Lecture 9; Variability due to environmental differences

Question 1

What is the most important determinant of drug dose?

Answer 1

Body size is the most important quantitative determinant of drug dose

• BW important in loading dose and volume of distribution
• Maintenance dose has a smaller range b/c of weight

Question 2

Describe the theoretical foundation for allometric scaling: Describe the equation:

Answer 2

Theory with the fundamental assumption that:

• All cells are similar in size and have similar energy requirements
• 3/4 exponent describes the non-linear relationship of clearance
• The energy delivery system and mass of structures to support i.e bones, increase overall mass without a linear increase function

Cl(child) = Cl(adult) x ((WT(child)/(WT (Adult)3/4)

Question 3

What has studies in animals shown?

Answer 3

The relationship between metabolic rate and body mass is remarkably robust and works across a large number of animals

But the relationship is (3/4) not one (allometric scaling)

Question 4

Describe how age influences clearance: In application to a baby

Answer 4

Post natal age: -> Doesnt account for in utero maturation

Post menstural age -> on average 2 weeks more than biological age (best pragmatically)

Post conception age -> Biological age but not widely recorded

Question 5

Describe maturation of drug clearance:

Answer 5

Maturation of drug clearance

• > Typically maturation is about 30% of adult values at full term delivery
• > Very premature neonates are around 10% adult values
• > In neonates and infants age accounts for a 10 fold increase in glomerular filtration rate from 24 weeks post menstural age up to 1 year of post natal age

Question 6

Describe ageing and drug clearance

Answer 6

Age in older adults has a minor (25% lower) influence on drug clearance once weight and other factors such as renal function are accounted for

Question 7

What are some things to consider when it comes to body composition:

Answer 7

• Distinguish between fat free mas and fat mass
• Fat mass ~22% body weight in men and 28% in women
• Fat free mass is predictable from total body weight, height and sex

Question 8

What is drug clearance and volume of distribution mainly driven by?

Answer 8

Drug clearance and volume of distribution is ‘driven’ mainly by fat free mass. The fraction of fat mass predicting drug elimination and distribution varies from drug to drug.

Question 9

Describe how renal function varies in clearance:

Answer 9

Differences in renal function can explain about a 10 fold difference in total drug clearance

• GFR varies 7L/h in health adults and 0.5L
• > There is always some non-renal clearance i.e via the gut which adds 0.5L/h to renal clearance even in renal failure

Question 10

Whats used to calculate renal clearance?

Answer 10

Serum creatinine is used to calculate creatinine clearance (Clcr)

ClCr is approximately the same as glomerular filtration rate

Renal function is calculated relative to normal Clcr for weight and age:

Renal function = Predicted CLcr / Normal CLcr

Question 11

When is clearance maturation complete?

Answer 11

2 years of age

• Then weight is the sole predictive factor for drug clearance

Question 12

Can we predict hepatic drug clearance?

Answer 12

Difficult to predict hepatic drug clearance without administering the drug

Liver function tests

• Measures liver damage; AST/ALT
• Albumin can be correlated in terminal heptic failure with heptic drug clearance

Child pugh system is loosely correlated with drug clearance

Question 13

What are the most important determinants of drug dose?

Answer 13

Body size, renal function and post-menstural age

• > Genotype pale into insignificance
• > Quantitative pharmacology can help put the role of using covariets to predict drug dose into a realistic perspective