Pharmacokinetics: Lecture four


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Extravascular administration: Calculating pharmacokinetic parameters from extravascular data

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Pharmacokinetics: Lecture four

  1. 1. Extravascular Administration Anas Bahnassi PhD RPhOne compartment Model
  2. 2. LECTURE’S OBJECTIVES• Upon completion of this lecture, the student will able to:• Calculate plasma drug concentration at any given time after the administration of an extravascular dose of a drug, based on known or estimated pharmacokinetic parameters• Interpret the plasma drug concentration versus time curve of a drug administered extravascularly as the sum of an absorption curve and an elimination curve• Employ extrapolation techniques to characterize the absorption phase• Calculate the absorption rate constant and explain factors that influence this constant• Explain possible reasons for the presence of lag time in a drug’s absorption• Calculate peak plasma drug concentration, (Cp)max, and the time, (tmax)at which this occurs• Explain the factors that influence peak plasma concentration and peak time• Decide when flip-flop kinetics may be a factor in the plasma drug concentration versus time curve of a drug administered extravascularly. 2 Anas Bahnassi PhD 2011
  3. 3. Xa Ka XWe Need the following info: Xu1. Equation for determining the plasma concentration at any time t.2. Determination of the elimination half life (t½) and rate constant (K or Kel).3. Determination of the absorption half life (t½)abs and absorption rate constant (Ka).4. Lag time (t0), if any. Anas Bahnassi PhD 20115. Determination of the apparent volume of distribution (V or Vd) and fraction of drug absorbed (F).6. Determination of the peak time (tmax).7. Determination of the peak plasma or serum concentration, (Cp)max. 3
  4. 4. Graph 2.50Concentration (ng/mL) 2.00 1.50 1.00 Anas Bahnassi PhD 2011 0.50 0.00 0 4 8 12 16 20 24 4 Hours
  5. 5. Amount Remaining in the First Administration Site Order Process − = ( ) − − ( ) = ( )=0 = Bioavailability Dose 100% Absorbed − ( ) =
  6. 6. Monitoring Drug in Site of First Measurement Order Process − = ( ) − ( )=0 − = − − − 0 − = − − −
  7. 7. Elimination Half life (t1/2)And Elimination Rate Constant(k) 0 = − − − ( − ) 10.00 1.00 Concentration t½ 0.10 0 4 8 12 16 20 24 Time
  8. 8. Calculating Absorption Rate Constant (ka) Method of Residuals Feathering MethodTime (h) Observed Plasma Extrapolated Plasma () = − Concentrations Concentrations (Cp)observed (Cp)extrapolatedTime values Values only from the Values only from the Differences betweencorresponding absorption phase extrapolated portion of extrapolated and observedto observed (i.e. all values prior to the plot of plasma values for each time in theplasma reaching maximum concentration–time absorption phase (units,concentrations or highest plasma (units, e.g. (mgmL1) e.g. mgmL-1)for absorption concentration) (units,phase only e.g. mgmL-1) 0 = − ( − ) 8 Anas Bahnassi PhD 2011
  9. 9. Calculating Absorption Rate Constant (ka)Method of ResidualsFeathering Method Slope=− 2.303 Anas Bahnassi PhD 2011 9
  10. 10. Lag Time (t0)Theoretically, intercepts of the terminal linear portionand the feathered line should be the same; however,sometimes, these two lines do not have the sameintercepts, Sometimes absorption starts afteradministration, this delay may be contributed to: • Slow tablet disintegration • Slow and/or poor dissolution • Incomplete wetting of drug particles • Poor formula • Delayed Release formula Anas Bahnassi PhD 2011 10
  11. 11. Negative Lag Time (t0)The presence of a negative lag time may be attributed toinadequate data points in the absorption phase as wellas in the elimination phase. Another possible reasonmay be that the absorption rate constant is not muchgreater than the elimination rate constant. Anas Bahnassi PhD 2011 11
  12. 12. Analysis of Absorption ≫ Rate Constant Quicker Faster Onset for a given drug canAbsorption of Action change as a result of: • Changing the formulation • Changing the dosage form or the extravascular route of administration. • Administration of a drug with or without food.
  13. 13. Apparent Volume ofCannot be calculated from plasma Distribution(Vd)drug concentration data aloneWHY?The fraction of drug absorbed (F) isnot known.If the drug is 100 percentabsorbed; F=1 then 0 = If F is not known then it is best to ( − ) calculate 0 1 = ( ) ( −) Anas Bahnassi PhD 2011 13
  14. 14. Calculating Peak Time(tmax) = − When t=tmax  = = ( ) − () = 0 ( ) = () 0 − = − − − 0 − = − − = − − Anas Bahnassi PhD 2011 14
  15. 15. Calculating Peak Time(tmax)Taking natural log of both sides: Anas Bahnassi PhD 2011 15
  16. 16. Significance of Peak Time(tmax)• To determine comparative bioavailability and/or bioequivalence• To determine the preferred route of drug administration and the desired dosage form for the patient• To assess the onset of action. Significance of Peak Concentration(Cmax)• Used to determine the comparative bioavailability and/or the bioequivalence between two products.• Used to determine the superiority between two different dosage forms or two different routes of administration• Correlates with the pharmacological effect of a drug. Anas Bahnassi PhD 2011 16
  17. 17. Plot the data and, using the plot, determineQuestion the following. a. The elimination half life (t1/2) for each dose. b. The elimination rate constant (K) for each dose. c. The absorption half life, (t1/2)abs, for each dose. d. The absorption rate constant (Ka) for each dose. e. The observed and computed peak time (tmax) for each dose. f. The observed and computed peak plasma concentrations, (Cp)max, for each dose. g. The y-axis intercept for each dose. h. The apparent volume of distribution (V). i. The fraction of drug absorbed (F). j. The characteristics of a plot on rectilinear paper of peak time (tmax) against the administered dose (then make an important observation). k. The characteristics of a plot on rectilinear paper of peak plasma concentrations, (Cp)max, i. Lag time if any. 17Anas Bahnassi PhD 2011
  18. 18. PharmacokineticsAnas Bahnassi PhD RPh attribution – non-commercial – share alike