Sources of Interindividual Variability

Question 1

What ADME factors impact Cp vs. time curves?

Answer 1

• Body weight/composition
• Sex, age
• Genetics
• Lifestyle factors
• Pregnancy
• Pathophysiology
• Circadian rhythm
• Drug interactions

Question 2

What biopharmaceutical factors impact Cp vs. time curves?

Answer 2

• Route of administration
• Size of dose
• Frequency of administration
• Formulation

Question 3

What are the specific impact of obesity on Cp vs. time curves?

Answer 3

• No consistent effects of obesity on absorption
• Lipophillic drugs tend to exhibit a higher Vd
• Decrease in Vd of drugs distributing to lean bosy mass when normalized to total body weight
• Conflicting effects on Cls, Clh, Clr

Question 4

What is the specific impact of sex on Cp vs. time curves?

Answer 4

Sex differences in PK not obvious for many drugs

Some drugs had important sex differences which relate physiological differences:
a. Women have slower GI transit time and gastric emptying rate
b. Men have higher total body weight; AAG levels are typically lower in women
c. GFR/body weight in men is about 10% higher vs. women; renal TS of a few drugs is higher in men

Question 5

What is the specific impact of genetics on Cp vs. time?

Answer 5

• SNPs result in changes in amino acids which have downstream effects on affinity and capacity of drug-protein complexes or altered protein activity (enzyme, transporter, plasma protein)

Significant ethnic diversity in SNP distribution

Question 6

What is the specific impact of age on Cp vs. time?

Answer 6

Developmental maturation and aging can cause the following:
a. Rate and extent of absorption
b. Plasma protein binding and extent of distribution
c. Systemic clearance

Question 7

What is the specific impact of pregnancy on Cp vs. time profiles?

Answer 7

Pregnancy causes a number of anatomical and physiological changes, all of which influence drug PK

Increased CO, TBW, renal blood flow and GFR,

Decreased BP

Variable changes in Phase I and Phase II enzyme activity

Question 8

What is the specific impact of lifestyle factors on Cp vs. time profiles?

Answer 8

Diet can impact rate and extend of absorption or food-drug interactions

Dietary deficiencies and malnutrition may result in reductions in hepatic metabolism of some drugs

Smoking is known to be a CYP1A2 induces (increasing Clh, and Cls by extension)

Question 9

What is the specific impact of the circadian rhythm on Cp vs. time curves?

Answer 9

Physiological system is subject to diural variations to cause time-dependent chanhes in PK during the day

PK process are faster in the morning

Question 10

What is the specific impact of disease on Cp vs. time curves?

Answer 10

Disease can have variable effects on the PK of drugs

a. Rate and extend of absorption and distribution
b. Hepatic and renal clearance

Question 11

What is the specific impact of drug interactions on Cp vs. time curves?

Answer 11

Polypharmacy is often the norm (but few drugs actually have concerning DIs)

Drugs with narrow therapeutic indexes are at high risk of clinically relevant DIs

Interactions often reduce systemic clearance and increase accumulation of drug in the body