Therapeutic Drug Monitoring - PowerPoint by 4fSZnd4

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									Therapeutic Drug Monitoring


         Roger L. Bertholf, Ph.D.
Chief of Clinical Chemistry & Toxicology
  Shands Jacksonville Medical Center
Why monitor plasma drug
concentrations?

•   Avert toxicity
•   Optimize dose/therapeutic response
•   Detect changes in pharmacokinetics
•   Monitor compliance
First Principle of TDM

• “Knowledge of serum concentrations is
  most helpful when the drug in question
  requires individualized dosing for optimal
  efficacy and more routine measures of
  therapeutic success are unavailable.”


    From W. J. Taylor and A. L. Finn (eds.) Individualizing Drug Therapy, 1981
Therapeutic Index
           Toxic
Toxicity




                    Therapeutic range
                                        Sub-therapeutic
                   Plasma drug concentration
Therapeutic Index
• High therapeutic index   • Low therapeutic index
   – NSAIDs                  – Lithium
      • Aspirin              – Neuroleptics
      • Tylenol                 • Phenytoin
      • Ibuprofen               • Phenobarbital
   – Sedative/hypnotics      – Some antibiotics
      • Benzodiazepines         • Gent/Vanco/Amikacin
   – Most antibiotics        – Digoxin
   – Beta-blockers           – Immunosuppressives
Introduction to Pharmacokinetics
• What are pharmacokinetics?
  – The study of the absorption, distribution, and
    elimination of drugs
  – Pharmacodynamics is the study of drug effects
• Most drugs exert their effect at tissue
  receptors, but we measure drug concentration
  in plasma.
Two Compartment Model

                                Kd
             Ka
Absorption          Blood             Tissue
                                K-d


                        Ke

                  Elimination
Drug absorption

• Route
  –   Oral
  –   Intravenous
  –   Intramuscular/subcutaneous
  –   Dermal
  –   Inhaled/intranasal
• Slow/sustained release
Rate of drug absorption



  IV  Inhaled > Intramuscular > Oral > Dermal
    seconds         minutes         hours
First-pass metabolism




              Prodrug  Active drug
                        or
        Active drug  Inactive metabolite
                        or
     Lipid soluble drug  Water soluble drug
Two Compartment Model

                                kd
             ka
Absorption          Blood             Tissue
                                k-d


                        ke

                  Elimination
Distribution () phase
• Once drug is absorbed into the blood, it
  begins to distribute to tissues
• The amount of drug that partitions into
  tissues depends on . . .
  – Lipophilicity
  – Protein binding
• The partitioning of drug between blood and
  tissues is expressed quantitatively as the
  Volume of Distribution
Volume of Distribution (Vd)


• The Volume of Distribution (Vd) is the
  amount of blood, per Kg body weight,
  necessary to contain all of the body burden
  of drug at equilibrium concentration.

                         Total Body Stores
Plasma Concentration 
                       Volume of Distributi on
Low Volume of Distribution


        Blood            kd           Tissue
       High blood                    Low tissue
      concentration      k-d        concentration
        (g/mL)



                       kd << k-d

                       Vd is low

     If kd = 0, Vd = 0.07 L/Kg (lower limit)
Drugs with low Vd
Drug                    Vd (L/Kg)
Amikacin                0.05 – 0.70
Gentamycin/Tobramycin    0.07-0.70
Phenytoin                   0.70
Primidone                   0.60
Theophylline                0.50
Valproic Acid               0.20
Ethanol                     0.53
High Volume of Distribution


          Blood             kd           Tissue
         Low blood                      High tissue
        concentration       k-d        concentration
          (ng/mL)



                         kd >> k-d

                         Vd is high

  For highly lipophilic drugs, Vd may be  100 L/Kg
Drugs with high Vd
Drug                 Vd (L/Kg)
Digoxin              500 – 600
Carbamazepine        0.8 – 1.9
Lidocaine              130
Procainamide            2.4
Propranolol          200 – 300
Quinidine               3.0
Interpreting Vd
• Drugs with low Vd are contained mostly in
  the plasma, because . . .
  – They are highly water soluble (plasma water
    content is higher than tissues), or
  – They are highly protein bound (which prevents
    them from freely diffusing into tissues
• Drugs with high Vd are mostly in tissues, and
  plasma levels may not reflect body burden
  Example of Vd calculation


A 70 Kg man takes a 5 mg dose of phenobarbital (Vd = 1.0 L/Kg).

What is the maximum plasma phenobarbital concentration you
can expect?


           5.0 mg       0.07 mg
                                70 g / L
                1.0 L      L
        70 Kg 
                 Kg
Example of Vd calculation


A 55 Kg woman has a plasma theophylline (Vd = 0.5 L/Kg)
concentration of 15 g/L.

How much theophylline does she have on board?


      15 g 0.5 L
                  55 Kg  412.5 g
        L    Kg
What can affect Vd?



• Body fat index (men vs. women)
• Tissue perfusion (CHF or edema)
• Concentration of plasma proteins
Effect of Vd on peak plasma level
Plasma drug concentration




                            Vd = 0.1


                            Vd = 0.2


                              Vd = 0.4



                                       Time 
Two Compartment Model


                                kd
             ka
Absorption          Blood             Tissue
                                k-d


                        ke

                  Elimination
Elimination () phase



• Can be renal, biliary, secretory, respiratory
• Often depends on metabolism
• Is the most variable pharmacokinetic
  parameter
What factors affect the rate of
drug elimination?

•   Hepatic function
•   Renal function
•   Urine pH
•   Genetic factors
•   Other drugs
                 Pharmacokinetics
Plasma drug concentration




                                Peak plasma concentration




                                           t1/2



                                   Time            
          The Steady State
                                                               Peak
Plasma drug concentration




                            Therapeutic range




                                                                      Trough



                  dose           d      d       d          d     d       d
                                                    Time
TDM methods

•   HPLC
•   RIA
•   FPIA
•   EMIT
•   CEDIA
Chromatography

• Separation of components based on their. . .
  – Solubility in mobile and stationary phases
• Terminology:
  –   Gas/liquid
  –   Liquid/liquid
  –   Ion exchange
  –   Partition
Chromatographic separations



           Mobile Phase


          Stationary Phase
Chromatographic separations



                A                           B


    Soluble in stationary phase   Soluble in mobile phase
       Long retention time         Short retention time
Chromatographic separations
Detector signal




                      A    The resolution of a chromatographic
                                 separation is defined as:
                  B
                                   t/mean peak width




                          Time 
What is the effect on resolution?

•   Increasing column length?
•   Decreasing/increasing solvent polarity?
•   Increasing flow rate?
•   Increasing temperature?
•   Increasing stationary phase film thickness?
HPLC Detectors


 Detector            Sensitivity   Specificity    Cost

 UV/Vis              Moderate         Low          Low

 Fluorescence        Moderate      Moderate      Moderate

 Refractive index       Low           Low          Low

 Electrochemical        High       Moderate      Moderate

 Mass spectrometer   Moderate         High        High
More recent TDM methods

•   Radioimmunoassay
•   Fluorescence Polarization Immunoassay
•   Enzyme-Multiplied Immunoassay Technique
•   Cloned Enzyme Donor Immunoassay
Theophylline

•   Bronchodilator
•   Therapeutic range: 5 - 20 g/mL
•   Neonates metabolize theophylline to caffeine
•   Vd = 0.5 L/Kg
•   Toxic at > 20 g/mL
    – Nausea, vomiting, diarrhea, stomach pain,
      headache, insomnia, tachycardia
    – Seizures, cardiac arrhythmia at > 35 g/mL
Gentamycin/Tobramycin

• Wide-spectrum aminoglycoside antibiotics
• Vd = 0.2 L/Kg
• Therapeutic
  – 4 - 10 g/mL (peak); 0.5 - 1.5 g/mL (trough)
• Toxic: 12 - 15 g/mL
  – Ototoxicity
  – Nephrotoxicity
Digoxin

• Improves cardiac output in CHF patients
• Vd = 500 - 600 L/Kg
  – Highly bound to tissues
  – What does this say about small changes in
    plasma digoxin concentration?
• Therapeutic range: 1.5 - 2.0 ng/mL
• Toxic levels (> 2.0 ng/mL) produce
  arrhythmias, GI, CNS symptoms
Procainamide

• Antiarrhythmic
• Active metabolite is NAPA
  – N-acetyltransferase
  – Fast vs. slow acetylators
• Vd = 2.4 L/Kg
• Therapeutic: 4 - 10 g/mL
• Toxicity: Heart block, n/v, diaphoresis,
  malaise at Procainamide + NAPA > 30 g/mL
Carbamazepine

• Anticonvulsant, and for Rx of TGN
  – Active in tonic-clonic (grand mal) sz
• Vd = 1.5 L/Kg (lipophyllic but 25% protein-
  bound
• Therapeutic range: 4 - 12 g/mL
• Toxicity in one fourth of patients
  – Diplopia, drowsiness, nystagmus, ataxia, n/v
  – Also, derm, hematol, hepatic
Phenobarbital

• Anticonvulsant (metabolite of Primidone)
    – Long-acting barbiturate (t1/2 = 2 - 4 days)
•   Vd = 1.0 L/Kg
•   Therapeutic range: 15 - 40 g/mL
•   Toxic symptoms at > 60 g/mL
•   Drug interactions (induction of hepatic
    microsomal enzymes)
Phenytoin

•   Most frequently prescribed anticonvulsant
•   Vd = 1.0 L/Kg
•   Therapeutic range: 10 - 20 g/mL
•   Toxicity at > 20 g/mL
    –   Nystagmus
    –   Blurred vision
    –   Ataxia
    –   Drowsiness/Coma
Valproic acid

• Broad spectrum anticonvulsant, but mostly
  used for absence (petit mal) seizures
• Vd = 0.2 L/Kg
• Therapeutic range: 50 - 100 g/mL (trough)
• Hepatotoxic

								
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