Week 9 - Pharmacokinetics After Multiple Dosing

Question 1

What do you need to consider when designing a dosage regimen

Answer 1

• Pharmacokinetics
• Efficacy vs toxicity
• Inter-indervidual variability
  - cant assume average therapuetic window or dose can be applied to all patients
• Clinical factors: patients age, weight, condition, DDIs
• Route of administration
• Tolerance

Therapeutic Window
Drug needs to be within specified range of conc.
- as conc. of drug ↑ the effectiveness ↑
- if below = ineffective theapy
- i.e. very low conc. of drug = low efficacy
- if above = adverse effects
- i.e. conc. becomes too ↑ = serious toxicity + adverese effects
- adverse effects as drug can have off target effects (bind other places)

Question 2

How is the maximum (peak) and minimum (trough) affected on dose-conc. profile during multiple dosing IV

Answer 2

Give a sinlge dose as IV as conc. begins to decrease adminster 2nd dose
= how accumulation of drug occurs (as we’re giving another dose before drug is completely eliminated)

Maximum conc. (peak)
- Cmax increases when administer another dose (as adding more drug to remaining drug in body)

Minimum conc. (trough)
- also increases as you adminster another dose (as drug from previous dose has not been fully eliminated)

As rech Css the conc. eventually levels off

Question 3

How do you predict the rate and extent of drug accumulation (for a given regimen)

Multiple dosing - IV

Answer 3

dosing frequency effects the degree / extent of drug accumulation
- ↑ dosing frequency = ↑ accumulation of drug

RAC (accumulation ratio) depends on t1/2 and dosing interval / frequency

SHORT t1/2:
- reach Css quicker (takes 3.3 t1/2 to reach 90% of ss)
- minimal drug accumulation = increased dosing frequency
- have fluctuation around Css
- e.g. Cmax and Cmin values = can have therpeutic issues if fall out of the window

LONG t1/2
- reach Css slower
- extensive drug accumulation = will have a shorter dosing interval
- give a loading dose to reach Css quicker
- multiple dosing maintains this drug conc. at steady state (maintains the Cmax and Cmin)
- have less fluctuations around Css

Question 4

How do you develop a dosage regimen of a drug from its known PK and its concentration-response relationships

Answer 4

1. Decide dosing interval based on t1/2
   - if have short t1/2 = dosing increased frequency
   - if have long t1/2 = shorter dosing frequency
2. Decide dose
3. Calculate the Cmin and Cmax at steady state and compare these values to the theapeutic window of the drug
4. If values within window the regimen is appropriate

Question 5

What is the average amount of drug in body at steady state (Cav) and the RAC goverened by

Aav = average amount of drug | RAC = Accummulation ratio

Answer 5

1. Half life of drug
   2.Dosing interval