Therapeutic Drug Monitoring

1. Therapeutic Drug Monitoring Roger L. Bertholf, Ph.D. Chief of Clinical Chemistry & Toxicology Shands Jacksonville Medical Center

2. Why monitor plasma drug concentrations? • Avert toxicity • Optimize dose/therapeutic response • Detect changes in pharmacokinetics • Monitor compliance

3. 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

4. Therapeutic Index Toxic Toxicity Therapeutic range Sub-therapeutic Plasma drug concentration

5. 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 Therapeutic Index

6. 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.

7. Two Compartment Model Kd Ka Blood Tissue Absorption K-d Ke Elimination

8. Drug absorption • Route • Oral • Intravenous • Intramuscular/subcutaneous • Dermal • Inhaled/intranasal • Slow/sustained release

9. Rate of drug absorption IV  Inhaled > Intramuscular > Oral > Dermal seconds minutes hours

10. First-pass metabolism Prodrug  Active drug or Active drug  Inactive metabolite or Lipid soluble drug  Water soluble drug

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

12. 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

13. 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.

14. Low Volume of Distribution kd Blood Tissue High blood concentration (g/mL) Low tissue concentration k-d kd << k-d  Vd is low If kd= 0, Vd= 0.07 L/Kg (lower limit)

15. Drugs with low Vd

16. High Volume of Distribution kd Blood Tissue Low blood concentration (ng/mL) High tissue concentration k-d kd >> k-d  Vd is high For highly lipophilic drugs, Vdmay be  100 L/Kg

17. Drugs with high Vd

18. 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

19. 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?

20. 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?

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

22. Effect of Vd on peak plasma level Vd = 0.1 Vd = 0.2 Plasma drug concentration Vd = 0.4 Time 

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

24. Elimination () phase • Can be renal, biliary, secretory, respiratory • Often depends on metabolism • Is the most variable pharmacokinetic parameter

25. What factors affect the rate of drug elimination? • Hepatic function • Renal function • Urine pH • Genetic factors • Other drugs

26. Pharmacokinetics Peak plasma concentration Plasma drug concentration t1/2   Time 

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

28. TDM methods • HPLC • RIA • FPIA • EMIT • CEDIA

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

30. Chromatographic separations Mobile Phase Stationary Phase

31. Chromatographic separations A B Soluble in stationary phase Long retention time Soluble in mobile phase Short retention time

32. Chromatographic separations The resolution of a chromatographic separation is defined as: t/mean peak width A B Detector signal Time 

33. What is the effect on resolution? • Increasing column length? • Decreasing/increasing solvent polarity? • Increasing flow rate? • Increasing temperature? • Increasing stationary phase film thickness?

34. HPLC Detectors

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

36. 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

37. 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

38. 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

39. 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

40. 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

41. 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)

42. 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

43. 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