PDTI exam 2

When multiple doses are given and steady-state isreached, the amount of drug eliminated during one dosinginterval is equal to the dose.

True

A drug with a relatively small ke (long t1/2) takes a shortertime to reach steady-state than a drug with a large ke.

False. It takes about 5 t1/2 to reach steady-state, so thelonger t1/2 (small ke), the longer it takes to reachsteady-state.

Decreasing the dosing interval while keeping the dose constant will result in lower steady-state concentrations.

False. By decreasing the dosing interval the amount of drug administered per unit time will increase, so steady-state concentrations will increase.

Which of the following dosing regimens will result in the greatest difference between peak and trough concentrations?

Large doses given at a long dosing interval

True or false: as the duration of infusion increases, fluctuation decreases

true

True or false: the rate of infusion does not change between simulations even if the duration is variable

False because it depends on the dose and duration of the infusion and the duration is variable

True or false: Time to reach steady only depends on the half-life of a drug

true

Pharmacogenetics definiton

single gene-drug interaction and how variation in gene impacts an individual's response to a single drug

Pharmacogenomics definition

influence of many genes, or entire genome and how variation of such impacts an individual's response to medication

benefits of PGx interventions

-improve disease outcomes

-decrease adverse effects

-decrease healthcare spending

-get the patient on the right drug sooner

What is the human genome project?

completed in 2003 and was a 13 year project; the goal was to identify all the genes in human DNA

What is the central dogma of biology?

a theory stating that genetic information flows only in one direction, from DNA, to RNA, to protein, or RNA directly to protein.

Genome definition

the entire genetic make-up of an organism

Exome defintion

only the protein coding segments (exons)

Regulome definition

DNA elements that modulate the expression of genes

True or False: Assuming linear kinetics, AUC0-∞ after single dose and AUC0-tau at steady-state are the same for a given drug.

True: At steady state, the AUC during one dosing interval (AUC0-tau) is identical to AUC0-∞ of the first dose.

True or false: Administration of a loading dose will cut the time needed to reach steady-state in half.

False: Steady-state is reached immediately through the use of a loading dose.

True of False: AUC stays the same as long as bioavailibility does not change

True

True or False: the lower the Cmax, the later the tmax

true

If ka<

flip flop kinectics (ke-ka)

What does tmax mean

the time needed to achieve peak concentrations

What is tmax independent of

dose and bioavailability

True or False: The larger the ka, the shorter the tmax, the lower the cmax

False: The larger the ka, the shorter the tmax, the higher the cmax

AUC of oral administration is directly related to what

dose and bioavailability

AUC of oral administration is independent of

Ka

If there is slower absorption, what happens to the fluctuation and the time it takes to reach steady state

The slower the absorption, the less fluctuation and the longer it takes to reach steady state

Are steady-state levels dependent on Ka?

no they are independent

True or false: Absorption of a drug from a tablet involves dissolution of the solid dosage form into GI fluids and diffusion through body fluids and membranes.

true

True or False: The terminal slope of the concentration-time profile following oral administration always provides the elimination rate-constant ke.

False (flip flop kinetics)

True or False: Information on Cmax and tmax is sufficient for determining bioequivalence between 2 drug products

False

How do you find F for oral administration?

take amount absorbed into the systemic circulation/amount of drug given orally

Two drugs are considered pharmaceutical equivalents when

- They contain the same active ingredient(s)

- They are of the same dosage form and route of administration

- They are identical in strength or concentration

According to the 2000 FDA BCS Guidance, which class of compound is most likely to be eligible for BCS biowaivers (waiver of clinical studies)?

Class I (High Permeability, High Solubility) Rapidly dissolving

Which main PK parameters are calculated to evaluate the bioequivalence studies?

AUC and Cmax

Relative bioavailability compares

"when the systemic availability of a drug administered orally, is compared with that of oral standard of same drug"

Example: comparison between a capsule and a tablet

Which of the following statement is INCORRECT:

A. Absolute bioavailability is measured by comparing the respective AUCs after extravascular and intravascular administration

B. The oral formulation of Propanolol that undergoes extensive first-pass metabolism must be administered in much larger doses than the equivalent IV formulation of the same drug

C. A relative bioavailability of 100 means that a drug is completely absorbed

D. The rate of absorption depends on the route of administration and the drug formulation

C

Remember!! The relative bioavailability is used to compare two formulations administered extravascularly. Therefore it means that both formulations have the same bioavailability that may not be 100%

Bioequivalence is accepted when

Log-transformed ratios (test:reference) of Cmax and AUC must pass the two one-sided tests about the 90% confidence interval limits of 0.8 - 1.25 (80 - 125%) of branded drug

What is the systemic availability of drug after extravascular administration in comparison to IV administration?

Absolute bioavailability

What is the ideal trial design for a bioequivalence study?

Randomize, two period, two-sequence, cross over design with adequate washout period

What type of trial design is recommended for drugs with long half-lives?

Parallel study design

What type of trial design is recommended for highly variable drugs (intra-subject variability > 30%)?

Replicate cross over study design

What type of administration is recommended for bioequivalence studies (single or repeated doses)?

Single dose study as it is considered more sensitive in assessing the primary question in a bioequivalence study, i.e., release of the drug substance from the drug product into the systemic circulation.A multiple-dose study is usually not recommended.

Do all strengths require a BE study?

In vivo BE studies needed only for highest strength

What is usually recommended to be measure in a BE study, parent or metabolite?

Parent in most cases

What is usually recommended to be measure in a BE study, enantiomers and/or racemic mixtures?

Racemic mixtures in most cases

untronic/untranslated region

RNA transcription and RNA splicing and processing

Allele

One of two or more versions of a genetic sequence at a particular location in the genome

genotype

an individuals collection of genes

phenotype

observable trait

Hardy-Weinberg equilibrium

States that gene frequencies and genotype frequencies will remain constant from generation to generation in an infinitely large, interbreeding population in which mating is at random and there is no selection, migration or mutilation

HWE equation

p^2 + 2pq + q^2 = 1

If two variants are in high linkage disequilibrium, what does that mean?

they will be inherited together

high linkage disequilibrium values

>0.7-0.8

Halotypes

a combination of alleles or SNPs along a chromosome that tend to be inherited together

Diplotype

two haplotypes that are inherited on a chromosome for a certain gene, or combination of alleles or SNPs

What resource can you find annotations of all of the following items: clinical guidelines, package labels, primary literature?

PharmGKB

CPIC

guidelines for prescribing; Designed to help clinicians understand HOW available genetic test results should be used to optimize drug therapy, NOT whether tests should be ordered

Which of the following phenotypes represents the least amount of enzyme activity?

intermediate metabolizer

CYP metabolism is a part of __________ phase metabolism?

one

is CYP1A2 conserved or polymorphic?

well conserved

Substrates of CYP1A2

olanzapine

duloxetine

caffeine

inhibitors of CYP1A2

Fluvoxamine

inducers of CYP1A2

smoking, rifampin

CYP2A6 genetic info

PM more common in asian population

CYP2A6*4 is no function

substrates of CYP2A6

nicotine

CYP2B6 genetic info

phenotypes include PM, IM, NM, RM, UM

CYP2B6 substrates

Efavirenz

Methadone

Bupropion

CYP2B6 inducers

carbamazepine

efavirenz

rifampin

CYP2C8 polymorphic or conserved

polymorphic

CYP2C8 substrates

Glitazones

CYP2C8 inducers

Rifampin

CYP2C9 2 and 3 allele functions

*2 decreased function

*3 no function

CYP2C9 substrates

warfarin, phenytoin, NSAIDs

CYP2C9 inducers

Rifampin

CYP2C9 inhibitors

fluconazole, amiodarone

CYP2C19 *2, 3, 17 allele function

*2, 3 no function

*17 increased function

CYP2C19 PM phenotype is common in what population

Asian populations

CYP2C19 substrates

Clopidogrel, PPIs, Select SSRIs, Voriconazole

CYP2C19 inhibitors

Fluvoxamine

Fluoxetine

CYP2C19 inducers

rifampin

CYP2D6 substrates

codeine

tramadol

paroxetine

fluvoxamine

CYP2D6 inhibitors

Bupropion

Duloxetine

Quinidine

CYP2D6 inducers

none

CYP3A4 conserved or polymorphic

well conserved

CY3A5 expressers are more common in which population

african americans

CYP3A5 *1 means

expressor

CYP3A5*3 means

non expressor

CYP3A4 substrates

CCBs, midazolam

CYP3A inhibitors

ketoconazole, verapamil

CYP3A5 substrates

tacrolimus

CYP3A inducers

Rifampin, St. John's Wort

UGT1A*28

decreased function allele

UGT1A substrates

bilirubin, irinotecan

UGT1A inhibitors

atazanavir

UGT1A inducer

rifampin

NAT2 slow acetylators

greater neuropathy and hepatitis, faster appearance of antinuclear antibodies, hydralazine induced lupus

NAT2 substrates

Isoniazid

Hydralazine

TPMT substrates

Azathioprine, 6-mercaptopurine