Interindividual Variability Flashcards
What is interindividual variability?
refers to the variability in PK characteristics of a given drug observed between different individuals
leads to differences in:
-Cp vs t profiles
-therapeutic outcome
What are the factors affecting Cp vs t profiles?
ADME
-body weight/composition
-sex, age
-genetics
-lifestyle
-pregnancy
-pathophysiology
-circadian rhythm
-drug interactions
biopharmaceutical factors
-route of admin
-size of dose
-frequency of admin
-formulation
What are the effects of obesity on Cp vs t profiles?
no consistent effects on absorption
lipophilic drugs tend to exhibit a higher Vd
decrease in Vd of drugs distributing to lean body mass
conflicting effects on Cls, Clh, and Clr
What are the effects of sex on Cp vs t profiles?
sex differences in PK not obvious for many drugs
some drugs have important sex difference which relate to physiological differences:
-woman have slower GI transit time and gastric emptying
-men have higher TBW; females have higher adipose levels
-AAG levels are typically lower in women
-GFR/body weight in men is about 10% higher vs women
-renal TS of a few drugs is higher in men
What is the impact of genetics on Cp vs t profiles?
important cause of interindividual variation in ADME
polymorphisms result in a change in aa and in turn changes affinity and capacity of drug-protein interactions and altered activity of protein
What is the impact of age on Cp vs t profiles?
developmental maturation and aging cause changes in:
-rate and extent of absorption
-plasma protein binding and extent of distribution
-systemic clearance
What is the impact of pregnancy on Cp vs t profiles?
cardiovascular:
-CO increases and BP decreases
=larger total body water volume, higher renal blood flow and GFR
variable changes in phase 1 and 2 enzyme activity
What is the impact of lifestyle factors on Cp vs t profiles?
diet can have variable effects on PK of drugs
-rate and extent of absorption, food-drug interactions
dietary deficiencies and malnutrition result in reduction of hepatic metabolism of some drugs
smoking induces drug metabolizing enzymes which enhances Cls
What is the impact of circadian rhythm on Cp vs t profiles?
diurnal variations cause time-dependent changes in PK
can result in faster PK processes in morning or evening which will impact Cp vs t profile throughout the day
What is the impact of disease on Cp vs t profiles?
rate and extent of absorption and distribution
hepatic and renal clearance
What is the impact of drug interactions on Cp vs t profiles?
drug interactions are usually of limited clinical significance
be cautious if low TI drugs
drug interactions can occur at any of the ADME processes
most common=competitive inhibition of CYP enzymes
-reduction in Cls
induction reactions are also common
-enhances Cls
