Aaditya- calculation of pk parameters

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A brief description of calculating pharmacokinetic parameters.

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Aaditya- calculation of pk parameters

  1. 1. Calculation of Pharmacokinetic Parameters
  2. 2. Although drug discovery is primarilydesigned to find compounds with desiredefficacy, the choice from among multiplecompounds potentially offering efficacyoften comes down to those with the mostfavorable pharmacokinetics(Welling and Tse, 1995).
  3. 3.  Pharmacokinetics is defined as the quantitative analysis of the processes of drug absorption, distribution, and elimination that determine the time course of drug action.
  4. 4.  ADME Scheme  Absorption, Distribution, Metabolism and Excretion LADME  Inclusion of new term Liberation  Liberation is the process of release of drug from the formulation
  5. 5.  Where is it measured?  For in-vitro data  In phase I studies for any new drug  During therapeutics to adjust dose  For toxicity studies and during poisoning
  6. 6.  What to measure?  Dose  Bio-availability  Clearance  Volume of distribution  Half-life  Area under curve  Steady state concentration
  7. 7.  How to measure?  Pharmacokinetic models ▪ Non compartmental ▪ Compartmental ▪ Physiological ▪ Bioanalytical methods  Equipment used ▪ High pressure liquid chromatography ▪ Gas liquid chromatography ▪ Fluorescence polarizing immunoassay
  8. 8. 8
  9. 9.  CTissue indeterminable directly  Indirect analysis using Cp vs Time data Several inter-connected compartments  mathematical entities Each compartment has pharmaco-kinetically similar tissues In graph, no. of models shown by lines with different slopes Drug administered to & eliminated from central compartment 9
  10. 10.  Non-compartmental Models  Offers little insight into the rate or processes involved in drug distribution  Mainly uses area under curve parameters Compartment Models  Catenary and mammalian models  Kinetic models to describe and predict the concentration-time curve  Simplest PK compartmental model one- compartmental PK model with IV bolus administration and first-order elimination
  11. 11. 11
  12. 12.  Body assumed to be one homogenous compartment Instantaneous distribution Elimination starts simultaneously Only one straight line in ln(Cp) vs time graph ke = Slope ln(C0) = y-intercept C0 = exp(y-intercept) 12
  13. 13.  Absorption + Elimination during upstroke Terminal straight line portion Elimination) 13
  14. 14.  One Central (1) & One Peripheral (2) compartment 14
  15. 15.  Slower distribution Ct = A * e-αt + B * e-βt α = Distribution + Elimination β = Elimination 15
  16. 16.  Consider absorption & distribution 17
  17. 17.  One Central (1) + Two peripheral (2, 3) Compartments Compartment 2 & 3 not interconnected 18
  18. 18.  Achieved by mathematically transcribing  anatomical,  physiological,  physical, and chemical descriptions of the phenomena involved in the complex ADME processes Used to extrapolate dose, metabolism and excretion of drugs prior to human exposure
  19. 19.  For single-dose study of an immediate release product: For at least three elimination half-lives (cover >80% of AUC) • Absorption phase : 3-4 points • Around Tmax : 3-4 points • During elimination : 4 points Intervals not longer than the half-life of the drug Truncated AUC undesirable except in entero-hepatic recycling (elimination half life difficult to calculate) If urine tested, collect it for at least 7 half-lives
  20. 20.  Plasma, serum or blood? Collect after steady state of drug is achieved (5-6 t½) Trough or Peak concentration? Immediate sampling in toxicity Other samples (Saliva)19/11/2008 Dept.of Pharmacology Grant Medical College
  21. 21.  Most cases: Active drug substance Active / Inactive metabolite maybe measured in cases of:  Concentration of drug too low  Limitation of analytical method  Unstable drug(s)  Drug(s) with very short half life  Pro-drugs Measurement of individual enantiomers is sometimes recommended for safety / efficacy purposes
  22. 22.  Quantity of a drug or other agent administered for therapeutic purposes Calculating drug dosages for humans based on the doses used in animal studies From  weight (eg. mg/kg) initial  surface area (eg. mg/m2) animal LD50 = Median lethal dose studies NOEL = No Observed Effect Level and human NOAEL = No Observed Adverse Effect Level extrapolati TWA = Time Weighted Average on
  23. 23.  Absorption : passage of drug from the site of administration into the blood stream. Bioavailability : is defined as the amount or percentage of drug that is absorbed from a given dosage form and reaches the systemic circulation following non-vascular administration 25
  24. 24. Parameters for assessing bioavailability T max : time to peak plasma concentration  depends on rate of absorption C max : peak plasma concentration AUC (area under the curve) (∫C dt): is a P measure of the total amount of the unaltered drug that reaches systemic circulation 26
  25. 25. 40 A Cmax 30plasma Tmaxconc.20(μg/ml) AUC 10 B 0 1 2 3 4 Time (hrs) 27
  26. 26. • AUC 0-t • AUC 0-∞For the segment from Cp2 to Cp3: AUC2-3 = Cp2 + Cp3 x (t3 - t2) 2AUC 0-∞ = AUC 0-t + Clast / k
  27. 27.  Describes the fraction of an administered dose of unchanged drug that reaches the systemic circulation By definition, when a medication is administered intravenously, its bioavailability is 100%
  28. 28. “The ratio of areas beneath the blood level-time curvesafter oral administration to that following intravenous administration ofthe same dose is a measure of the absorption of the drug administered” Nimodipine AUC Oral : 1.17 % Nasal : 67.4 % www.chinaphar.com
  29. 29. Apparent volume of distribution is thetheoretical volume that would have to beavailable for drug to disperse in if theconcentration everywhere in the body were thesame as that in the plasma or serum, the placewhere drug concentration sampling generallyoccurs.
  30. 30.  VD is a theoretical Volume and determines the loading dose Clearance is a constant and determines the maintenance dose CL = kVD CL and VD are independent variables k is a dependent variable
  31. 31. Volume of Distribution, Clearance and Elimination Rate ConstantV Volume 100 L Clearance 10 L/hr
  32. 32. Volume of Distribution, Clearance and Elimination Rate ConstantV V2 Cardiac and Skeletal Muscle Volume 100 L (Vi) Clearance 10 L/hr
  33. 33. V2 Cardiac andSkeletal Muscle V Volume 100 L (Vi) Clearance 10 L/hr Volume of Distribution = Dose_______ Plasma Concentration
  34. 34. V2 Cardiac andSkeletal Muscle V Volume 100 L (Vi) Clearance 10 L/hr Clearance =Volume of blood cleared of drug per unit time
  35. 35. V2 Cardiac and Skeletal Muscle V Volume 100 L (Vi) Clearance 10 L/hrClearance = 10 L/hrVolume of Distribution = 100 LWhat is the Elimination Rate Constant (k) ?
  36. 36. CL = kV k = 10 Lhr -1 = 0.1 hr -1 100 L10 % of the “Volume” is cleared (of drug) per hourk = Fraction of drug in the body removed per hour
  37. 37. CL = kVIf V increases then k must decrease asCL is constant
  38. 38.  An abstract concept Gives information on HOW the drug is distributed in the body Used to calculate a loading dose
  39. 39. Loading DoseDose = Cp(Target) x VD
  40. 40.  What Is the is the loading dose required for drug A if;  Target concentration is 10 mg/L  VD is 0.75 L/kg  Patients weight is 75 kg
  41. 41.  Dose = Target Concentration x VD VD = 0.75 L/kg x 75 kg = 56.25 L Target Conc. = 10 mg/L Dose = 10 mg/L x 56.25 L = 565 mg This would probably be rounded to 560 or even 500 mg.
  42. 42.  Ability of organs of elimination (e.g. kidney, liver to “clear” drug from the bloodstream Volume of fluid which is completely cleared of drug per unit time Units are in L/hr or L/hr/kg Pharmacokinetic term used in determination of maintenance doses
  43. 43.  Major Factors  Drug delivery α Q  Extraction Ratio (ER) = (Cin – Cout) / Cin 46
  44. 44. Total Body Clearance  ClTotal = ClHepatic + ClRenal + ClOthers  ClTotal = aVd * Ke  ClTotal = Dose / AUC 47
  45. 45. RCR = ClDrug / ClCreatinine 48
  46. 46.  Maintenance Dose = CL x CpSSav CpSSav is the target average steady state drug concentration The units of CL are in L/hr or L/hr/kg Maintenance dose will be in mg/hr so for total daily dose will need multiplying by 24
  47. 47.  What maintenance dose is required for drug A if;  Target average SS concentration is 10 mg/L  CL of drug A is 0.015 L/kg/hr  Patient weighs 75 kg
  48. 48.  Maintenance Dose = CL x CpSSav CL = 0.015 L/hr/kg x 75 = 1.125 L/hr Dose = 1.125 L/hr x 10 mg/L = 11.25 mg/hr So will need 11.25 x 24 mg per day = 270 mg
  49. 49.  Half-life is the time taken for the drug concentration to fall to half its original value The elimination rate constant (k) is the fraction of drug in the body which is removed per unit time.
  50. 50. Biological half-life Time it takes for the blood plasma concentration of a substance to halve ("plasma half-life") its steady-state First-order elimination Proportional to the initial concentration of the drug A0 and inversely proportional to the zero-order rate constant k0 Logarithmic process Fall in plasma concentration: Ct is concentration after time t C0 is the initial concentration (t=0) k is the elimination rate constant
  51. 51.  The relationship between the elimination rate constant and half-life is given by the following equation: Half-life is determined by clearance (CL) and volume of distribution (VD) In clinical practice, this means that it takes 4 to 5 times the half- life for a drugs serum concentration to reach steady state after regular dosing is started, stopped, or the dose changed.
  52. 52. Drug ConcentrationC1 Exponential decay dC/dt  C = -k.CC2 Time
  53. 53. Log Concn. C0C0/2 t1/2 t1/2 t1/2 Time Time to eliminate ~ 4 t1/2
  54. 54. Integrating: Cp2 = Cp1 .e -kt Logarithmic transform: lnC2= lnC1 - kt logC2 = logC1 - kt/2.303 Elimination Half-Life: t1/2 = ln2/k t1/2 = 0.693/k
  55. 55.  Steady-state occurs after a drug has been given for approximately five elimination half-lives. At steady-state the rate of drug administration equals the rate of elimination and plasma concentration - time curves found after each dose should be approximately superimposable.
  56. 56. Accumulation to Steady State 100 mg given every half-life 194 … 200 187.5 175 150 100 97 … 100 87.5 94 75 50
  57. 57.  Rate in = Rate Out Reached in 4 – 5 half-lives (linear kinetics) Important when interpreting drug concentrations in TDM or assessing clinical response
  58. 58.  Develops ADMET modeling and simulation software  GastroPlusTM predicts the absorption, pharmacokinetics, for drugs administered orally.  ADMET Predictor TM  Estimate kinetics based on chemical structure  ClassPharmerTM  Estimate screening data analysis  DDDPlusTM  simulates the in vitro disintegration and dissolution of solid dosage forms
  59. 59.  Metabolism  Human liver microsomes Human intestinal microsomes Human kidney microsomes Human hepatocytes Recombinant CYP and UGT enzymes PK profiles  Prediction of volume of distribution based on lipophilicity, ionisation, protein binding and tissue composition Drug – drug interactions  Competitive enzyme inhibition (including auto-inhibition) Enzyme-induction (including auto-induction)
  60. 60.  Continuous line of heterogeneous human epithelial colorectal adenocarcinoma cells When cultured under specific conditions the cells become differentiated and polarized such that their phenotype, resembles the enterocytes lining the small intestine Used as a model to estimate absorption of drugs at pre- clinical stage of development Other cell cultures with expression of transporters and enzymes are used in calculation of PK parameters E.g.: P-glycoprotein (ABCB1) and BCRP (ABCG2)
  61. 61. HPLCColorimeterSpectrophotometerSpectrophotofluorimeterGLCFlame photometry 19/11/2008 Dept.of Pharmacology Grant Medical College
  62. 62.  High ER (Liver, Blood, Lungs) indicates high PRE-SYSTEMIC ELIMINATION (Lidocaine in liver) Maximal clearance = Blood flow 69

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