Bioavailability studies lecture7


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Bioavailability studies lecture7

  1. 1. Bioavailability Adapted by: Sereta Campbell-Elliott B. Pharm; M Pharm. Sc Prepared By: Marcia Williams
  2. 2. What is a drugs’ bioavailability? <ul><li>- Rate and (relative) amount of a dose of a drug that reaches systemic circulation intact </li></ul><ul><li>May be affected by: </li></ul><ul><li>- physiological factors </li></ul><ul><li>- formulation/manufacturing factors </li></ul><ul><li>- physicochemical properties of active </li></ul><ul><li>drug </li></ul>
  3. 3. Assessment of Bioavailability <ul><li>Cannot assess precise concentration at site of action </li></ul><ul><li>Assumption that conc. of drug in body fluids such as plasma, urine or saliva over a period of time after administration correlates with the clinical efficacy of the drug’s therapeutic action. </li></ul>
  4. 4. Important parameters in bioavailability studies <ul><li>Time to Peak (T max ): the time after admin that it takes for the drug to reach C max. This is an indication of the rate of absorption. </li></ul><ul><li>Max. conc. Attained (C max ): assesses whether conc. is in therapeutic range </li></ul><ul><li>Area Under the Curve (AUC): Total drug abs. - reflects changes in distr. metabolism & excret </li></ul><ul><li>Onset of Action: The time required to reach the MEC. following drug admin . </li></ul><ul><li>Duration of Action: The time period in which the plasma conc. Exceeds MEC. </li></ul><ul><li>Intensity : the difference in the MEC and C max . </li></ul>
  5. 5. Important parameters in bioavailability studies (cont’d) <ul><li>Absorption rate conctant (k a ): assesses the rate of drug absorption from a formulation </li></ul><ul><li>Minimum Effective Concentration (MEC): minimum plasma conc. that must be reached before achieving therapeutic effect. </li></ul><ul><li>Maximum Safe Concentration (MSC): the conc. above which toxic effects are seen. </li></ul><ul><li>Minimum Toxic Concentration (MTC): The minimum concentration at which the toxic effect of the drug is seen. </li></ul><ul><li>Therapeutic Range: Plasma conc. range bet. MEC and MSC. </li></ul>
  6. 6. Illustration of bioavailability variables
  7. 7. Representation of Bioavailability Data <ul><li>Construction of plasma concentration vs time curve. </li></ul><ul><li>Initial rise in curve indicates that drug is absorbed at a faster rate than it is metabolized or excreted. (absorption phase) </li></ul><ul><li>It continues to rise until a peak conc. is obtained (C max ) - rate of absorption = rate of excretion. </li></ul>
  8. 8. Representation of Bioavailability Data(cont’d) <ul><li>At the beginning of the descending portion of the curve, both absorption and elimination is taking place - elimination is faster. </li></ul><ul><li>After a time absorption ceases and the conc. of drug in plasma is determined only by the rate of elimination. (the elimination phase of the curve) </li></ul>
  9. 9. AUC Measurement <ul><li>Most common method is the trapezoid method </li></ul><ul><li>For each trapezoid [AUC] = C n-1 + C n (t n – t n- 1) </li></ul><ul><li>2 </li></ul><ul><li>AUC total = AUC extrap + AUC 0-t </li></ul><ul><li>where AUC extrap = C last /k el </li></ul>
  10. 10. Illustration of Trapezoid Method from graph
  11. 11. AUC Measurement 4.10 5 6.77 4 11.1 3 18.4 2 30.3 1 38.9 0.5 Plasma Conc (  g/ml) Time (hr)
  12. 12. Absolute and Relative Bioavailability <ul><li>Absolute Bioavailability (B A ) </li></ul><ul><li>The fraction of the administered dose which is absorbed intact into the systemic circulation . </li></ul><ul><li>B A = (Auc tab /AUV IV ) x 100% </li></ul><ul><li>F = fraction of drug absorbed </li></ul><ul><li>Relative Bioavailability (B R ) </li></ul><ul><li>A measure of the fraction of a given drug that is absorbed intact into the systemic circulation from a dosage form relative to a recognized standard dosage form of that drug. </li></ul><ul><li>B R = (AUC test(oral) /AUC std,(oral) ) x 100% </li></ul>
  13. 13. Urinary Drug Excretion Data <ul><li>Measures conc. of intact drug &/or its metabolite in the urine. </li></ul><ul><li>Collection of urine is easier and less unpleasant for the patient than collection of blood samples. </li></ul><ul><li>Conc. Of drug in urine is higher than in blood. </li></ul><ul><li>Lower conc. of protein & other endogenous substances makes drug assay easier. </li></ul><ul><li>Useful only if drug is extensively excreted in the urine and rate of excretion is proportional to the conc. of drug in plasma. </li></ul>
  14. 14. Urinary Drug Excretion Data (cont’d) <ul><li>Drug excreted in urine will not be proportional to conc. in plasma if the drug or its metabolites are: </li></ul><ul><li>excreted by active transport. </li></ul><ul><li>weakly acidic or weakly basic - since rate of excretion will depend on the pH of the urine. </li></ul><ul><li>Urine flow determines excretion rate. </li></ul><ul><li>E r (mcg/hr) = Amt of drug </li></ul><ul><li>time interval </li></ul>
  15. 15. Urine Data
  16. 16. Urine Data <ul><li>Time for the maximum rate of excretion is an index of the rate of bioavailability </li></ul><ul><li>The total cumulative amount of drug excreted in the uring is an index of the extent of bioavailability </li></ul><ul><li>B A = (D’ u (oral) /D’ u IV ) x 100% </li></ul><ul><li>B R = (D’ u test(oral) /D’ u std(oral) ) x 100% </li></ul>
  17. 17. The following tetracycline plasma and urinary data are obtained following intravenous administration of 250 mg tetracycline to a 70 kg subject: 62.0 73     8.0 13 0.90 12 10.0 11 1.05 10 12.0 9 1.2 8 13.0 7 1.50 6 16.6 5 1.71 4 29.4 3 2.40 1.5 X,urine (mg) t(h) C,plasma (ug/ml) t(h)