Lec 10- Dosage regimen design

Question 1

Dosage regimes- Definition

Answer 1

• Thinking about dosing regimens, why do you think they are important and what do you think is the primary purpose
  
  • Efficacy of drug treatment
  • Patient compliance
  • Minimal Adverse effects

Question 2

So why do we take multiple doses

Answer 2

• Maintain therapeutic effect

Question 3

Dosage regimen

Answer 3

• Black line- Dosage every 6 hours (QDS)
• Red line- Dosage every 24 hours (OD)
• We see accumulation because there is some drug remaining when each NEW DOSE is administered
• Accumulation only occurs until we reach a plateau (Css- steady state) when IN=OUT

Question 4

Dosage regimen example

Answer 4

• Whilst many drugs have a wide therapeutic window, some drugs have a very narrow therapeutic window
• Dosage regimens for these drugs need to be very carefully dassigned

Question 5

Factors affecting dosage reimen

What factors determine dosage regimen

Answer 5

• Activity-toxicity
  
  • Therapeutic window
  • Side effects
  • Toxicity
  • Conc-response release
• PK- ADME
• Clinical factors
  
  • Patients (Age, weight, Pathophysiologic conditions)
  • Management of there (multiple drug therapy, Convenience of a regimen, compliance of patient)
• Other factors
  
  • Route of administration
  • Dosage form
  • Tolerance-dependence
  • Drug interaction
  • Cost

Question 6

Accumulation

Answer 6

• Consider giving an IV bolus dose to a patient where we dose at a frequency that is equivalent to the half-life of a drug= 0.5 x t1/2 (red); 1xt1/2 (black)
• If the half-life is 4 hrs- give a dose every 4 hrs
• First dose (black line) Amax= 100mg; Amin= 50mg
• Second dose (Black line) Amax= 150mg; Amin= 75
• The small amount of drug remaining in patients body leading to accumulation
• If we dose shorter than the half-life (case A), this leads to more accumulation as a more drug remains after each dose- reach Css quicker

Question 7

Dose- accumulation

Answer 7

• So far we can see that the dosing interval (tau) is important in controlling the accumulation and this appears to be related to the half-life and dosing interval (time) of the drug
• Because we often see fluctuation which gives us A mix and Amin (Cmax; min) we prefer to look at the average concentration at the plateau
• Amount in= amount out
  *

Question 8

Building up

Answer 8

• If an oral dose is taken after the previous dose has been fully eliminated then the profile is a series of single dose events
• NO accumulation
• OD dosing- with a tau of 24 hrs

Question 9

Changing the dosing frequency

OD, BD, TDS, QDS

Answer 9

• If we alter the dosing frequency we are chaningtau (dosing intercal)
• This will often lead to accumulation over the course of the dosing regimen
• QDS dosing
  
  • NB the change in tau from 24 to 6hr and how this leads to an increase in the C_ave

Question 10

Increasing dose

Answer 10

• we can also opt to give the patient a higher dose for each dosing interval this may help in attaining our therapeutic window
  
  • Are there any problems
    
    • Side effects
    • Higher than TW
      *

Question 11

Dosing regimen

Answer 11

• Although the dose and dosing frequency are important, it is the relationship between the
  
  • DOSE and HALF-LIFE and TAU
  • Which governs the final dosing regimen

Question 12

Relationship to half life

Answer 12

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Question 13

Concentration fluctuatio

Answer 13

• Remeber that accumulation and time to SS is dependant on the half-life fluctuations are very important for narrow therapeutic index drugs
• If such a drug has a large therapeutic index so that a large degree of fluctuation over the dosing interval dose not result in toxicity due to high peak concentrations, it can be given at intervals longer than the half-life
• Other factors- liver/renal + plasma concentration

Question 14

Dosage regimen- other formulation

Answer 14

• Modified release forms can avoid the peak-trough problems seen with some narrow TI drugs
• NB- how the dosing frequency has been reduced along with the difference between the peaks and troughs (fluctuations)

Question 15

How to design a dosage regiment

6 steps to designing the dose regimen

Answer 15

1. What is your therapeutic window
2. Work out the target average concentration (C_{av, ss})
3. Select the dosing interval (normally start with = half-life)
4. Work out starting dose
5. Round the dose to the nearest dosing unit (110mg down to 100mg tablet) and half-life to the nearest whole number (4.65 hrs down to 4hrs)
6. Can then work out the C_{av, ss} AND the peak and trough concentrations