Csf Test 2 Kuma (Dlp)

Front 1

A change in Vd...

Back 1

Vd does not influence Css ave (R0/CL) or AUC.

Vd influences Cmax and loading dose (dose=C0*Vd).

Vd alters the shape of the drug concentration time profile including Cmax and Cmin…

Vd influences ke (CL/Vd) and t-1/2, and therefore, the time to reach SS and accumulation.

Front 2

Dosing summary of Vd

Back 2

Vd influences the loading dose to “load the tank to a certain desired concentration”.

If the concentration target is Css ave, then dose changes are NOT needed with Vd changes.

If concentration target is Cmax or Cmin, dose changes may be needed with Vd changes.

Front 3

A change in CL...

Back 3

CL is the “drug removal” process from the tank.
“drug input” (dosing) and CL (“drug removal”) alone determine AUC and average concentration in the body (Css).
CL tell us what maintenance dose will keep the “tank full” to a desired drug level.
Changes in CL shift the entire concentration time profile so its difficult to imagine that dose changes won’t be needed.
CL also influences ke (=CL/V) and t-1/2
And the elimination rate
And the time to reach steady state
And the accumulation ratio
Css = R0/CL

Ave Css with chronic dosing always = (dose*F*S/) / CL
If the target concentration is the Css ave (not Cmax, Cmin), then the maintenance dose can be calculated (dose and/or  can be chosen):(dose * F * S)/T = Css * CL

Front 4

Changes in F translate into changes in ________

Back 4

Dose = dose*F
As F changes so changes the dose.

Front 5

Summary of dosing for constant infusion

Back 5

Vd influences the loading dose to “fill the tank”. [dose = Vd*desired conc].

Vd affects the time to reach steady state.

CL influences the dosing rate [dose rate = CL*Css].

Front 6

Because CL is the fundamental ___________process, and the determinant of , __________and it affects___, then changes in CL encountered clinically are ___________(e.g. renal failure, liver disease, etc).

Back 6

“drug removal” , AUC and Css, ke, most important for dose changes

Front 7

A constant IV infusion of vancomycin is begun with the goal of maintaining a constant plasma concentration of 15 mg/L.

If CL were double the usual value, how would you need to adjust the administration rate?

Back 7

R0 (dose rate) = CL*Css
If CL increase by 2-fold, you need to increase the dose rate by 2-fold

Front 8

The same general considerations apply for bolus and _________ equations with changing Vd or CL.
__________will shift the entire conc time profiles Css ave, Cmax, and Cmin.
__________ will influence Cmax and Cmin, but will but will not shift entire conc effect profile (Css ave is same).

Back 8

short infusion
Changes in CL
Changes in Vd

Front 9

CL

Back 9

Css = R0/CL

Dose/ = Css*CL

AUC = dose/CL

Accumulation factor

Cmax and Cmin

Ke (and t-1/2)

Front 10

Vd

Back 10

LD = Conc * Vd

Cmax and Cmin

Accumulation factor

Ke (and t-1/2)

Front 11

Dosing considerations rules of thumb

Back 11

Vd and CL are separate…a change in one does not cause a change in the other…a change in either one will cause a change in ke and t-1/2.

3. A change in CL shifts the concentration time curve and influences Css ave, Cmax and Cmin.

2. A change in Vd will not shift the concentration time curve (not affect Css ave) but does influence Cmax/Cmin

4. A change in either CL or Vd influences ke (so accumulation and t-1/2).

Front 12

Which of the following about CL and Vd is FALSE?
a)Ke=CL/Vd
b)As Vd increases, CL decreases.
c)T-1/2 = 0.693*Vd/CL
d)Vd can be calculated if Ke and CL are known.

Back 12

b)As Vd increases, CL decreases.

Front 13

What does a change in F NOT affect?
a) Single dose bolus Cmax.
b) Accumulation ratio.
c) Css ave.
d) Multiple dose Cmax.

Back 13

b) Accumulation ratio.

Front 14

Which PK variable does Vd NOT influence?
a) Time to reach SS for a constant infusion.
b) Css ave.
c) Cmax for bolus equation.
d) Cmax for short infusion equation.

Back 14

b) Css ave

Front 15

Rifampin is an anti-mycobactrial that induces metabolic enzymes and increases the CL of some drugs. Which of the following would you NOT expect as a result of increased CL?
a) Half-life would be smaller (shorter).
b) Css ave would be lower.
c) Cmax and Cmin at SS would be lower.
d) Accumulation will be greater.

Back 15

d) Accumulation will be greater.

Front 16

Weight and CL

Back 16

Lean body weight is usually positively correlated with CL.

The physiological basis is that the liver / kidneys are proportionally sized to the lean mass of the person and larger organs have larger capacity to clear drug.

Front 17

Weight in the Cockcroft-Gault

Back 17

Weight is also fundamental to the most widely used equation for estimating creatinine clearance as a surrogate for GFR/renal function. Renal drug dosing is usually based on this calculation.

Front 18

IBWmales(kg)

Back 18

IBWmales(kg) = 50 + (2.3 * height inches > 5 ft)

Front 19

IBWfemales(kg)

Back 19

IBWfemales(kg) = 45.5 + (2.3 * height inches > 5 ft)

Front 20

Males: CLcr

Back 20

Males: CLcr = (140 – Age) (IBW)/72(Scr)

Front 21

Females: CLcr

Back 21

Females: CLcr = males * 0.85

Front 22

What difference in maintenance doses between the two patients, one big and one small?

Back 22

R0 is proportional to CL (R0 = Css*CL)

If Big:Small CL is 6.9L/hr / 4L/hr (=1.73), then R0 should be the same proportions, or 1.73-fold higher in the Big patient…

Front 23

Weight and Vd

Back 23

Lean body weight is also positively correlated with Vd.
The physiological basis is that the actual size of the “tank” is larger. The increase in Vd will depend, however, on the drug characteristics…whether it distributes into lean muscle vs fat…

Front 24

PK Considerations in the obese

Back 24

Obesity is generally defined as > 30% total body weight is adipose tissue. It is estimated by the BMI calculation (weight in Kg/square of height in meters). A BMI > 30 is defined as obese. Morbid obesity is defined as 195% of ideal body weight (about twice ideal body weight).

300 million people world-wide are obese.

Obesity has been associated with high rates of diabetes type II, gall bladder disease, cancers (hormone-mediated and bowel), and artery disease.

Front 25

Physiologic characteristics in obesity that influences PK

Back 25

Increased organ mass (slight – not proportional to total weight).

Potentially elevated renal clearances.

Liver can be inflamed with fat infiltration. Hepatic CL can be increased or decreased; e.g. CYP2E1 is increased, 3A is decreased, and phase II enzymes are increased (glucuronidation and sulfation).

Absorption rate is not thought to be changed (under-studied).

Front 26

Influence of obesity on Hepatic and Renal drug CL processes

Back 26

HEPATIC
• Phase I enzymes decrease in (3A?), no change in (2D6?), increase in (2E1?)
• Phase II enzymes increased sulfation AND increased glucuronidation
• Blood flow unchanged
RENAL
• GFR increased
• Tubular secretion increased
• Blood flow unchanged
• Reabsorption decreased

Front 27

Weight in the Cockcroft-Gault

Back 27

Weight is also fundamental to the most widely used equation for estimating creatinine clearance as a surrogate for GFR/renal function. Renal drug dosing is usually based on this calculation.

A weight adjustment of: (Actual-IBW)*0.3+IBW) is often used for IBW for obese subjects

Front 28

The CL of gentamicin is equal to CLcr. Compare gentamicin CL for a 35 y.o. 250kg 5’11” obese man versus a 35 y.o. 5’2” 45 kg lean male (use cockroft-gault to estimate CLcr). Both subjects have serum creatinine of 1.2mg/dL

Back 28

Obese: 50 + 2.3(11) = 75kg + (250-75)*0.3 = 145kg
…[(140-35)*128 / 72(1.2)] = 156ml/min ~ 130 ml/min or 7.8L/hr

Small: 50 + 2.3(2) = 55kg (use either 45 or 55)
…[(140-35)*55 / 72(1.2)] = 67ml/min or 4L/hr

Front 29

Physiologic characteristics in obesity that influences Vd

Back 29

Drugs that distribute into fat tissue may have much higher Vd in obesity (of note, this is not universal … cyclosporine).

Drugs that distribute into extracellular water (hydrophilic) may also have increased Vd because there is generally more extracellular water in obesity (e.g. aminoglycosides).

Overall, the Vd of most drugs, whether distributed in fat or not, may be increased. The magnitude is related with how much the drug distributes into fat. Unfortunately, this area is understudied.

Front 30

Gentamicin: hydrophilic…octanol/water partition coefficient = 0.1;
Aminoglycoside Vd in obese patients V = 0.25 L/kg x [IBW + 0.1 (TBW – IBW)]

Calculate a single dose bolus equation Cmax for 120 mg dose in the same 250kg versus 45 kg patient.

Back 30

Obese patient Vd=0.25*(75kg+(0.1)*250-75) = 23L

Non-obese patient Vd=0.25*45kg=11L
************************************

Obese patient
Cmax = 120mg/23L = 5.2mg/L

Non-obese patient
Cmax = 120mg/11L = 10.9mg/L

Front 31

Given a 3-fold increase in Vd for diazepam in obese patients which of the following PK parameters would be changed?

Back 31

T-1/2
Cmax
Cmin
Time to reach SS
Accumulation factor
Loading dose

Front 32

Vd changes may be more pronounced than CL changes.

What are potential consequences?

Back 32

Thus, the need for loading dose changes and more time needed to reach SS may be more pronounced than the need for maintenance dose changes.

Front 33

Because Renal CL is predictably increased...

Back 33

a weight adjustment to IBW in CG may be warranted

Front 34

Because Liver CL is less predictable…may be increased for some CYPs (2E1) and glucuronidation/sulfation, but decreased for CYP3A ...

Back 34

maintenance doses may need to be increased or decreased in response

Front 35

Define the stages when a drug's PK profile has two or more phases

Back 35

The initial steep decline is called an “alpha-phase” or “distribution-phase”. It occurs because the drug distributes from the vasculature / highly perfused and rapidly equilibrating organs to more slowly equilibrating tissues. This results in a mass transfer of drug into these slowly equilibrating tissues initially until equilibrium is reached, thus the steep fall in plasma levels in the alpha-phase.

The terminal decline is called the “beta-phase”. It is when the distribution is at equilibrium...the terminal decline is the drug elimination from the body…this is analogous to the one-compartment model…

Front 36

In a single bolus, during the Alpha-phase the drug moves from the ________ and _____ to _______

Back 36

vasculature and rapidly equilibrating organs to slowly equilibrating tissues

Front 37

In a single bolus example, during the beta phase all tissues are in _______ , terminal __________ in concentrations, like _________ drug at this point

Back 37

equilibrium
decline
one compartment

Front 38

When do we use a multi-compartment model?

Back 38

When we need to describe the movement of drug with in the body

Front 39

In a single bolus, multicompartment model, how is the total volume calculated?

Back 39

V = Vi + Vt

(Vt = Volume tissues
Vi = “Initial” or “Central” volume)

Front 40

T or F

The multicompartment model is more accurate that the single compartment model and is prefered clinically.

Back 40

FALSE

Front 41

General equation for biexponential concentration time profile :

Back 41

C=A*e-α*t + B*e-β*t

Front 42

Can the one compartment model be use for a multicompartment drug?

Back 42

A 1-compartment model can be used except for drugs where significant elimination occurs during the distribution phase (maybe methotrexate, lidocaine, lithium).
We just have to make sure to sample after distribution.
We also have to understand Vd and how to give loading doses.

Front 43

Vancomycin is a 2-compartment drug, but we treat it as a 1-compartment drug clinically.A 56 y.o. man with a staph bone infection received a 1000mg IV dose over one hour. The distribution phase (alpha) lasts about 1 to 1.5 hours.
The following concentrations were measured:
TPD (hr) -Conc (mg/L)
0.5 - 48
5 - 23
11 - 14
Estimate Ke.

Back 43

Ke=ln (C1/C2)/Δt
Ke=ln (23/14)/6h = 0.083/h

Front 44

Volume considerations for the two compartment model

Back 44

* Vi is the initial volume immediately after the infusion (rapid equilibrium).
* Vt is the tissue volume into which the drug distributes during the alpha phase (slow equilibrium).
* V is the sum of the two volumes.
* V = (Vi + Vt) – this is typically the V for calculating loading doses…
* If the entire loading dose is given into the Vi…concentrations will be very high before distribution…this might matter for some drugs where the “effect site” is as if its in the Vi tissues. For other drugs, in will not matter if the “effect site” is as if its in the Vt tissues.

Front 45

What are the implecations of a two-compartment drug having a "site of effect" in the tissues?

Back 45

Its “effect site” resides in the slowly equilibrating tissues (Vt). Thus, when the loading dose is given…concentrations are initially very high in Vi, but this does not cause toxicity because the concentration has not equilibrated with the slowly equilibrating tissue Vt where the “effect site” resides.
Digoxin is the example.

Front 46

What are the implecations of a two-compartment drug having a "site of effect" in the blood?

Back 46

Its “effect site” is as if it is in the rapidly equilibrating volume Vi (in other words high initial levels in the Vi correspond with efficacy or toxicity), then the loading dose will need to be delivered slowly or in small increments to allow for distribution (so levels are not too high in Vi during the loads). This is common in practice (lidocaine, phenobarbital, procainamide, theophylline). The loading doses would be delivered in small or slow increments until the concentration based on Vtotal is reached.
Lidocaine is the example.

Front 47

Which of the following about the association between weight and CL is FALSE?
a. Weight and CL are typically positively correlated.
b. The cockroft-gault equation accounts for weight in the estimate of renal function for dosing renally-cleared drugs.
c. Differences in CYP activity (phase I) according to obesity is well-characterized and consistent.
d. The activity of phase II metabolizing enzymes may be increased in obese patients.

Back 47

c. Differences in CYP activity (phase I) according to obesity is well-characterized and consistent.

Front 48

Obese patients may have a larger Vd of some drugs compared with non-obese patients. Which of the following would be FALSE if Vd was increased in obese patients (all else being equal)?
A. The maintenance dosing rate would need to be higher
B. The loading dose would need to be higher.
C. The half-life would be longer.
D. It would take longer to reach steady state.

Back 48

A. The maintenance dosing rate would need to be higher

Front 49

Which of the following most accurately describes the alpha phase for two compartment drugs?
A. It is the terminal elimination phase in the concentration time profile.
B. It is the half-life of a drug.
C. It is the phase where drug is moving from the rapidly equilibrating to the slowly equilibrating tissues.
D. It is steady state for the drug.

Back 49

C. It is the phase where drug is moving from the rapidly equilibrating to the slowly equilibrating tissues.

Front 50

Which of the following does NOT accurately describe how two compartment drugs are handled clinically?
A. Concentrations are obtained in the beta phase and the drug is treated as though it is a one compartment drug.
B. If the “effect site” behaves as if its in the Vi (initial compartment), loading doses will need to be delivered slowly or in increments.
C. If the “effect site” behaves as if its in the Vt (tissue compartment), high concentrations in Vi following loading doses do not cause effects, but effects will not be seen until equilibrium is reached with the tissues.
D. The alpha and beta rate constants are determined as a basis for dosing.

Back 50

D. The alpha and beta rate constants are determined as a basis for dosing.

Front 51

What clinical factors that change or affect CL, F and Vd ?

Back 51

Weight
Age
Protein binding
Renal or liver dysfunction
Drug-drug interactions
Genetics
Etc

Front 52

Describe the effect of age on physiologic processes.

Does this affect drug removal processes?

Back 52

The elderly experience a decline in multiple physiological processes.

Drug removal processes are affected.

Front 53

Gentamicin is renally cleared. The CL of gentamicin is equal to CLcr. Compare gentamicin CL for a 82 y.o. 60kg woman versus a 22 y.o. 60kg woman (use cockroft-gault to estimate CLcr thus CL). Both have a serum creatinine of 0.9mg/dL.

Back 53

Young: [(140-22)*60 / 72(0.9)*0.85 =93ml/min or 5.6L/hr

Old: [(140-82)*60 / 72(0.9)]*0.85 =47ml/min or 2.8L/hr

Front 54

Gentamicin is renally cleared. The CL of gentamicin is equal to CLcr.
The patient is a 22 y.o. 60kg woman (use cockroft-gault to estimate CLcr thus CL). She has a serum creatinine of 0.9mg/dL.
Assume the target concentration for gentamicin is Css ave. If the maintenance dose for the young woman is 100mg 8h hours, what should the maintenance dose be in the elderly woman?

Back 54

Young: [(140-22)*60 / 72(0.9)*0.85 =93ml/min or 5.6L/hr

Young: Css = R0 / CL … R0 = 100mg/8h, CL = 5.6L/hr, therefore Css = 2.2mg/L

Old: CL=2.8L/h, want same Css= 2.2mg/L, Solve for R0 …
2.2mg/L * 2.8L/h = 6.2mg/h * 8h = 50mg q8h

Note: You can also note that R0 is proportional to CL so a halving in CL will require a halving of R0 to keep Css the same…

Front 55

Liver CL in the elderly

Back 55

Unlike renal function, liver function changes with aging is less predictable and we do not have a handy equation (like cockroft-gault) for estimating liver function.

Generally, physiological processes that control hepatic CL are reduced with age. Liver volume/weight and liver blood flow decrease in the elderly.

Phase I enzyme (CYPs) activity may decrease, whereas Phase II enzymes (glucuronidation, etc) may be relatively preserved.

The extent of absorption (F) may be higher in the elderly for drugs that undergo high first-pass extraction.

Front 56

Our elderly patient needs a benzodiazepine. The elderly may have increased drug sensitivity to benzodiazepines, as well as, warfarin, oral hypoglycemics, and drugs with anticholinergic properties (e.g. antihistamines).

Some benzodiazepines are short half-life drugs metabolized by phase II enzymes (oxazepam, temazepam, lorazepam). Others are long-half-life drugs (flurazepam, diazepam, etc) metabolized by phase I enzymes.

What benzodiazepine would you recommend. Why?

Back 56

oxazepam, temazepam, or lorazepam

Front 57

Absorption and Vd changes in the elderly

Back 57

The rate of absorption is either slower or the same in the elderly.

The % of body weight that is lean muscle goes down and % that is fat goes up so the Vd can increase or decrease. Drug that distributes into lean muscle may have a lower Vd in which drug distributes. If the drug distributes into fat, the Vd may increase.

Front 58

Elderly people can be expected to have slower __, especially for ________-eliminated drugs. _______ changes are less predictable; phase _ enzymes may decline more than phase_.

Back 58

CL, especially for renally-eliminated drugs. Hepatic changes are less predictable; phase I enzymes may decline more than phase II.

Front 59

Changes in absorption and ___ are possible, but _________ and _________.

Back 59

Changes in absorption and Vd are possible, but unpredictable and understudied.

Front 60

How do drugs usually bind to protein?

Back 60

Drugs usually bind to proteins reversibly via hydrogen bonding or van der Waals forces in plasma and in tissue.

Front 61

Albumin

Back 61

Synthesized by the liver.
 Maintains osmotic pressure of the blood and transports endogenous and exogenous substances (free fatty acids, bilirubin, hormones, tryptophan)
Most common plasma protein for acidic drug binding.
Albumin is a common clinical lab test.
Clinically, you may encounter conditions that reduce albumin with possibly reduced drug binding (end stage renal disease, end-stage liver diseases).

Front 62

1-Acid Glycoprotein (AAG or orosomucoid)

Back 62

Synthesized by the liver.
 Transport of substances in the blood (corticosteroids).
 Bind primarily basic drugs (i.e. propanolol,
imipramine, lidocaine).
Acute-phase reactant (increases with inflammation, trauma by up to 5-fold).
AAG is not a common clinical lab.
Clinically, you may encounter conditions that increase AAG concentrations with possibly increased binding.

Front 63

Erythrocytes

Back 63

Both endogenous and exogenous compounds can bind to RBC’s.
If drug concentrations are to be in whole blood it will be stated as such (drug levels are assumed to be in plasma/serum). Plasma and blood concentrations will differ if drug binds to RBC.

Front 64

Free (unbound) concentrations

Back 64

Total plasma concentrations (bound plus free) are measured clinically.

Free plasma concentrations are considered “pharmacologically active”.

Fraction unbound (fu) =
C unbound/C bound + C unbound = C total

Front 65

What do we almost always assume that C unbound (Cu) is a function of?

Back 65

We almost always assume that C unbound (Cu) is a predictable function of C total (Ct), i.e. fu is constant:
fu * Ct = Cu

If fu is constant, then Cu varies directly in relation to Ct (if Ct doubles, Cu doubles, etc).

Front 66

When might fu not be constant with lower binding albumin?

Back 66

Renal or liver failure.
Drug displacement interaction.
Serious burns.
Pregnancy.

Front 67

When might fu not be constant with Higher binding (AAG)?

Back 67

Trauma.
Surgery.
MI.
Arthritis.

Front 68

When should we be concerned that fu could be non-constant because of one of these clinical scenarios?

Back 68

* In the case of therapeutic index:
-We don’t worry about potential protein binding issues if the drug has a wide therapeutic index.
-This is because small to moderate variability in fu will probably not result in big enough changes to cause toxicity or loss of effect.

*Second, is it highly protein bound
-We don’t worry about small to moderate protein binding variability if fu is already “big” (> 0.3 or 30%)…(books use > 0.1 to to 0.3).
-This is because small to moderate changes in fu will not result in big enough changes in free drug (“the drug is mostly free already anyway”).

Front 69

Consider the HIV protease inhibitor, indinavir. It has a typical fu of 0.5.

Now consider the HIV protease inhibitor, lopinavir. It has a typical fu of 0.05.

Which fu is “already big”?

Calculate the % change in fu if fu changed by 5%.

Back 69

For indinavir, fu changed from 0.5 to 0.55 or, 0.55/0.5 = 10% (not much).

For lopinavir, fu changed from 0.05 to 0.1 or, 0.1/0.05 = 100% (double).

Point: small to moderate changes in fu cause a substantial change if fu is very small to start with.

Front 70

What are other concerns regarding non-constant fu?

Back 70

Does the patient have low albumin concentrations, a drug-displacement interaction, or other?

Does the patient have serious trauma where you worry about high AAG?

Front 71

Typically with reduced protein binding and increase in fraction unbound is equal to ________

Back 71

a decrease in bound drug and a decrease in total drug

Front 72

For low E drugs and high E drugs given orally increased fraction unbound correlated to a decrease in bound drug and a decrease in total drug.

Why is this not true for high E drugs given IV?

Back 72

Fu is one of the factors that determine CL and F (Fish metabolism slides 33-39)
CLint … the intrinsic enzymatic or filtration activity of the organ (liver of kidney).
fu … plasma protein binding, unbound drug is available for clearance.
Blood flow (Q), which delivers the drug to the clearance organ.

CL of low E and high E drugs given PO are rate-limited by CLint * fu, so as fu , CL . (CL  to fu and CLint)

High E drugs given IV are rate-limited by blood flow to the liver only (CL  Q). (high E given PO are sensitive to CLint*fu because of F)

Front 73

True or False:

A decrease in binding (increased fu) can reult in lower Css Ave

Back 73

True because
Decreased binding (increased fu) can result in increased CL.

An increase in CL results in lower Css ave (Css=R0/CL).
The difference here with protein binding is a higher fu will impact Css unbound when we multiply fu*Css total and will offset the lower Css such that Css unbound does not change.

Front 74

How does protein binding effect low E drugs with regards to CL and Css?

Back 74

* iFor low E IV drugs:
Icreased fu * decreaed Css (total) = unchanged Css (unbound)
* For low E drugs oral (where F >0.7 by definition or ~1):
increased fu * decreased Css(total) = unchanged Css(unbound)

Front 75

How does protein binding effect high E drugs with regards to CL and Css?

Back 75

High extraction IV drugs:
no change in CL because CL ~ Q so and increase in fu * unchanged Css (total) = an increase in Css(unbound)

High E drug oral :
(F~q/CLimnt*fu so CL/F = Q/Q/CLint*fu)
High E oral drugs an increase in fu * a decrease in Css(total) = no change in Css (unbound)

Front 76

How are low E drugs rate limited and what are the implications of a change in these parameters?

Back 76

Low extraction drug (E<30%) are rate-limited by fu and CLint. So, a change in fu (or CLint) will change the CL.

Front 77

How are hihg E drugs rate-limited and what are the implications?

Back 77

High extraction drugs (E>70%) are rate-limited by blood flow (Q). So, a change in fu will not affect CL.

Front 78

PO administration of Low E drugs

Back 78

Low extraction drug (E<30%) have high F (>70%). Since F is so near 1, most drug gets past the organ and small changes in fu, CLint, or Q won’t change that much (of course, big changes will).

Front 79

PO administration of high E drugs

Back 79

High extraction drugs (E>70%) have low F (<30%) and so small changes in F will be important (small to moderate changes in F can translate to big differences…). F is rate-limited by blood flow (Q) divided by CLint*fu.

Front 80

Will a change in Q, fu, and/or CLint alter F?

Back 80

Systemic CL (IV) depends upon getting the drug from the body to the organ(site of action)…which is determined by Q. F is different in that the drug is not in the body yet and the liver has only one shot at removing more drug … so a change in Q, fu, or CLint will alter F.

Front 81

What factors can increase Vd?

Back 81

Decreased plasma protein binding (free drug can leave plasma - fup)

Front 82

Factors that can decrease Vd?

Back 82

Increased plasma protein binding (more drug stays in plasma -  fup)

Front 83

Renal failure may decrease digoxin binding in tissue. What would this due to Vd? What would this do to the digoxin loading dose?

Back 83

↓ loading dose = desired conc * ↓Vd

Front 84

If fu in plasma increases, this causes drug to leave the plasma and Vd increases. Should the loading dose change if Vd changes?

Back 84

Yes, because loading dose = desired conc * Vd

But recall that Ct will be lower for the same Cu.

So increased Vd will be offset by the lower Ct that is desired. No loading dose change indicated.

Front 85

True or False:
An increase fu would decrease Vd and increase CL, so Ke (and t-1/2) would change.

Back 85

False:

An ( fu would  Vd and  CL, so Ke (and t-1/2) would not change much).
Ke=CL/Vd
T-1/2=0.693*Vd/CL

Front 86

On your daily rounds, you evaluate a 55 y.o. man with renal failure and uremia. He has seizures and has begun phenytoin. Today, he presents with difficulty speaking and lethargy. He has a phenytoin level of 15 mg/L (therapeutic range is 10 to 20 mg/L). You recall that uremia can reduce plasma protein binding of phenytoin Phenytoin fu is normally 0.1. The normal therapeutic range for total phenytoin is 10 to 20 mg/L. What is the normal therapeutic range for free phenytoin?

Back 86

Cu=Ct*fu… 10mg/L*0.1 to 20mg/L*0.1 = 1 to 2mg/L

Front 87

The fu of phenytoin can change from 0.1 to 0.2 in patients with uremia. Calculate the patient’s free concentration using a fu of 0.2.


What is an appropriate therapeutic range for this patient with uremia?

Back 87

Cu=Ct*fu… 15mg/L*0.2 = 3mg/L

Ct=Cu/fu… 1mg/L/0.2 to 2mg/L/0.2 = 5 to 10mg/L

Front 88

Phenytoin is mainly bound to albumin. A patient with new onset seizures has low albumin concentrations (2.2 g/dL; normal is 4/4g/dL) and is given phenytoin (po). Is there potential for clinically relevant change in fu for this patient? A total concentration comes back from the lab and the level is 5.5 mg/L. How should this level be interpreted?

Example equation to adjust level for interpretation:
InterpretedC= Cobserved / (1-fu)[Pobserved/Pnormal] + fu

Back 88

InterpretedC=5.5/(1-0.1)[2.2/4.4]+0.1 = 10mg/L

The interpreted C tells you what the patient’s level would be with normal binding.

Front 89

Flow chart for determining clinical significance

Back 89

Front 90

Which of the following about PK changes in the elderly is FALSE?
A. A decline in renal function and CL of renally eliminated drugs is predictable with advanced age.
B. There is no handy equation to predict declines in liver function with advanced age.
C. The elderly may be more sensitive to the effects of some drugs.
D. The phase II enzymes are the first to decline with advanced age.

Back 90

D. The phase II enzymes are the first to decline with advanced age.

Front 91

If CL were to decline in the elderly, which of the following would be FALSE (all else being equal)?
A. The entire concentration time profile would be shifted higher (Css ave, Cmaxss, Cminss).
B. Half-life would be longer.
C. A dose reduction might be warranted.
D. Vd would decrease since changes in CL cause changes in Vd.

Back 91

D. Vd would decrease since changes in CL cause changes in Vd.

Front 92

For which kind of drugs are plasma protein binding changes (fu) probably NOT relevant?
A. Narrow therapeutic index.
B. A drug with fu=0.8 (80% unbound).
C. A drug with fu=0.01 (1% unbound).
D. Protein binding is always clinically relevant.

Back 92

B. A drug with fu=0.8 (80% unbound).

Front 93

There is one kind of drug where a change in Css ave unbound, thus a potential change in pharmacologic activity, is possible with a change in fu. Which one is it?
A. Low E IV.
B. High E IV.
C. Low E PO.
D. High E PO.

Back 93

B. High E IV.

Front 94

Which PK parameters can renal failure affect?

Back 94

Absorption
Distribution
Metabolism
Excretion

Front 95

How can renal failure decrease bioavailability of certain drugs?

Back 95

Bowel Edema: furosemide
increase in gastric pH: ketoconazole
Decreased gastric motility

Front 96

How can renal failure increase bioavailability of certain drugs?

Back 96

Decreased 1st pass metabolism: beta-blockers, propoxyphene

Front 97

What is “Apparent” Vd?"

Back 97

the volume that accounts for the total drug administered based on the observed plasma concentration
Does not refer to specific tissue compartments
Factors affecting Vd: lipophillicity, plasma protein binding

Front 98

How does renal failure affect Vd?

Back 98

Increased Vd
Hypoalbuminemia:decreased binding of drug to plasma proteins  increased free fraction of drug  and migration out of plasma compartment (phenytoin)

Changes in shape of plasma proteins  decreases binding affinity (phenytoin)

Increased plasma volume: gentamicin (Vd normal = 0.25 L/kg Vd renal failure = 0.35 L/Kg)

Front 99

What is the effect of renal failure on drug metabolism?

Back 99

* Kidney is active in metabolizing drugs (Phase I and II)
-Phase I: Oxidation- CYP P450
-Phase II: Glucuronidation, glutathione and sulfate conjugation may be reduced. (furosemide)
* Contribution of these processes is relatively minimal compared to hepatic metabolism for most drugs

Front 100

What effect does renal failure have on hepatic drug metabolism?

Back 100

*Hepatic CYP activity is altered:
* Phase I: Cytochrome P450 superfamily
* Reduced activity of some CYP enzymes have been observed in chronic renal failure (3A and 2C)
* Not well studied, may be related to uremic toxins or inflammatory cytokines that downregulate transcription of the CYP genes
* May be also be altered due to changes in protein binding: increased free fraction of drug leads to increased hepatic clearance

Front 101

What effect does renal failure have on drug elimination?

Back 101

* Reduced elimination of drugs that are primarily renally excreted (digoxin, gabapentin)

* Reduction in elimination of metabolites of parent drug
- Consider if active or toxic
-Normeperidine
-Morphine-6-glucuronide
-Pentoxyfylline ???
-Linezolid ???

Accumulation of endogenous metabolic waste products may compete with the active secretion of drugs in the proximal tubule

Front 102

What are the excretory processes of the kidney?

Back 102

Filtration (F)
Active Secretion (AS)
Tubular Reabsorption (TR)

Front 103

How is renal clearance calculated?

Back 103

ClRenal = F + AS - TR

Front 104

What is GFR?

Back 104

GFR stands for Glomerular Filtration Rate which is:

* volume of plasma filtered across the glomerulus per unit of time
* normal = 120-130 ml/min/1.73m2
* single best predictor of functioning renal mass
* age-related decline after age 40 ~ 10ml/min/1.73 m2 per decade

Front 105

Elimination of drugs correlates best with ______________.

Back 105

GFR

Tubular function (secretion & reabsorption) hard to measure

Front 106

How are the type and severity of kidney disease assessed?

Back 106

Laboratory Values
Urinalysis
Urine chemistries
Imaging/Biopsy
Estimation of GFR (Clcr)

Front 107

What is creatinine?

Back 107

breakdown product of creatine & phosphocreatine in muscle

Front 108

Serum concentration of creatinine is dependent on its ____________ as well as its ____________.

Back 108

Serum concentration of creatinine is dependent on its production as well as its elimination

Front 109

What factors can effect production of creatinine?

Back 109

Production dependent on muscle mass and can be affected by age, gender, race, body mass (wt.), drugs, diet and disease states

Front 110

What factors can effect elimination of creatinine?

Back 110

Elimination = primarily by filtration through the glomerulus (GFR); ~10-50% secreted in proximal tubule (depending on kidney function); does not undergo reabsorption

Front 111

What is the normal range for Serum creatinine?

Back 111

Normal range ~ 0.4-1.2 mg/dl (depending on lab)
Mean value (women) = 0.96 mg/dl
Mean value (men) = 1.16 mg/dl

Front 112

Should Serum creatinine be the sole determinant of the degree of kidney dysfuntion?

Back 112

NO

Front 113

What is Creatinine an estimate of?

Back 113

Creatinine is frequently used to estimate of GFR

Front 114

What assumptions are needed for accurate estimation of GFR?

Back 114

* Daily creatine production is constant
* Daily conversion of creatine to creatinine is constant
* Creatinine is filtered freely by the kidney
* Measurement of creatinine in serum and urine is accurate
* The urine collection is complete

Front 115

Define Stage 1 CKD

Back 115

Kidney damage is present GFR is normal

eGFR > or = 90 mL/min/1.73m2

Front 116

Define Stage 2 CKD

Back 116

Kidney damage with mild decrease in GFR

eGFR 60-89 mL/min/1.73m2

Front 117

Define Stage 3 CKD

Back 117

Kidney damage with moderate decrease in GFR

eGFR 30-59 mL/min/1.73m2
(predialysis)

Front 118

Define Stage 4 CKD

Back 118

Kidney damage with Severe decrease in GFR

eGFR 15-29 mL/min/1.73m2(predialysis)

Front 119

Define stage 5 CKD

Back 119

Kidney failure

eGFR < 15 oml/min/1.73m2 or dialysis dependent (ESRD)

Front 120

When would reduced GFR have less impact on drug elimination?

Back 120

Reduced GFR has less impact on drugs that are extensively actively secreted (Clrenal > 300 mL/min) compared to those primarily dependent on filtration

Front 121

Cockcroft-Gault
Rules of Thumb

Back 121

* If actual body weight (ABW) < ideal body weight (IBW), use ABW
* Obese (>30% IBW): use adjusted dosing weight (ADW)
ADW = (ABW - IBW) (0.3) + IBW
* If Scr is low (< 0.8) - round it up to 0.8
* Equation of choice for adjusting drug doses

Front 122

What are limitations of the Cockcroft-Gault equation?

Back 122

* Accurate only in adult patients with stable kidney function (Scr not rapidly changing)
* Not adequately studied in women, elderly, obese
* Not accurate in patients with liver disease
* Controversial/highly debated
-Issues rounding vs. no rounding of Scr
-body weight: no one can agree on what to do in patients who are obese, short (< 5 feet tall), have amputations (e.g., BKA or below the knee amputation)

Front 123

What are advantages of the MDRD equation?

Back 123

* Equation of choice for staging of CKD
* Better estimate of true GFR
* Do not need weight or height

Front 124

What are limitations of the MDRD equation?

Back 124

* Accurate only in adult patients with stable kidney function (Scr not rapidly changing)
*Not adequately studied in patients with diabetes, obesity, elderly, pediatrics, or for drug dosing
* Should not be used at this time for drug dosing adjustments
* Not accurate in patients with liver disease

Front 125

What are limitations of all estimation equations?

Back 125

1. They all use serum creatinine:
-other things besides kidney function can affect Scr concentrations
-Scr can be higher than normal due to increased production…
-severe trauma, major surgery, sepsis & high dietary intake of protein (cooked meat), exercise, increased muscle mass
-Scr can lower than normal due to decreased production…. cachexia, paralysis, hyperthyroidism, chronic steroids therapy, cirrhosis
-diurnal variation in creatinine production
-drug interactions: cimetidine and trimethoprim can competitively inhibit proximal tubular secretion of creatinine leading to an elevated Scr concentration
-interferences with picric acid assay (Jaffé reaction)
-standardization to “calibrated” serum creatinine assay
2. They do not take into consideration urine output:
if urine output = 0 then Clcr/GFR =0

Front 126

Define unstable kidey function

Back 126

* previously normal kidney function: increase in Scr >50% in 24 hrs
* previous CKD (Scr > 2mg/dL): increase by >1mg/dL in 24 hrs

Front 127

What equations are used to estimate GFR in patients with unstable kidney function?

Back 127

Non-steady state equations (Chiou, Jelliffe, Brater):
* should be used for patients with changing kidney function (i.e., acute renal failure)
* very long and complicated equations

Front 128

Is ClCr a good indicator of kidney function?

Back 128

Cockcroft-Gault or MDRD:
* can overestimates the actual kidney function during the initial stage of ARF
* can underestimates the actual kidney function during the recovery stage of ARF

This is because changes in CrCl lag behind changes in kidney function.

Front 129

Drug Concentration Monitoring

Back 129

Useful in adjusting doses

Can calculate PK parameters

Only available for limited number of drugs

Consider total vs free assays

Front 130

Desired Plasma Concentration (Cp)

Back 130

* Most assays report drug concentrations as the sum of amount bound to plasma proteins and unbound (free).

* Only free drug is pharmacologically active

Front 131

What are two approaches to adjusting drug doses in patients with renal failure?

Back 131

Extended Interval
Dose Reduction

Front 132

What are two main things we take into consideration when adjusting drug doses in patients with renal failure?

Back 132

“Therapeutic window”
Pharmacodynamics

Front 133

What are the advantages and disadvantages to extending the interval when adjusting drug doses in patients with renal failure?

Back 133

* Advantages:
-Similar peak and trough concentrations to those achieved in normal renal function
-Concentration dependent bacteriocidal activity: aminoglycosides and quinolones
-Less pharmacy/nursing time
* Disadvantages:
-Interval may be “impractical” (ie q 90 hours)

Front 134

What are the advantages and disadvantages of dose reduction when adjusting doses for patients with renal failure?

Back 134

* Advantages:
-Provides sustained serum concentrations
-Desirable for agents that have favorable pharmacodynamics with consistent serum concentrations: “Time above MIC”-beta-lactams
* Disadvantages:
-Lower peaks and troughs
-May require unusual dosages

Front 135

What factors affect drug removal during hemodialysis?

Back 135

1. Drug characteristics:
* Molecular weight: conventional limit 1,000 daltons; hi-flux limit 20,000 daltons

* Extent of plasma protein binding:
>80% less likely to be removed

* Volume of Distribution: >0.6 L/kg
>0.6 L/kg less likely to be removed

2. Dialysis Factors:
* Blood flow rate and dialysate flow rate
* Membranes
-Pore size
-UF coefficient
-Charge

Front 136

What are two methods to estimate drug removal by dialysis a.k.a. Dialyzer Clearance?

Back 136

2 methods
* Extraction ratio (paired A-V sampling)
* Dialysate Recovery

Front 137

What is a benefit to using dialyer ccclearance?

Back 137

Gives a more accurate estimate of drug removal by dialysis

Front 138

Continuous Renal Replacement Therapies (CRRT)

Back 138

* CAVH and CVVH (continuous hemofiltration)
-Drug removal depends entirely on convection (ultrafiltration)
-Amount of drug removed is dependent on the sieving coefficient (SC)
* CAVHD and CVVHD (continuous hemodiafiltration)
-Drug removal is primarily dependent on the diffusive component

Front 139

CRRT Membrane Characteristics and Drug Removal

Back 139

* Composed of synthetic or semisynthetic substances

* Allow passage of solutes up to 20,000D
-Surface area
-ultrafiltration coefficient

* Drug removal may vary widely between membranes

Front 140

Dosing in Continuous Hemodialysis and Hemofiltration

Back 140

* Consult literature

* Use drug concentrations when available


* Caveats
-Frequent dialyzer clotting
-Changes in blood flow rate

Front 141

Peritoneal Dialysis

Back 141

* Drug removal less efficient than HD

* Drug-specific factors:
-MW, solubility, degree of ionization, protein binding and Vd
*Peritoneal membrane factors:
-Peritoneal membrane surface area, blood flow and peritonitis

Front 142

Intraperitoneal Drug Therapy

Back 142

*Drugs may be added to dialysate to achieve a local or systemic effect

*Drugs administered IP
-Antibiotics (peritonitis)
-Insulin
-Erythropoietin

Front 143

General Principles for dose dosing in renal failure

Back 143

  1. Have a good understanding of the pharmacokinetics of the drug, including what changes may be expected in renal failure. Consider the importance of other routes of elimination
 
· 2. If possible, utilize drugs whose pharmacokinetics are not affected by compromised renal function.

· 3. Use current literature resources and pharmacokinetic principles to determine the optimal dosage regimen.
 
·4. Use serum drug concentrations when available to help guide dosage adjustments
 
5. Assess the patients clinical response to the drug to monitor for efficacy and toxicity

Front 144

Inderindividual variability exists in drug ______, _______, and _______.

Back 144

Interindividual variability exists in drug:
Disposition (pharmacokinetics)
Response (pharmacodynamics)
Toxicity (adverse effects)

Drugs do not work the same way in all people

Front 145

What extrinsic factors contribute to variability in drug disposition and action?

Back 145

Drug-drug interactions
Smoking
Diet
Alcohol use
Regulatory
Medical practice
Environment
etc

Front 146

What intrinsic factors contribute to variability in drug disposition and action?

Back 146

Age
Race
Gender
Organ dysfunction
Disease
Pregnancy/lactation
Genetics
etc

Front 147

What is pharmacogenetics?

Back 147

Study of the relationship between single gene variants and variability in drug disposition, response, and toxicity

Front 148

What is pharmacogenomics?

Back 148

Study of the relationship between variants in a large collection of genes (up to the whole genome) and variability in drug disposition, response, and toxicity

Front 149

What proportion of package inserts for FDA approved drugs contain Pharmacogenomic information ?

Back 149

10%

Front 150

Examples of Drugs with Pharmacogenomic Information in FDA-approved Labeling

Back 150

Atomoxetine (CYP2D6)*
Codeine (CYP2D6)*
Thioridazine (CYP2D6)*
Fluoxetine (CYP2D6)
Tetrabenzine (CYP2D6)
Clopidogrel (CYP2C19)*
Voriconazole (CYP2C19)
Warfarin (CYP2C9, VKORC1)*
Celecoxib (CYP2C9)
Azathioprine (TPMT)*
6-Mercaptopurine (TPMT)*
Irinotecan (UGT1A1)*
Nilotinib (UGT1A1)
Fluorouracil (DPD)
Rifampin (NAT)
Isoniazid (NAT)
Rasburicase (G6PD)
Primaquine (G6PD)
Abacavir (HLA)*
Carbamazepine (HLA)*
Maraviroc (CCR5)*
Trastuzumab (Her2/neu)*
Cetuximab (EGFR)*
Erlotinib (EGFR)
Dasatinib (Ph1)*
Busulfan (Ph1)
Imatinib (C-Kit)
Panitumumab (KRAS)
Tretinoin (PML/RAR)

Front 151

FDA Guidance on Application of Pharmacogenomic Information in Drug Labels

Back 151

* Genomic biomarkers can play an important role in identifying drug responders and non-responders, avoiding toxicity, or adjusting drug dosages to optimize efficacy and safety.

* In the context of approved drug labels, genomic biomarkers can be classified on the basis of their specific use:
-Clinical response
-Risk identification
-Susceptibility, resistance, and differential disease diagnosis
-Polymorphic drug targets

* Most drug labels provide pharmacogenomic information with no recommendation for a specific action (e.g., required genetic testing)

* A few drug labels recommend or require genetic testing, thereby specifying the use of these genomic biomarkers for reaching therapeutic decisions

Front 152

Drugs in which a Pharmacogenetic Test is REQUIRED

Back 152

* Cetuximab
* Trastuzumab
* Maraviroc
* Dasatinib

Front 153

Drugs in which a Pharmacogenetic Test is RECOMMENDED

Back 153

* Carbamazepine
* Abacavir
* Warfarin
* Azathioprine, 6-MP, thioguanine
* Irinotecan
* Rasburicase

Front 154

Name the 4 nucleotides in DNA

Back 154

ACTG: Adenine, Thymine, Cytocine, Guanine

Front 155

What is a codon?

Back 155

A sequence of three nucleotides that code for an amino acid

Front 156

What is a gene?

Back 156

Stretch of DNA that contains instructions for synthesis of proteins

Front 157

What is the difference between an exon and an intron?

Back 157

* Exons are the coding regions of the gene

* Introns are the non-coding regions of the gene

Front 158

What is a genotype?

Back 158

For a particular location in DNA, a person carries two alleles, one from each parent. This is called a GENOTYPE.

Front 159

Define Allele

Back 159

DNA sequence at a particular location on a chromosome

Front 160

What is the difference between homozygous and heterozygous alleles?

Back 160

Homozygous: two identical alleles

Heterozygous: two different alleles

Front 161

Define genetic variant

Back 161

difference in DNA sequence compared with a
reference sequence

Front 162

Define Polymorphism

Back 162

Polymorphism: DNA variants that are common, often defined as greater than 1% in a given population
* Single nucleotide polymorphism (SNP): change in one nucleotide (base pair) in a DNA sequence
* Insertion/Deletion polymorphism (indels): insertion or deletion of multiple sequential nucleotides
* Repeat polymorphisms: variable number of nucleotide repeats (e.g., doublets or triplets)
* Gene duplications
* Gene deletions

Front 163

Define Mutation

Back 163

Mutation: Rare DNA variants (most often in coding regions) that are often associated with genetic diseases (e.g., cystic fibrosis, sickle cell anemia)

Front 164

Where can Variants Occur in a Gene?

Back 164

* Promoter - May alter transcription factor binding and subsequently increase or decrease gene transcription

* Exons
- May change codon sequence resulting in a different amino acid sequence
- May change codon sequence and result in a premature stop codon
- May have no effect

* Introns
- Often have no consequence (introns get spliced out)
- Are often “linked” to other variants in the gene

* Intron/exon splice junctions - May alter site of splicing and result in a transcript that lacks exons or contains pieces of introns

* Variants in 3’ UTR - May alter mRNA stability, structure, or degradation

Front 165

Define Phenotype

Back 165

Measurable characteristics of an organism. Phenotypes are a result of genetics, environment, or the combination of genetics and environment

Traditional examples: eye color, hair color, height

Front 166

How does phenotype apply to pharmacology?

Back 166

* Phenotype also applies to pharmacology. Examples:
- Metabolism phenotype may be characterized as “extensive metabolizer”, “intermediate metabolizer”, “poor metabolizer”
- Pharmacokinetic phenotype may be measured as plasma drug concentrations
- Pharmacodynamic phenotype may be measured as a specific drug response outcome (e.g., blood pressure for antihypertensive drugs)

* Genetic polymorphisms (i.e., variations), coupled with environmental factors, often underlie differences in phenotype

Front 167

How can genetic polymorphisms in DME genes lead to a decrease metabolizing enzyme function?

Back 167

Genetic polymorphisms in DME genes may decrease metabolizing enzyme function
- decrease in enzyme efficiency or activity
- decrease in affinity of enzyme for substrates (Km)
- Result in an inactive (non-functional) enzyme

Front 168

How would a decrease in DME affect drug clearance, plasma concentrations, and half-life?

Back 168

Drug clearance - decrease
Plasma concentrations - increase
Half-life - increase

Front 169

How do genetic polymorphisms resulting in multiple copies of the gene (i.e., gene duplications) affect DME?

Back 169

* Increased amount of metabolizing enzymes
* Increase in metabolizing enzyme function

Front 170

How would a genetic polymorphism resulting in multiple copies of a gene affect drug clearance, plasma concentrations, and half-life?

Back 170

Drug clearance - increase
Plasma concentrations - decrease
Half-life - decrease

Front 171

Why are the genes that code for CYP2D6 important to phamacogenetics?

Back 171

* CYP2D6 is not the most abundant CYP enzyme; however it metabolizes 25-30% of clinically available drugs

* CYP2D6 substrates: antidepressants, antipsychotics, antiarrhythmics, beta-blockers, tamoxifen

* CYP2D6 gene is highly polymorphic
- SNPs, Gene Deletions, and Gene Duplications

Front 172

What is the result of CYP2D6 variant allele *5?

Back 172

No enzyme

27% of caucasians, 6% of Asians, and 4% of Black Africans have this polymorphism

Front 173

CYP2D6 Metabolism Phenotype Exhibits a Trimodal Distribution between what three types of metabolizers?

Back 173

Ultra-rapid Metabolizers (UM)
Extensive Metabolizers (EM)
Poor Metabolizers (PM)

Front 174

What CYP2D6 phenotype would exibit increased drug metabolism, decreased plasma concentrations, and decreased drug response?

Back 174

Ultarapid Metabolizers

Front 175

What CYP2D6 phenotype would exibit expected drug metabolism, expected plasma concentrations, and expected drug response?

Back 175

Extensive Metabolizers

Front 176

What CYP2D6 phenotype would exibit decreased drug metabolism, increased plasma concentrations, and increased drug response?

Back 176

Poor metabolizers

Front 177

Atomoxetine (Strattera)

Back 177

*Selective norepinephrine reuptake inhibitor
*Treatment of attention deficit hyperactivity disorder (ADHD) in adults and children
*Atomoxetine is metabolized by CYP2D6 to 4-hydroxyatomoxetine -The metabolite is pharmacologically active, but it is present at low levels. Therefore, the metabolite does not contribute to a significant extent to drug efficacy or toxicity
* Side effects of atomoxetine therapy: insomnia, tachycardia, increased blood pressure, irritability, nervousness, nausea

* EM oral clearance = 0.35 L/hr/kg vs. PM oral clearance = 0.03 L/hr/kg
* EM half-life is 5.2 hours vs PM half-life is 21.6 hours
* PM AUC is 10 fold higher than EMs
* PM Cmax is 5 fould higher than EMs
* Increased plasma concentrations can predispose individuals to a higher rate of some adverse effects.

* Dosing adjustments for use of Atomoxetine (Strattera) with strong CYP2D6 hinhibitors in PM patients are provided in the package insert

Front 178

Katie is a 30 year old woman who delivered a baby boy, Junior, via caesarean section 10 days ago. Katie is currently taking codeine for pain associated with the caesarean section.

When Katie breastfeeds, she notices that Junior gets very lethargic and sleeps for 6 hours after feeding. She takes Junior to the pediatrician, and it is found that Junior has abnormally high morphine levels in his blood. Why?

Back 178

* Approximately 50-70% of codeine is metabolized to codeine-6-glucuronide by UGT2B7.

* Approximately 10-15% of codeine is metabolized by CYP3A4 to norcodeine.

* About 15% of codeine is metabolized by CYP2D6 to morphine, the most active metabolite, which has 200 fold greater affinity for the mu opioid receptor compared to codeine.
* CYP2D6 UMs metabolize codeine to morphine to a greater/faster extent
- Greater analgesic effects/exaggerated efficacy
- Increased risk of adverse effects

* CYP2D6 PMs do not metabolize codeine to morphine as efficiently or to a slower extent
- Decreased analgesic effects/lack of efficacy

Front 179

Thioridazine (Mellaril)

Back 179

* Indicated only for schizophrenic patients who fail to show an acceptable response to adequate courses of treatment with other antipsychotic drugs

* Thioridazine is associated with a dose-dependent increase in the QT interval (i.e., ventricular depolarization and repolarization) on an EKG
- QT interval prolongation is associated with ventricular arrhythmias and sudden death

* Thioridazine is metabolized by CYP2D6. In one study, thiordazine AUC was 4.5-fold higher in CYP2D6 PMs than EMs.

* Use of thiordazine in patients known to have reduced activity of CYP2D6 is contraindicated

Front 180

Tamoxifen

Back 180

* Selective estrogen receptor modulator (SERM) used in the treatment and prevention of breast cancer

* Tamoxifen is metabolized by CYP enzymes to several primary and secondary metabolites

* 4-hydroxy-tamoxifen (primary metabolite) has approximately 30- to 100-fold more potent antiestrogenic activity than tamoxifen

* Endoxifen (secondary metabolite) is as potent as 4-hydroxytamoxifen in terms of antiestrogenic activity
* CYP2D6 PMs make less active metabolites

* Therefore, CYP2D6 PMs have poorer drug response
- Lower relapse-free survival (in other words, they are more likely to have a breast cancer recurrence)

* Currently, FDA is evaluating whether information about CYP2D6 PM status should be included in prescribing information

Front 181

The graph shown below represents the fluoxetine plasma concentrations of three groups of patients who were administered an oral dose of Fluoxetine 20 mg (a CYP2D6 substrate).
Group A would most likely
represent which CYP2D6
phenotype group?
A. CYP2D6 Ultrarapid Metabolizers
B. CYP2D6 Extensive Metabolizers
C. CYP2D6 Poor Metabolizers

Back 181

C. CYP2D6 Poor Metabolizers

Front 182

What is the importance of the CYP2C19 gene?

Back 182

* CYP2C19 accounts for ~10% of CYP-mediated metabolism

* CYP2C19 gene is polymorphic and some of the polymorphisms code for inactive protein
- CYP2C19*1 Wild-type (non-variant)
- CYP2C19*2 Inactive protein
- CYP2C19*3 Inactive protein

* Polymorphisms result in three main phenotypes:
- Extensive metabolizers
- Intermediate metabolizers
- Poor metabolizers

* Ethnic differences exist in polymorphism allele frequencies
- PM (Caucasian) 1-3%
- PM (Asian) 15-25%
* Substrates: Proton pump inhibitors (e.g., omeprazole), Clopidogrel (Plavix), Phenytoin (antiseizure)

Front 183

Proton pump inhibitors (e.g., omeprazole) are used for the treatment of gastroesophageal reflux disease (GERD) and peptic ulcer disease

Used in combination regimens with antibiotics for the treatment of peptic ulcers caused by the bacteria, H. pylori


Ulcer cure rate for H. pylori infection using omeprazole and amoxicillin
Ann Intern Med 1998;129:1027-1030
Cure Rate
CYP2C19 Extensive metabolizers 28.6%
CYP2C19 Intermediate metabolizers 60%
CYP2C19 Poor metabolizers 100%

Why do PMs have the best cure rate?

Back 183

Poor metabolizers have higher plasma concentrations of the drug
There is not increased risk of side effects due to wide therpeutic range

Front 184

Clopidogrel (Plavix)

Back 184

* Antiplatelet agent used to reduce atherosclerotic events (MI, stroke, and vascular death) in patients who have had a recent stroke, recent MI, or have established peripheral vascular disease

* Metabolized to 2-oxo-clopidogrel (intermediate metabolite) and an active metabolite by numerous CYP enzymes

* CYP2C19 is an important enzyme responsible for the formation of the active metabolite

* The active metabolite binds to and inhibits P2Y12 receptors on platelets, thereby inhibiting platelet activation and aggregation
*CMAX and AUC are decreased by about 40% in Poor metabolizers
* Carriers of a CYP2C19 non-functional allele (e.g., *2) had a 53% higher risk of death from CV causes, MI, or stroke as compared to non-carriers of a CYP2C19 non-functional allele (i.e., wild-type).

Front 185

Warfarin and CYP2C9

Back 185

* Warfarin exists as a racemic mixture of S-warfarin and R-warfarin
- S-warfarin is the pharmacologically more active enantiomer
- CYP2C9 metabolizes S-enantiomer of warfarin
* CYP2C9 gene is polymorphic
- CYP2C9*1 Wild-type (non-variant)
- CYP2C9*2 (Arg144Cys) Reduced CYP2C9 activity
- CYP2C9*3 (Ile359Leu) Reduced CYP2C9 activity (worse than *2)

Front 186

CYP2C9 polymorphisms are associated with decreased warfarin clearance.

How would decreased clearance affect concentration of drug in blood?

How would this impact the required dose of the drug?

Back 186

Increased blood concentration

Decreased required dose

Front 187

Meta-analysis of warfarin dose requirements, by CYP2C9 genotype, from many clinical studies

Back 187

CYP2C9 genotype *1/*1 = Normal
CYP2C9 genotype *1/*2 = 19.6% reduction in dose
CYP2C9 genotype *1/*3 = 33.7% reduction in dose
CYP2C9 genotype *2/*2 = 36% reduction in dose
CYP2C9 genotype *2/*3 = 56.7% reduction in dose
CYP2C9 genotype *3/*3 = 78.1% reduction in dose

Front 188

Does CYP2C9 Genotyping Improve Warfarin Management?

Back 188

Prospective studies have evaluated CYP2C9 genotype-guided warfarin dosing versus traditional dosing. They showed:
* a decrease time to first therapeutic INR
* a decrease time to stable anticoagulation
* and a higher percent of time spent within therapeutic range

Front 189

Why aren’t we performing CYP2C9 genotyping on everyone who starts warfarin therapy?

Back 189

* CYP2C9 polymorphisms account for only 10% of the total variability in warfarin dose requirements
* Does not account for polymorphisms in genes involved in warfarin’s pharmacologic effect (to be discussed later in this lecture)
* Influence on bleeding-related outcomes has not yet been determined in a large study

Front 190

Thiopurine S-Methyltransferase (TPMT)

Back 190

* Thiopurine drugs (azathioprine and 6-mercapturine) are used in the treatment of cancer (6-MP), transplant (azathioprine), and autoimmune diseases (e.g., rheumatoid arthritis, lupus)

* Thiopurine drugs undergo sequential metabolism to form active 6-thioguanine nucleotide metabolites

* TPMT metabolizes/inactivates thiopurine drugs to the inactive metabolite, 6-methyl mercaptopurine
* Accumulation of the active metabolite can severely suppress bone marrow
* Polymorphisms in the TPMT gene result in decreased TPMT enzyme activity

* Decreased TPMT activity predisposes individuals to severe, life-threatening thiopurine toxicities due to accumulation of active 6-thioguanine nucleotide metabolites
- Bone marrow suppression (myelotoxicity)
- death

Front 191

Genotype-Guided Thiopurine Dosing

Back 191

TPMT*1 Wildtype = standard dosing
TPMT*2/TPMT*3A/TPMT*3C polymorphisms
- if heterozygote 65% of standard dose
- if homozygous 6-10% of standard dose

Front 192

What gene would you type to find polymorphisms that affect Azathioprine?

Back 192

TPMT

Front 193

UGT1A1

Back 193

* UGT1A1= uridine diphosphate glucoronosyltransferase 1A1
* Responsible for the glucuronidation of endogenous substances (e.g. bilirubin) and drugs
* The most common polymorphism in UGT1A1 is a variation in the number of TA repeats in the TATA box region of the gene.
- The presence of seven TA repeats (UGT1A1*28) instead of the normal six TA repeats (UGT1A1*1) reduces gene expression and results in impaired metabolism
- This variant *28 allele is common in many populations, and occurs in 38.7% of Caucasians, 16% of Asians and 42.6% of Africans

Front 194

Irinotecan and UGT1A1 Polymorphisms

Back 194

* Irinotecan is a topoisomerase I inhibitor used to treat colon cancer

* Irinotecan is metabolized to the active metabolite, SN-38

* SN-38 is inactivated by the enzyme UGT1A1 (through glucuronidation)

* Patients with the UGT1A1*28 polymorphism are unable to glucuronidate SN-38, and subsequently have increased concentrations of the active SN-38 metabolite

* Increased SN-38 concentrations are associated with neutropenia and diarrhea
* Individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia following initiation of CAMPTOSAR treatment.

Front 195

Drug Transporters

Back 195

* Some drugs require transport proteins to assist in their movement across biological membranes
- Efflux transporters: pump drugs out of cells
- Influx transporters: pump drugs into cells

* Drug transporters are most commonly located in the liver, intestine, kidney, and blood brain barrier

* Drug transporters influence drug disposition (pharmacokinetics) and therapeutic effect (pharmacodynamics)

* Polymorphisms exist in drug transporter genes and can alter the function of the transporter

Front 196

Organic Anion Transporting Polypeptide 1B1 (OATP1B1)

Back 196

* Statin medications inhibit the 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase) enzyme in the liver. HMG-CoA reductase is a key enzyme for cholesterol synthesis.

* Statins require transport into the hepatocyte via the OATP1B1 influx drug transporter. Once in the hepatocyte, statins can exert their therapeutic effect by inhibiting the HMG-CoA reductase enzyme.

Front 197

Why are polymorphisms in genes encoding drug target proteins important to consider?

Back 197

Polymorphisms in genes encoding drug target proteins may influence variability in drug response (i.e., pharmacodynamics)

Front 198

Give 3 examples of drug targets:

Back 198

Receptors
Enzymes
Proteins involved in pharmacologic response

Front 199

Why is drug target pharmacogenomics more difficult to study than drug metabolism pharmacogenomics?

Back 199

Drug metabolism Pgx:
* Monogenic
* Polymorphisms often lead to non-functional or absent proteins
* Distinct phenotypes
- Bimodal/trimodal distribution
* Phenotypes are easily measured
- Drug concentration
- In vitro catalytic activity
VS. Drug Target Pgx which is:
* Polygenic
* Polymorphisms usually don’t result in lack of protein function
- More “subtle” effects
* Lack of distinct phenotypes distributions
* Measurement of phenotypes is difficult
- Imprecise and variable

Front 200

Warfarin Drug Target Pharmacogenomics (VKORC1)

Back 200

* Warfarin inhibits Vitamin K Epoxide Reductase (VKOR)

* VKOR helps recycle vitamin K, which helps make functional clotting factors

* By inhibiting VKOR, warfarin prevents vitamin K recycling, and prevents the production of functional clotting factors

* Polymorphisms exist in VKORC1 (the gene that encodes VKOR)

* VKORC1 polymorphisms result in decreased VKOR quantity and function

Front 201

VKORC1 Polymorphisms and Warfarin Dose

Back 201

G/G 46 mg/wk (6.6 mg/day)
G/A 33 mg/wk (4.7 mg/day)
A/A 21 mg/wk (3 mg/day)

Front 202

What % of variability in warfarin doses can be explained by CYP2C9 SNPs?

Back 202

around 10%

Front 203

What % of variability in warfarin doses can be explained by VKORC1 SNPs?

Back 203

around 20-25%

Front 204

Almost 50% of variability in warfarin doses can be explained by a combination of factors:

Back 204

Almost 50% of variability in warfarin doses can be explained by a combination of factors:
* VKORC1 SNPs (~20-25%)
* CYP2C9 SNPs (~10%)
* Non-genetic factors (age, weight, concomitant drugs, concomitant disease states)

Front 205

Disease Risk Polymorphisms

Back 205

* Polymorphisms can predispose individuals to a disease/adverse effect or increase the risk for disease/adverse effect

* If a drug with a know adverse effect is given to a person with a genetic susceptibility to that adverse effect, there is an increased likelihood for that adverse effect

Front 206

Abacavir Hypersensitivity

Back 206

* Nucleoside reverse transcriptase inhibitor used in the treatment of HIV/AIDS

* Abacavir hypersensitivity reactions (rash, fever, malaise, N/V) occur in 5% of Caucasian individuals

* Initial reaction is usually not life-threatening; however, if the drug is re-challenged, life-threatening reactions can occur

* Human leukocyte antigen (HLA) genes code for proteins that play a critical role in the immune system
- Polymorphisms in HLA genes have been associated with hypersensitivity reactions and severe rashes following administration of drug therapy

Front 207

Do polymorphisms in HLA genes influence abacavir hypersensitivity?

Back 207

YES

Front 208

In the Prospective Abacavir Pharmacogenetic Study, eliminating what patient group eliminated abacavir hypersensitivity?

Back 208

eliminating HLA-B*5701 positive patients eliminated the hypersensitivity rxn

Front 209

Prospective Genetic Screening for Abacavir Hypersensitivity

Back 209

* Prospectively excluding HLA-B*5701 carriers from receiving abacavir eliminated immunologically-confirmed abacavir hypersensitivity reactions and significantly reduced the rate of clinically diagnosed abacavir hypersensitivity reactions

* 14 patients would have to be genetically-screened to prevent one case of abacavir-induced hypersensitivity reaction

* Antiretroviral Guidelines recommend screening for HLA-B*5701 before starting any patient on an abacavir-containing regimen. Any patient with a positive HLA-B*5701 test should not receive abacavir. A positive HLA-B*5701 test should prompt documentation of an abacavir allergy in the patient's chart.