, don’t hope to salvage
• Toxicity mimics disease (digoxin, PA, phenytoin)
• Toxicity cannot be tolerated
• Likely PK aberrations (drug interactions, polymorphisms, hepatic or renal disease, pregnancy)

Question 23

What is the therapeutic index?

Answer 23

Therapeutic Index = Toxic conc. ÷ Therapeutic conc.

Question 24

TDM measuring methods

Answer 24

Immunoassay – preferred method for most

• homogeneous (EMIT, CEDIA, KIMS)
• –adaptable to most standard chemistry analyzers
• fluorescence polarization – Roche Integra
• heterogeneous – often chemiluminescent
• –standard immunassay analyzers

HPLC – flexible but poorly automated
—Useful if no commercial assay available
(manual work ie precipitation before)
-mult drugs can be measures unlike immunoassay

GLC – ditto, but often requires derivatization, sometimes drugs dont exist in gas form

Question 25

When should TDM be sampled?

Answer 25

- Steady-state required (4-5 half-lives) - JBND (just before next dose, “trough”) – suitable for most drugs. - Peak – occasionally for antibiotics - ---well-defined for i.v. drugs - --more variable for oral, i.m. or subcutaneous - --relation to distribution phase - Ideally, dosing info is available – but reality? - ---dose, time of dose, route (CAP checklist)

Question 26

What are TDMs drawn in?

Answer 26

Gel barrier tubes: SST (B-D) – dec. in phenytoin, lidocaine, carbamazepine Corvac (Tyco Kendall) – dec. in lidocaine only Greiner – no effects? (no peer-reviewed study?) Gel adsorbs or dissolves drug. Decrease is dependent upon drug, sample volume and duration of contact Reference labs usually have blanket no SST rule for all drugs, whether affected or not

Question 27

What is the only Cardioactive drug that is monitored today really?

Answer 27

Digoxin Uncommonly monitored: Procainamide Lidocaine Quinidine Rarely monitored flecainide, tocainide, amiodarone, verapamil, disopyramide, diltiazem, nifedipine

Question 28

Digoxin

Answer 28

Natural product – foxglove plant Therapeutic 0.8-2.0 ng/mL, toxicity may be seen at 1.5 ng/mL = LOW THERAPEUTIC INDEX children may tolerate up to 4.0 ng/mL Renal excretion req. dosage adjustment in renal disease Half-life 30-45 hrs Long distribution: draw ≥8 hrs post dose (JBND preferred) Increased toxicity with ↓K+, ↓Mg2+, ↑Ca2+ Quinidine → ↑digoxin levels Measure by immunoassay

Question 29

Digoxin assay interferences?

Answer 29

DLIS – digoxin-like immunoreactive substance steroids – synthesized in the adrenal (“cardenolides”) increased in pregnant women and newborns increased in renal, hepatic and cardiac failure assay dependent interference – check drug-free patients Aldactone (spironolactone) - K+ sparing diuretic neg. interference – IMx, AxSym, Dimension pos. interference – TDx, Elecsys no interference – EMIT, Vitros, Tina-Quant (Roche latex) Fab fragment of digoxin antibody Given to treat digoxin overdose May interfere (positive) with digoxin assays: marked – Immulite, Vitros, Dimension, Access moderate – Elecsys, Integra, EMIT, Centaur minimal – AxSym, Synchron, CEDIA Ultrafiltration allows “accurate” free digoxin level

Question 30

Procainamide

Answer 30

Hepatic metabolism – N-acetylation to NAPA PA and NAPA both active, always measure both Fast acetylators (half-life ~3 hrs) PA:NAPA ≥ 1.0 @ 3 hr post dose Slow acetylators (half-life ~5 hours) PA:NAPA > 2.0 @ 3 hrs post dose more likely to develop lupus-like syndrome Japan - 10%, Mediterranean - 90%, U.S. Caucasian - 50% Measure by immunoassay, HPLC

Question 31

Anticonvulsants

Answer 31

``` Carbamazepine (CBZ, Tegretol®), Oxcarbazepine (Trileptal®) Phenobarbital (ΦB); Primidone (Mysoline®) Phenytoin (DPH, Dilantin®), Fosphenytoin (Cerebryx®) Valproic Acid (VPA, Depakene®) Primidone (Mysoline®) Ethosuximide (Zarontin®) Clonazepam (Klonopin®) Gabapentin (Neurontin®) Lamotrigine (Lamictal®) Felbamate (Felbatol®) Zonisamide (Zonergan®) Levitiracetam (Keppra ®) Tiagabine – (Gabitril®) ```

Question 32

Carbamazepine (CBZ)

Answer 32

``` Tegretol® 80% protein bound (± free drug monitoring) Hepatic metabolism – induced by DPH, ΦB, and CBZ CBZ-10,11-epoxide active metabolite may accumulate in children w/ nl CBZ Erratic absorption T1/2 15-20 hrs Therapeutic range 4-12 mcg/mL Monitor trough levels ```

Question 33

Phenytoin

Answer 33

Dilantin® - diphenylhydantoin (DPH) ~90% protein bound candidate for free drug monitoring (esp. in renal patients)-things displacing pheny from albumin increasing free and decreasing bound Low H2O solubility: erratic oral & im absorp. Hepatic metabolism – T1/2 ≈ 20 hrs metabolism begins to saturate >5 mcg/mL induced by EtOH, PB and CBZ comp. by cimetidine, dicumarol, INH Protein binding competition by ASA and VPA Collect samples JBND (no SST tubes) Therapeutic range 10-20 mcg/mL, critical >35-40 Free phenytoin – therapeutic range 1.0-2.0 mcg/mL 90% bound, 10% free

Question 34

Phebobarbital

Answer 34

40-60% protein bound Hepatic metabolism – T1/2 70-100 hrs draw trough levels Induces metabolism of other drugs (DPH, CBZ) Dec. clearance with VPA and ASA (↑10-20%) Ther. range 15-40 mcg/mL, critical >80 mcg/mL

Question 35

Primidone

Answer 35

Mysoline® Metabolized to phenobarbital (PB) (T1/2 = 10 h) monitor both, steady state depends on phenobarbital Therapeutic range 5-12 mcg/mL, toxic >15 mcg/mL DPH → ↑ PB:Prm due to dec. PB metab. VPA decreases clearance of PB and Prm Collect JBND

Question 36

Valproic Acid

Answer 36

Depakene® Hepatic metabolism (T1/2 16→12 hrs, 8 in children) short T1/2 in children can lead to subtherapeutic levels >90% protein bound, dec. in uremia, cirrhosis competes w/ DPH (slide 15) Hepatotoxic – monitor LFT’s (esp. ALT) Not recommended during pregnancy (teratogenic) Draw JBND

Question 37

Theophylline

Answer 37

Aminophylline, TheoDur (sustained release) bronchodilator – asthma, neonatal apnea largely replaced by ß2-agonists Hepatic metabolism (half-life 3-11 hrs) saturation occurs ≈ 20 mcg/mL Therapeutic range 10-20 mcg/mL, toxic >25-30 Neonatal apnea – 5-10 mcg/mL (caffeine preferred) Peak – 2 hrs w/o food, 3-5 w/ food or SR Measure peak or trough (rare now)

Question 38

Caffeine

Answer 38

``` Treat neonatal apnea Advantages over theophylline: less frequent dosing more central respiratory stimulation less peripheral cardiovascular toxicity Therapeutic range – 8-20 mcg/mL Measure by HPLC or immunoassay ```

Question 39

Which antibiotics can we use TDM on?

Answer 39

``` Aminoglycosides Gentamicin, Tobramycin, Amikacin Vancomycin Anti-tubercular INH, Rifampin, Ethambutol, Pyrazinamide Rare ```

Question 40

Aminoglycosides

Answer 40

Gentamicin, Tobramycin, Amikacin Bactericidal against aerobic gram-negatives O2 dependent active transport into bacteria often combined w/ cell wall Abx (e.g., penicillins) Poor oral absorption, given iv or im Vd ≈ 0.2 L/kg, consistent with blood & ECF Vd – volume of distribution 100% renal excretion, T1/2 2-3 hrs Renal disease req. dec. dose and/or inc. dosing interval ***nephrotoxic

Question 41

Historical protocol for Aminoglycosides

Answer 41

Historical protocols: dosed tid (3/day, iv or im), draw peak & trough peak – 4-10 mcg/mL (20-30 amikacin) 15-30 min. post iv infusion 2 hrs post im-injection trough - therapeutic (?) nephrotoxicity (reversible) at trough > therapeutic

Question 42

Modern protocol for Aminoglycosides

Answer 42

``` Current protocols: Once-a-day dosing same total dose (3-5 mg/kg IBW/day) no levels if 60 mL/min goal is 18 hr post level ```

Question 43

Aminoglycosides sampling

Answer 43

Heparin – binds aminoglycosides, blocks antigenicity (hep neg and amino positive so attracts and then antibodies cant see aminogly so false low levels) No green top tubes Carbenicillin, ticarcillin, piperacillin covalent binding – blocks antigenicity and action assay quickly or freeze after separation Measured by immunoassay

Question 44

Vancomycin

Answer 44

Glycopeptide – unrelated to aminoglycosides Effective against gram-pos bacteria Enterococci developing resistance (VRE) Given iv Monitor by immunoassay: peak (30 min post iv) – 30-50 mcg/mL trough (JBND) – 5-15 (to 20 in hosp. acquired pneumonia, osteomyelitis) ototoxicity and nephrotoxicity low (historical?) CDP-1 – degradation product that cross-reacts in some assays, esp. in renal patients Poor standardization among manufacturers Up to 35% variance

Question 45

Immunosuppressants

Answer 45

Cyclosporine A Tacrolimus (ProGraf, FK-506) Sirolimus (Rapamycin) Mycophenolic acid All are isolated from molds Block T-lymphocyte proliferation via several mechanisms Prevent T-cell mediated organ rejection

Question 46

Cyclosporin A

Answer 46

Targets levels vary with organ and duration of therapy Whole blood is preferred sample Draw trough levels after 3-5 days therapy Measure by immunoassay (req. pretreatment) or LC-MS/MS Many metabolites, therefore immunoassay results may be higher than LC-MS/MS, esp. with polyclonal assays

Question 47

Tacrolimus

Answer 47

``` Less nephrotoxic than cyclosporine Slight neurotoxicity in ≤5% of patients Therapeutic range 3-15 ng/mL Collect whole blood after at least 5 days Measure by immunoassay or LC-MS/MS ```

Question 48

Sirolimus

Answer 48

Structural, mechanistic similarity to FK-506 Collect whole blood JBND after 3 days Measure by LC-MS/MS or immunoassay Keep trough levels >30 ng/mL for 8 wks, then maintain >15 ng/mL Values above 60 ng/mL associated with significant complications

Question 49

Mycophenolic Acid (MPA)

Answer 49

``` MMF - prodrug hydrolyzed in liver to MPA Conjugation to MPA-glucuronide (MPAG) Monitor trough levels in serum/plasma: MPA – 1.0-3.5 mcg/mL MPAG – 35-100 mcg/mL (value?) Immunoassay or LC-MS/MS ```

Question 50

Psychoactive drugs

Answer 50

Lithium (Tri)cyclic antidepressants SSRI’s – selective serotonin reuptake inhibitors Antipsychotic (neuroleptics) *Except for lithium, rarely need monitoring

Question 51

Lithium

Answer 51

Used to treat manic phase of bipolar disorder Administered as Li2CO3. Draw JBND Very low therapeutic index therapeutic range: 0.5 -1.2 mM mild toxicity: >1.5 mM (not life-threatening) severe toxicity: >2.5 mM (seizures) Renal excretion, dehydration increases toxicity Therapeutic effects are delayed

Question 52

Lithium Measurment

Answer 52

``` Flame photometry – outdated Atomic absorption (flame) - cumbersome Ion-selective electrode – semi-automated Electrode has slight Na interference Measure (and QC) both Na & Li and correct mathematically Chemical – adaptable to chemistry analyzers Substituted proprietary porphyrin Li-dependent phosphatase ```