Pre-Clinical and Clinical PK models

Question 1

In vitro PK characteristic determination

Answer 1

• Lipophilicity, solubility, pKa, MW, LOG D, BCS classification
• Use cell line or artificial membranes to determine absorption
• PPB
• Liver microsomes
• Drug transporting systems

Question 2

Physiological based PK models

Answer 2

In vitro data used to determine likely in vivo parameters through the use of estimates and scaling factors

Considerations:

1. amount of comound
2. Formulation/vehicle required
3. Bioanalytical assay used, lower concentratino => greater sensitivity required
4. Time and number of blood samples to get the best data
5. number of blood samples taken per animal
6. number of animals to be utilized to get the bet data
7. need for a full-mass balance study

Question 3

Allometric scaling

Answer 3

• notion that many anatomical and physiological characteristic can be correlated using a power function of body weight
• CLhuman = Clmouse * (weight human/weight mouse) ^0.75

Question 4

Data collection in in vivo rat design

Answer 4

• take data points at high frequency in time frame soon after dosing as this is when the most dramatic change in plasma concentrations occur
• 10 -15 data points required for a good time profile
• only 1-2 blood samples can be taken out of a mouse
• need to take measurement untill plasma concentration is close or equal to 0
• 3 samples in absorption phase others distributed throughout and concentrated towards C max

Question 5

Reviews of clinical trial

Answer 5

independent review board within the company and then an external institutional human research ethics committee

Question 6

Declaration of Helinski

Answer 6

• based in scientific principles
• protocol assessed by independent committees
• supervised by medically qualified personal
• importance of the trial is in proportion to risk
• accuracy of the results
• subject welfare is more important than scientific outcomes
• all patients give freely informed consent

Question 7

Phase 1 trials

Answer 7

• Aim to determine safety and tolerability over the dose range; pharmacokinetic profile
  (SAD OR MAD)
  Design:
• NOAEL determined from pre-clinical data using allometry or HED
• First subject cohort is administered a very low dose which is increased from one study to the next . Before dose progression data evaluation by an indepedent entity is required; stopping criteria based on efficacy/toxicity
  Subjects:
• healthy with/without disease
• tight age/gender/health requirements
• intensely monitored renal/hepatic function screened prior and after

Question 8

SAD study design

Answer 8

• aims to obtain an understanding of single dose PK (saturable or not)
• 3 or more dose levels, see if AUC increases proportionally
• parallel