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Practical Pharmacokinetics

Practical Pharmacokinetics. September 11, 2007 Frank F. Vincenzi. Learning Objectives (Fundamental pharmacokinetic concepts). Volume of distribution Half life & first order elimination Zero order elimination (capacity-limited) Clearance Bioavailability and area under the curve (AUC)

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Practical Pharmacokinetics

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  1. Practical Pharmacokinetics September 11, 2007 Frank F. Vincenzi

  2. Learning Objectives(Fundamental pharmacokinetic concepts) • Volume of distribution • Half life & first order elimination • Zero order elimination (capacity-limited) • Clearance • Bioavailability and area under the curve (AUC) • Urinary vs. liver elimination & first pass effect • Plasma protein binding • Drug accumulation • Two compartment behavior

  3. Simplified Table of Pharmacokinetic Parameters(also, Goodman & Gilman, Katzung, etc.) • Metabolism • Oral availability (%) (or as a fraction, 0.4, etc.) • Urinary excretion (%) • Plasma binding (%) • Volume of distribution (L/kg) (or total liters) • Half life (hours) • Effective concentrations (µg/mL, etc.) (= mg/L) • Toxic concentrations (µg/mL, etc.) • pKa - acid or base

  4. Drug ADME(absorption, distribution, metabolism & excretion)

  5. Clearance: a useful way of looking at drug elimination • The sum of all processes that eliminate a drug from the plasma (e.g., CL = CLliver + CLkidney + …) • Quantification:(For most drugs, the rate of elimination is proportional to the plasma concentration. The proportionality is called the clearance (CL) ) CL (liters/h) = rate of elimination (mg/h)/plasma conc (mg/liter)

  6. A simple-minded view of the kidney nephron

  7. A simple minded view of the liver systemic circulation drug and/or drug and/or drug portal circulation Gut

  8. Volume of distribution (Vd) • Relationship between the total amount of drug in the body and the plasma concentration of the drug • Quantification: Vd(liters) = total drug (mg)/plasma conc (mg/liter)

  9. Talk about simple minded!The body as a bathtub

  10. General determinants of drug distribution Intracellular Plasma Interstitial ‘Ideal’ 70 kg person 4 L (~5%) 11 L (16%) 28 L(35%)(Total body water = 42 L)

  11. A small volume of distribution Isoniazid = 0.067 L/kg

  12. General determinants of drug distribution Plasma water ~5% Interstitial water ~16% Intracellular water ~ 35% Fat ~20%

  13. A large volume of distribution Loratadine = 120 L/kg

  14. The blood-brain barrier (BBB)

  15. Displacement by sulfisoxazole (91% plasma binding) of bilirubin (normally ~100% plasma binding):

  16. First order elimination (most drugs) • The rate of elimination is proportional to the concentration of the drug in the plasma • There is a characteristic half life for elimination of the drug • Doubling the dosing rate doubles the concentrationof the drug in the steady state (linear pharmacokinetics)

  17. Plasma half life (t 1/2) of a drug • Time required for elimination of half of the drug from the plasma (determined experimentally)Quantification: half life (h) = (0.693*Vd (liters))/CL (liters/h) 0.693 = natural logarithm of 2

  18. First order elimination • Half lives % remaining %eliminated0 100 01 50 502 25 753 12.5 87.54 6.25 93.755 3.125 96.8756 1.5625 98.4375

  19. Drug X, 2 mg IV, 77 kg subject:What is the half-life?

  20. Drug x, 2 mg IV, 77 kg subject:Concentration (log scale) versus time

  21. Drug X, 2 mg IV, 77 kg subject:What is the Vd?

  22. How to calculate a theoretical loading dose (clinical practice may vary) • The problem: fill the total volume of distribution with an appropriate initial concentrationThe solution:loading dose (mg) = Vd (liters) * initial target conc (mg/liter)

  23. Diazepam (Valium®), to be given by rapid IV injection in a patient with status epilepticus • Pharmacokinetic Parameters: • Oral availability (%) 100 (N/A) • Urinary excretion (%) 1 • Bound in plasma (%) 99 • Clearance (ml/min/kg)0.38 • Volume of distribution 1.1 L/kg • Half life (h)43 • Effective concentrations (µg/ml, etc.) 300-400 ng/ml • Toxic concentrations (µg/ml, etc.) ...

  24. Calculating a ‘Vd filling’ IV dose of diazepam for a 70 kg (154 pound) patient • Target concentration = 300 ng/ml = 0.30 mg/liter • Total Vd = (70 kg) * (1.1 L/kg) = 77 liters • Dose = 77 liters * 0.30 mg/liter = 23.1 mgIs this reasonable? PDR Usual Adult Dosage (for status epilepticus): 5-10 mg initially (IV preferred), may be repeated if necessary at 10-15 min intervals up to a maximum dose of 30 mg - may repeat in 2-4 hrs etc.

  25. Zero-order (capacity-limited) elimination applies to a few drugs • Rate of drug elimination is independent of its concentration • Elimination process is saturated at plasma concentrations • Doubling the dosing rate more than doubles the concentration of drug - steady state not reached (‘non-linear pharmacokinetics’)

  26. Examples of drugs with zero-order or mixed elimination kinetics • ethanol • phenytoin • nifedipine

  27. Ethanol in a 70 kg human consuming 19 ‘drinks’ over 6 hours (~3 drinks/hour)

  28. Time-concentration curve typical of drugs with first order elimination

  29. Bioavailability • Fraction of drug absorbed into the systemic circulation from a given route of administration; usually the oral route. • Determined by comparing the ‘area under the curve (AUC) of plasma concentration vs. time when taken orally as compared to IV injection.F = (AUC)oral/(AUC)IV

  30. Drugs with little or no first pass effect ( high % bioavailability) diazepam (100) clonidine (95) metronidazole (99) sulfamethoxazole (100) Drugs with major first pass effect(low % bioavailability) imipramine (40) lidocaine (35) morphine (24) propranolol (26) dicloxacillin (50) First pass effect: Destruction or elimination of a drug on its first pass by the liver

  31. Plasma levels during 6 hours following oral or IV dicloxacillin (bioavailability ~ 0.5, t 1/2 = 0.7 h)

  32. Time to peak concentration: absorption = elimination: Plasma concentrations following a single oral dose of dicloxacillin

  33. Drug accumulation depends on half life and dosing interval • During repeated dosing the plasma concentration of drug increases until (in the steady state) the rate of elimination equals the rate of dosing • Extent of accumulation can be expressed as:accumulation factor# = 1/(1-fraction remaining*)#steady state level compared to first dose level*at the end of the dosing interval (‘trough’)

  34. Lack of accumulation of dicloxacillin (half-life = 0.7 hours) given at 4 hour intervals

  35. Accumulation of digoxin (half-life = 39 hours) during 10 days of dosing 70 kg patient with 0.3 mg daily (THERAPEUTIC)

  36. Long half-life • Advantages Once a day dosage or less Easy to maintain plasma levels in therapeutic window Missed doses are no big deal • Disadvantages Initial therapeutic effects develop slowly without a loading dose If toxicity occurs, it is a long wait**can accelerate removal of some drugs by dialysis

  37. Short half-life • Advantages Onset of therapeutic effects tends to be rapid Can dynamically titrate effects by I.V. infusion If toxicity occurs, it is not a long wait • Disadvantages Missed doses drop plasma levels below therapeutic Difficult to maintain plasma levels in therapeutic window Multiple daily dosage or … May require a slow release dosage form

  38. Time concentration curve during 10 days of treatment with metoproplol, 25 mg every 6 hours (half life = 3.2 hours), peak/trough ~ 4

  39. Time concentration curve during 10 days of treatment with slow release metoprolol, 100 mg every 24 hours (half life = 3.2 h), peak/trough ~ 1.4

  40. I.V. infusion

  41. lidocaine, pharmacokinetic parameters • Oral availability (%) 35 • Urinary excretion (%) 2 • Bound in plasma (%) 70 • Clearance (9.2 ml/min/kg) 38.4 • Volume of distribution (L/kg) 1.1 • Half life (h) 1.8 • Effective concentrations (µg/ml, etc.) > 1.5-6 mg/L • Toxic concentrations (µg/ml, etc.) > 6 mg/L

  42. I.V. infusion of lidocaine (half life 1.8 h), 100 mg/h without or with a bolus loading dose

  43. Some drugs display two compartment behavior: Initial distribution Potential for initial overdosage

  44. Two compartment behavior, equilibrated,in terminal (or beta) elimination phase

  45. Elimination of a drug exhibiting two compartment behavior

  46. Thiopental: an ultrashort acting, intravenous anesthetic agent whose action is terminated by redistribution, not elimination; 12 minutes of plasma, brain, muscle and fat levels

  47. How to predict steady state plasma concentration • Average concentration of drug in the steady state (Css)Quantification: Css (mg/liter) = (dosing rate (mg/h) * bioavailability)/CL (liters/h)

  48. How to calculate dosing rate for a given target steady state plasma concentration • Dosing rate (average, may be given in divided doses, be sure to calculate for 24 hours, or etc.)Quantification: (dosing rate (mg/h) = Css (mg/liter) * CL (liters/h)/ bioavailability (F)

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