Week 4

• Generic medication


  An additional brand of existing medicine
• Generic brands


  • Contain the same active ingredient as the name brand
  • Typically cost less
  • Inactive ingredients may differ to brand names but are deemed acceptable by regulatory bodies
• Generic substitution


  Policy that allows pharmacists to dispense a different brand of drug even though the prescriber has written a prescription for a particular brand, without reference back to the prescriber
• Generic substitution


  • Prescribers can endorse the prescription to prevent substitution
  • Pharmacists must obtain patient consent before substitution of medicines
  • Pharmacists must consider the safety and suitability of alternative brands for the patient and provide adequate and appropriate information to the patient regarding the proposed substitution so that an informed decision can be made
• Bioequivalence


  Demonstrated by conducting a 'bioavailability' study in which volunteers are given the original medicine and, on a separate day, the generic medicine, and the rate and extent of absorption of the active ingredient into the blood is compared
• Pharmaceutical equivalence


  The same drug, the same dosage form, for the same route and meeting the same compendia standards
• The TGA requires a generic manufacture to provide data to show that there is interchangeability between their generic (test) product and the market leader (reference/innovator) product
• Bioequivalence study design


  1. Single dose, open-label, cross-over design

  2. Market leader is usually the 'reference' (innovator) product

  3. Typically done on healthy, young adult male subjects

  4. Administers sub-clinical oral doses
• Bioequivalence testing


  • Typically involves 20 subjects
  • Subject receives both the reference and the test drug product in a randomised order of administration, with a washout period between the occasions
  • Cross-over studies are performed to control for between-subject pharmacokinetic variability
  • Comparing bioavailability between the innovator and the generic drug product to minimise all other sources of variability except that which arises due to product differences
• Strict controls in a bioequivalent study are to minimise all sources of variability except differences between the formulations with respect to the rate and extent of drug absorption
• A bioequivalent study while fit-for-purpose, is unlikely to fully characterise the pharmacokinetics of the drug being tested due to the restrictive nature of the study
• Relevant pharmacokinetic parameters


  • Cmax (maximum observed plasma concentration)
  • Tmax (time to reach the maximum concentration)
  • AUCo-infinity (extent of systemic absorption estimated as area under the plasma-level-time curve)
• Example of data


  • Reference (R): doseR = 50mg, AUCR = 264mg/L.h
  • Generic (G): doseG = 75mg, AUCG = 465mg/L.h
  • Calculations: FG vs R = (AUCG x DoseR)/(DoseG x AUCR) = 1.17 (117%)
• Statistical criteria for bioequivalence


  The 90% confidence limit for the mean value of the ratios of a pharmacokinetics parameter (over all subjects) must fall within the range: 0.80 to 1.25
• Asymmetric confidence limits are used due to pharmacogenetics and population clearance skewed to lower values due to mutation(s) on drug metabolism gene(s)
• Subclinical, single dose is usually given in bioequivalence studies (note: in clinical practise long-term higher doses may be used)
• AUC is generally the most important parameter to consider as it is used to estimate the extent of absorption ("exposure")
• Effects of variable physiology are "disregarded" in bioequivalence studies, thus there is an underestimation of the true PK variability which is seen in clinical practise
• Results of dissolution testing of the test and reference product are also considered during the bioequivalence assessment
• For drugs with a narrow therapeutic index, and/or saturable metabolism, and/or absorption problems, narrower bioequivalence limits and limits on the number of generics may be needed
• In specific cases of products with a narrow therapeutic index, the acceptance interval for AUC has been tightened to 90 - 111%. Where Cmax is of particular importance for safety, efficacy or drug level monitoring a 90-111% acceptance interval may also be applied for this parameter
• In specific cases of products involving highly variable drugs where Cmax is of less importance for clinical efficacy and safety the acceptance criteria for Cmax can be widened to a maximum of 75-133%
• t1/2


  Drug half-life, the period of time that it takes for the concentration or the amount of drug in the body to halve
• k


  Elimination rate constant, a proportionality constant describing the proportion of drug in the body eliminated per unit time
• Drug half-life (t1/2)


  1. Drug half-life is the period of time that it takes for the concentration (C) or the amount of drug in the body (Ab) to halve

  2. Drug half-life is the most widely used PK parameter (and sometimes also misused)

  3. t1/2 stands for half-life of a drug
• Elimination rate constant (k or ke)


  1. The elimination rate constant is symbolised by a small k

  2. The elimination rate constant (k) is a proportionality constant describing the proportion of drug in the body eliminated per unit time

  3. The elimination rate constant has the units 'per hour' (h-1)

  4. The larger the elimination rate constant of a drug the greater the proportion of that drug is eliminated from the body over a given time period
• Equation of the concentration-time curve (iv bolus dose): Cpt = Cp0 x e-kt
• V


  A constant that describes the ratio of the amount of drug in the body (A) to its concentration in the plasma (C)
• Computing half-life


  T1/2 = 0.693/k
• Most drugs are eliminated by first-order elimination, where the rate of elimination is directly proportional to the plasma drug concentration
• The rate of elimination (RE) represents the amount of drug eliminated per unit time and has units such as 'mg/h'
• The elimination rate constant (k) is a proportionality constant expressing the proportion of drug in the body eliminated per unit time. It has units such as 'per hour'
• When the elimination rate constant is 0.10 h-1, one tenth of the drug in the body is eliminated per hour
• A plot of the concentration-time curve using a log scale on the y-axis results in a straight line
• The slope of the straight line on the log-linear plot correlates to k
• What determines half-life


  • T1/2 = 0.693/k
  • k = CL / V
  • T1/2 = (0.693 x V) / CL
  • Drug half-life is directly proportional to V, drug half-life is inversely proportional to CL
• Why does drug volume of distribution determine drug half-life


  • The larger the volume of distribution of a drug the more the drug is concentrated in a person's body tissues compared to their blood
  • If the volume of distribution of a drug is small, most of the drug is in the blood rather that the body tissues
  • It is drug in the blood that is exposed to hepatic or renal elimination
  • If a drugs volume of distribution increases, there will be less drug in the blood, less drug will be exposed to elimination processes and the drug will have a longer half-life
• Equation of a line for mono-exponential decline


  1. Ln(Cpt) = -k x t + In(Cp0)

  2. The log of the drugs concentration at any time point post dose equals the slope of the line (-k as drug concentration is falling) multiplied by time plus the log of the drug concentration at time zero
• When determining PK parameters and describing body systems we use the natural log
• Pharmacokinetic equation for drug concentration in plasma after a single iv bolus dose


  Cpt = (dose / V) x e-(CL/V) x t