L46 - Extravascular administration 2

• Give the eqn to describe the variation of A in the compartment with time.

  Rate of change of drug in body = Absorption rate - Elimination rate.

  
• How can we estimate K from the elimination phase?


  - can't estimate K in absorption phase, as BOTH elimination and apsorption occur.

  
  

  - After Tmax, absorption stops so can treat as IV bolus...

  C = B x e^-kt.

  
• How can we estimate k from a graph of lnC vs time?

  
  

  What about B?

  -K = gradient.

  
  

  lnB = extrapolate to t=0

  
• How can we estimate clearance from extravascular data?

  
  

  Eqn? (NOT given in exam so learn!)

  Use AUC!

  AUC = D x F / Cl

  
• How can we find the area of a trapezoid when calculating AUC?

  area = (B + b) h / 2
• What is "oral clearance"? When do we calculate this?

  When bioavailability (F) is unknown, so we only get the combined value of F/Cl in the eqn.

  
• How can we estimate Volume of Distribution from extravascular data?

  - Vd can't be directly obtained from oral data.

  
  

  - Need Cl = k x V, or V = Cl/k!

  
  

  - OR from B, we know F, D, Ka and K.

  
• What values should we look at when comparing formulations?

  Tmax:- indicated absorption rate from dif formulations.- The smaller Tmax, the faster the absorption rate.

  Cmax/peak Cp:- Is it between MEC and MTC?

  AUC: Cp vs time:- Reflects amount of drug reaching systematic circulation. Extent of absorption, NOT amount of drug (A).

  
• If you increase the extravascular dose, what happens to Tmax and Cmax?

  Tmax = same.

  
  

  Cmax = increases.

  
• If Ka is kept the same and K increases, what happens to Tmax and Cmax?

  They both decrease.

  
• Define bioavailability.


  The rate at and the extent to which the API is absorbed and becomes available at its site of action.
• How do we experimentally measure bioavailability?

  Why?

  - Plasma drug levels /urine.

  
  

  - Site of action is often inaccessible.
• What is absolute bioavailability?

  IV vs Extravascular.
• When are products considered pharmaceutically equivalent?

  If they contain the same amount of API in the SAME dosage forms that meet the SAME comparable standards.

  
  

  
  

  Does NOT mean bioequivalence, as there are differences in excipients/manufacturing processes that can lead to faster/slower dissolution/absorption.
• What are pharmaceutical alternatives?

  Medicines with different salts/esters/isomers/complexes of an API, or which differ in form/strength.
• What are therapeutic equivalents?

  Can be substituted to provide the same clinical effect and safety profile as the prescribed product.

  
  

  = Pharmaceutical equivalents AND bioequivalent.

  
  

  Eg, NOT a K+ and Na+ salt form of same drug.
• What constitutes a generic product, according to EMA?

  - A medicine developed to be the same as the Reference Medicine (RM).

  
  

  - The same pharmaceutical form as RM.

  
  

  - And whose bioequivalence with RM has been demostrated by bioavailability studies.

  
  

  SAME API used at SAME dose in SAME form to treat SAME disease.

  
  

  Excipients may differ.
• When can generics be developed?

  
  

  What must developers provide info on?

  - After patent runs out.

  
  

  Provide info on:

  - quality of generic.

  - prove it produces same level of API in body as RM.
• To manufacture a generic, you must ensure it is...

  1) Pharmaceutically equivalentto the Reference Listed Drug (RLD) - same API, form, strength and route of administration under same conditions of use.

  2) Bioequivalent to RLD- no significant dif in rate/extent of absorption of API.

  3) Therapeutically equivalent- must be substitutable for RLD and have same safety/efficacy.
• How can we establish bioequivalence?

  Compare rate and extent of absorption from the test and reference formulations.

  
• How do we determine the extend of absorption of a drug?


  Through relative bioavailability!

  
• What's the eqn to work ut relative bioavailability?

  F relative = (AUC, oral,test / Dose oral, test) / (AUC oral, ref / Dose oral, ref).

  
• How do we determine the rate of absorption of a drug?

  Via comparison of Tmax/Cmax.

  
  

  - The faster a drug is absorbed, the higher the Cmax, the lower the Tmax.

  
  

  - If absorption rate is too slow, [drug] may be insufficient to get a therapeutic response.
• What is an acceptable bioequivalence level?

  When the 90% confidence interval of a log-transformed exposure lies within the range of80-125%.

  This corresponds to a difference in clinical exposure of less than 20%