Clinical Pharmacokinetics-II [dosing of drugs, tdm]


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Clinical Pharmacokinetics-II [dosing of drugs, tdm]

  2. 2.  To discuss dosing schedules of drugs based on pharmacokinetic principles  To discuss therapeutic drug monitoring
  3. 3.  Effective dose: It is the amount of drug which will produce specific intensity of effect i.e.; either to treat the disease or prevent the disease successfully
  4. 4.  Median effective dose (ED50): It is the amount of a drug which produces the desired therapeutic effect in 50% of experimental animals OR  It is the dose of a drug required to produce a specific intensity of effect in 50% of individuals  It is measure of effectiveness of a drug
  5. 5.  Lethal dose: It is the amount of a drug which will kill certain percentage of experimental animals to whom the drug is administered  Fatal dose: When lethal dose reaches 100% or LD100 is known as fatal dose
  6. 6.  Median lethal dose (LD50): It is the amount of a drug which is fatal to 50% of the experimental animals  [i.e.; which kills 50% of the experimental animals]  It is the measure of acute toxicity of drugs
  7. 7.  Initial loading dose: In some conditions certain drugs are given in large doses in the beginning to obtain an effective blood level rapidly, this is known as initial loading dose
  8. 8.  Maintenance dose: After achieving a desired blood level by initial loading dose, smaller quantity of drug is then required to maintain the blood level, this is known as maintenance dose
  9. 9.  e.g. initial loading dose of sparfloxacin is 400 mg. on the first day then maintenance dose is 200 mg / day as single daily dose  Initial loading dose of digoxin is 1-1.5 mg the maintained at 0.25 mg once or twice daily dose
  10. 10. Loading Dose Dose = Cp(Target) x Vd Dose = Cp(Target) x Vd
  11. 11.  What 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  Answer is on the next slide   
  12. 12.  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
  13. 13.  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
  14. 14.  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  Answer on next slide
  15. 15.  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
  16. 16.  Effective Dose50 [ED50]  Toxic Dose50 [TD50]  Therapeutic Index  Therapeutic window
  17. 17.  Not all people respond to a similar dose of a drug in the exact same manner  This variability is based upon individual differences and is associated with toxicity
  18. 18. Drug Therapeutic Concentration Range Aminoglycoside (gentamicin, tobramycin) 0.5 < - > 8 mg/L Digoxin 0.5 < - > 8 2.0 ug/L Phenytoin 10 < - > 8 20 mg/L Theophylline 10 < - > 8 20 mg/L
  19. 19.  This variability is thought to be caused by: • Pharmacokinetic factors contribute to differing concentrations of the drug at the target area • Pharmacodynamic factors contribute to differing physiological responses to the same drug concentration - • Unusual, idiosyncratic, genetically determined or allergic, immunologically sensitized responses
  20. 20.  The therapeutic index (also known as therapeutic ratio), is a comparison (ratio) of the amount of a drug that causes the therapeutic effect to the amount that causes death  Quantitatively, it is the ratio of median lethal dose to median effective dose  It is an approximate assessment of the safety of the drugs
  21. 21. A high therapeutic index is preferable to a low one  This corresponds to a situation in which one would have to take a much higher dose of a drug to reach the lethal threshold than the dose taken to elicit the therapeutic effect
  22. 22.  Larger the TI greater is the relative safety of the drug  For therapeutic use TI of a drug must be more than one A drug might have different TI depending on its clinical use  e.g.; Aspirin used in headache TI is high  Aspirin used in Rheumatoid arthritis TI is very low
  23. 23.  Drugs with high TI: Penicillin [dose up to 48 lac units] Diazepam [up to 200 mg at once, LD is 750 mg]  Drugs with low TI: Digitalis [digoxin] Anticancer drugs Phenobarbitone Warfarin
  24. 24.  In animal studies, the therapeutic index is usually defined as the ratio of the TD50 to the ED50  The precision, possible in animal experiments may make it useful to estimate the potential benefit of a drug in humans
  25. 25.  The therapeutic index of a drug in humans is almost never known with real precision  Drug trials and accumulated clinical experience often reveal a range of usually effective doses and a different (but sometimes overlapping) range of possibly toxic doses
  26. 26.  The clinically acceptable risk of toxicity depends critically on the severity of the disease being treated  For example, the dose range that provides relief from an ordinary headache in the great majority of patients should be very much lower than the dose range that produces serious toxicity
  27. 27.  However, for treatment of a lethal disease such as Hodgkin's lymphoma, the acceptable difference between therapeutic and toxic doses may be smaller
  28. 28.  It is the ratio of the lethal dose to 1% of population to the effective dose to 99% of the population (LD1/ED99)
  29. 29.  This is a better safety index than the LD50 for drugs that have both desirable and undesirable effects, because it factors in the ends of the spectrum where doses may be necessary to produce a response in one person but can, at the same dose, be lethal in another
  30. 30.  Useful range of concentration over which a drug is therapeutically beneficial  Therapeutic window may vary from patient to patient
  31. 31.  Drugs with narrow therapeutic windows require smaller and more frequent doses or a different method of administration  Drugs with slow elimination rates may rapidly accumulate to toxic levels….can choose to give one large initial dose, following only with small doses
  32. 32. Some Principles
  33. 33.  An established relationship between concentration and response or toxicity  A sensitive and specific assay  An assay that is relatively easy to perform  A narrow therapeutic range  A need to enhance response/prevent toxicity
  34. 34.  Lack of therapeutic response  Toxic effects evident  Potential for non-compliance  Variability in relationship of dose and concentration  Therapeutic/toxic actions not easily quantified by clinical endpoints
  35. 35.  Assuming patient is at steady-state  Assuming patient is actually taking the drug as prescribed  Assuming patient is receiving drug as prescribed  Not knowing when the [drug] was measured in relation to dose administration  Assuming the patient is static and that changes in condition don’t affect clearance  Not considering drug interactions
  36. 36.  Invasive: blood, spinal fluid, biopsy  Noninvasive: urine, feces, breath, saliva  Most analytical methods designed for plasma analysis  C-14, H-3
  37. 37. At the end of the lecture the students will be able to Explain with examples the principles of dosing schedules of drugs based on pharmacokinetic principles  Explain with examples the clinical significance of therapeutic drug monitoring