Therapeutic Drug Monitoring Roger L Bertholf Ph D

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 Toxicity Toxic Therapeutic range Sub-therapeutic Plasma drug concentration

Therapeutic Index • High therapeutic index – NSAIDs • Aspirin • Tylenol • Ibuprofen – Sedative/hypnotics • Benzodiazepines – Most antibiotics – Beta-blockers • Low therapeutic index – Lithium – Neuroleptics • Phenytoin • Phenobarbital – Some antibiotics • Gent/Vanco/Amikacin – Digoxin – 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 Absorption Ka Kd Blood Ke Elimination K-d Tissue

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 Absorption ka kd 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.

Low Volume of Distribution Blood High blood concentration ( g/m. L) kd Tissue k-d Low tissue concentration kd << k-d Vd is low If kd = 0, Vd = 0. 07 L/Kg (lower limit)

Drugs with low Vd Drug Amikacin Gentamycin/Tobramycin Phenytoin Primidone Theophylline Valproic Acid Ethanol Vd (L/Kg) 0. 05 – 0. 70 0. 07 -0. 70 0. 60 0. 50 0. 20 0. 53

High Volume of Distribution Blood Low blood concentration (ng/m. L) kd Tissue k-d High tissue concentration 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 Quinidine 200 – 300 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?

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?

What can affect Vd? • Body fat index (men vs. women) • Tissue perfusion (CHF or edema) • Concentration of plasma proteins

Plasma drug concentration Effect of Vd on peak plasma level Vd = 0. 1 Vd = 0. 2 Vd = 0. 4 Time

Two Compartment Model Absorption ka kd Blood ke Elimination k-d Tissue

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 p. H Genetic factors Other drugs

Plasma drug concentration Pharmacokinetics Peak plasma concentration t 1/2 Time

Plasma drug concentration The Steady State Peak Therapeutic range dose Trough d d d Time d d d

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 Long retention time Soluble in mobile phase Short retention time

Detector signal Chromatographic separations A B The resolution of a chromatographic separation is defined as: 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

More recent TDM methods • • Radioimmunoassay Fluorescence Polarization Immunoassay Enzyme-Multiplied Immunoassay Technique Cloned Enzyme Donor Immunoassay

Theophylline • • • Bronchodilator Therapeutic range: 5 - 20 g/m. L Neonates metabolize theophylline to caffeine Vd = 0. 5 L/Kg Toxic at > 20 g/m. L – Nausea, vomiting, diarrhea, stomach pain, headache, insomnia, tachycardia – Seizures, cardiac arrhythmia at > 35 g/m. L

Gentamycin/Tobramycin • Wide-spectrum aminoglycoside antibiotics • Vd = 0. 2 L/Kg • Therapeutic – 4 - 10 g/m. L (peak); 0. 5 - 1. 5 g/m. L (trough) • Toxic: 12 - 15 g/m. L – 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/m. L • Toxic levels (> 2. 0 ng/m. L) 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/m. L • Toxicity: Heart block, n/v, diaphoresis, malaise at Procainamide + NAPA > 30 g/m. L

Carbamazepine • Anticonvulsant, and for Rx of TGN – Active in tonic-clonic (grand mal) sz • Vd = 1. 5 L/Kg (lipophyllic but 25% proteinbound • Therapeutic range: 4 - 12 g/m. L • Toxicity in one fourth of patients – Diplopia, drowsiness, nystagmus, ataxia, n/v – Also, derm, hematol, hepatic

Phenobarbital • Anticonvulsant (metabolite of Primidone) – Long-acting barbiturate (t 1/2 = 2 - 4 days) • • Vd = 1. 0 L/Kg Therapeutic range: 15 - 40 g/m. L Toxic symptoms at > 60 g/m. L Drug interactions (induction of hepatic microsomal enzymes)

Phenytoin • • Most frequently prescribed anticonvulsant Vd = 1. 0 L/Kg Therapeutic range: 10 - 20 g/m. L Toxicity at > 20 g/m. L – 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/m. L (trough) • Hepatotoxic