personalized therapeutics

lassila

concepts of pharmacokinetic variability

* the same dose of a drug does not produce the same blood levels in all patients
* interindividual variability exists in absorption, distribution, metabolism, and excretion

examples of intrinsic factors

* genetics
* age
* race
* organ dysfunction
* disease
* pregnancy
* gender

examples of extrinsic factors

* drug-drug interactions
* smoking
* diet
* alcohol use
* environment

monogenic

one or more genes have a large function

what do polymorphisms result in

* non-functional/absent proteins
* distinct phenotypes

what can variable PK properties influence

drug dosing, efficacy, and/or toxicity

effects of genetic variants on metabolism

genetic variants in drug metabolizing enzymes may ^^decrease^^ metabolizing enzyme function

* decrease enzyme efficiency/activity
* decrease affinity of enzyme for substrates
* result in inactive enzyme

some genetic variants may result in _______

multiple copies of the gene

* increased amount of metabolizing enzymes
* increase in metabolizing enzyme function/activity

what does the impact of drug metabolizing enzyme depend on

whether the drug is in its ^^active, parent form^^ or if it is a ^^prodrug^^

CYP2D6

metabolized 25-30% of clinically available drugs

4 groups of 2D6 metabolizing activity phenotypes

* ultrarapid metabolizers
* normal metabolizers
* intermediate metabolizers
* poor metabolizers

how are 2D6 alleles categorized

into groups based on function

normal function 2D6

2D6\*1 and 2D6\*2

decreased function 2D6

2D6\*9, 10, 17, 41

no function 2D6

3, 4, 5, 6

2 superfamilies of drug transporters

* ATP binding cassette: cellular efflux
* solute carrier: cellular uptake
* transporters influence PK/PD

drug metabolism

* monogenic
* polymorphisms = non-functional proteins
* distinct phenotypes that are easy to measure

drug targets

* polygenic
* polymorphisms = subtle effects on protein function
* lack of distinct phenotype distributions that have variable/imprecise measurements