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PCEUT 510 > #1 Inter-Individual Variability in Drug-Disposition and DDIs > Flashcards

#1 Inter-Individual Variability in Drug-Disposition and DDIs Flashcards

1
Q 
The following are examples of \_\_\_\_\_\_\_\_ PATIENT factors that affect a drugs PK/PD: 
Age
Pregnancy
Renal Function
Liver Function 
Pharmacogenetics
Disease
A

INTRINSIC

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2
Q 
The following are examples of \_\_\_\_\_\_\_ factors that affect a drugs PK/PD: 
Drug-Food interactions
Drug-Drug interactions
Environment
Medical Practice
Regulatory
Smoking
A

EXTERNAL

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3
Q

The age at which children gain most of their CYP2D6 enzyme function?

A

12 months

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4
Q

Neonates and infants (INCREASED/DECREASED) GFR?

A

DECREASED

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5
Q

Neonates and infants have (INCREASED/DECREASED) renal transporter activity?

A

DECREASED

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6
Q

Renal function is HIGHLY variable in neonates and infants depending on if they are ________ or ________?

A

ill

Premature

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7
Q

T/F

Many of the p450s such as 2D6 and 2C19 aren’t expressed at birth

A

T

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8
Q

What is the age-dependent PK of Lansoprazole (2C19) in Neonates and infants?

A

CL/F increases during the first year; presumably because of hepatic 2C19 expression

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9
Q

Before birth you have a lot of _____ and some 3A5, after 5 months 3A4 starts to take over and is highest in adulthood.

A

3A7

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10
Q

What drug is given for sedation for ventilation and treatment of hyperbilirubinemia in neonates which is BOTH an inducer and has compromised clearance in neonates?

A

Phenobarbital

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11
Q

What are TWO reasons why there is DECREASED drug clearance in the ELDERLY?

A
  1. Decreased enzyme activity [P450s and Glucoronidation]

2. Decreased Renal Clearance [reduced renal function]

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12
Q

What is the only blood chemistry measurement of liver enzyme function (UGT1A1)?

A

Total bilirubin

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13
Q

In end stage liver disease which CYP enzymes MAINTAIN function longer?

A

2E1

2D6

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14
Q

In end stage liver disease what CYP enzymes will have decreased function?

A

1A2
2C19
3A4
[lesser extent = UGT & Sulfotransferases]

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15
Q 
Patients with alcoholic liver disease will have an INCREASE in which of the following enzymes? 
A. MRP3
B. BSEP, MRP4, NTCP, OATP1B1
C. MATE1, MRO2, OATP2B, Pgp
**
A

A. MRP3

**(Probably wont need to know this level of detail)

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16
Q 
Patients with alcoholic liver disease will have a DECREASE in which of the following enzymes? 
A. MRP3
B. BSEP, MRP4, NTCP, OATP1B1
C. MATE1, MRO2, OATP2B, Pgp
**
A

B. BSEP, MRP4, NTCP, OATP1B1

**(Probably wont need to know this level of detail)

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17
Q 
Patients with alcoholic liver disease will have NO CHANGE in which of the following enzymes? 
A. MRP3
B. BSEP, MRP4, NTCP, OATP1B1
C. MATE1, MRO2, OATP2B, Pgp
**
A

C. MATE1, MRO2, OATP2B, Pgp

**(Probably wont need to know this level of detail)

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18
Q

Patients with HEP C have an INCREASE in which enzymes?

**

A

MATE1

**(Probably wont need to know this level of detail)

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19
Q

Patients with HEP C will have a DECREASE in which enzymes?

**

A 
BESP, 
MRP2, 
NTCP, 
OATP1B3, 
OCT1, 
Pgp
**(Probably wont need to know this level of detail)
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20
Q

Patients with HEP C will have NO CHANGE in which enzymes?

**

A 
BCRP,
MR3,
OATP1B1, 
OATP1B2
**(Probably wont need to know this level of detail)
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21
Q

Glomerular Disease (filtration) affects drugs with moderate [HIGH/LOW] plasma protein binding that are efficiently filtered; [HIGH/LOW]

A

LOW protein binding

HIGH free fraction

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22
Q

What is the most common cause of Acute Interstitial Nephritis (AIN)?

A

DRUGS! Especially:
antimicrobials
NSAIDS

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23
Q

Serum creatinine is not an accurate indication of renal function especially in people with [MORE/LESS] muscle mass?

A

LESS muscle mass

[ex = elderly people]

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24
Q

The Crockcroft Gault [UNDER/OVER] estimates clearance in obese patients/

A

OVERESTIMATES

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25
Q

The MDRD is more accurate than the CG-equation but estimates clearance in patients with?

A

HIGHER kidney function

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26
Q

Historically, renal dosing has been based on the intact nephron theory.
What does this assume?

A
  1. Renal drug clearance is proportional to CrCl
  2. Non-renal clearance is NOT affected by renal impairment
    Assumptions = NOT TRUE
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27
Q

_______syndrome (typically refers to DECREASED renal function in patients with severe liver dysfunction but severe renal dysfunction can result in SEVERE liver failure)

A

Hepato-renal syndrome

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28
Q

At what GFR does drug disposition of renally cleared drugs start be considered SIGNIFICANTLY altered?

A

60 mL/min

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29
Q

How did ESRD affect

Fexofenadine & Midazolam?

A
  1. REDUCED non-renal clearance (transporter mediated) of fexofenadine
  2. NO effect on Midazolam 3A4 clearance
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30
Q

T/F

Clarithromycin had no effect on Digoxin clearance either in regular patients or renal disease patients?

A

FALSE

  • No effect in healthy subjects
  • Elevated Digoxin levels in patients with renal failure given clarithromycin by 3-4 fold increase
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31
Q

What is the DDI effect of colchicine and clarithromycin in patients with renal disease?

A

FATAL colchicine toxicity

32
Q

Chronic inflammation in someone with something like Rheumatoid Arthritis tends to have [HIGHER/LOWER] p450 levels and thus [HIGHER/LOWER] clearance?

A

LOWER p450 levels
LOWER clearance
=
INCREASED drug levels

33
Q

Inflammatory disease can downregulate drug metabolizing enzymes and transporters via DECREASING ________?

A

Gene transcription

34
Q

What happens when you treat RA with anti-cytokine therapy ?

A

The repression of p450 enzymes (3A4) goes away and p450 levels and clearance increase = drug levels DROP

35
Q

Which cytokine inhibits P450 creation (3A4)?

A

IL-6

36
Q

This drug was shown to ultimately lower levels of simvastatin due to inhibition of IL-6; leading to more P450 synthesis

A

Tocilizumab

37
Q

The most significant interactions between inflammation and drug clearance involve drugs metabolized by which enzymes?

A

3A4
2C9
1A2

Clearance is INCREASED with the resolution of inflammatory condition

38
Q

This drug INCREASE adalimumab exposure by 79%

A

Methotrexate

39
Q

This increases trastuzumab exposure by 150%

A

Paclitaxel

40
Q

This dug didn’t show much interaction with digoxin in healthy renal patients, but renal failure patients saw digoxin toxicity

A

Clarithromycin

41
Q

This population has LESS muscle mass so CrCl is LESS reliable

A

Elderly

42
Q

Tocilizumab inhibits this messenger

A

IL-6

43
Q

This cytokine inhibits P450 creation/synthesis

A

IL-6

44
Q

This drug was shown to ultimately lower levels of simvastatin due to inhibition of IL-6; leading to more P450 synthesis

A

Tocilizumab

45
Q

T/F

Tocilizumab’s effect on IL-6 is similar to inductor effects?

A

FALSE

46
Q

This drug increase adalimumab exposure by 79%

A

Methotrexate

47
Q

This drug increases trastuzumab exposure by 150%

A

Paclitaxel

48
Q

This form of kidney damage is usually caused by antimicrobials and NSAIDS

A

AIN (acute interstitial nephritis)

49
Q

This drug didn’t show much interaction with digoxin in healthy renal patients, but renal FAILURE patients saw digoxin toxicity

A

Clarithromycin

50
Q

What is the 2D6 variability with AGE?

A

Very MINIMAL in newborns: gradually INCREASES over 1 year to adult levels

51
Q

What is the 3A7 variability with AGE?

A

HIGH in neonates, then DECLINES until 1 yo

52
Q

What is the 3A4 variability with AGE?

A

LOW at birth, INCREASES until adulthood

53
Q

1A2 variability with AGE?

A

INCREASES until pre-teen years

54
Q

What is the 2C9 variability with AGE?

A

INCREASES a TON in the first 0-2 weeks of life, then pretty stable thereafter

55
Q

Lansoprazole + Infants

Interaction?

A

Infants 2C19 enzyme hasn’t kicked in yet = super HIGH lansoprazole AUC

56
Q

3 CYPS that get to adult levels QUICKLY after birth?

A

2C9
2C8
2D6

57
Q

2 CYPs that get to adult levels SLOWLY after birth?

A

3A

2B6

58
Q

Liver disease:

Child-Pugh Scoring

A 
A = 5-6 pts 
B = 7-9 pts 
C = 10-15 pts
59
Q

Liver biomarkers:

ALT

A

Tells you acute liver injury only does NOT tell you anything about liver metabolism

60
Q

Liver biomarkers:

Bilirubin

A

Tells you DRUG metabolism in liver

61
Q

Which CYPs DECREASE in activity when you have worsening liver disease?

A

2C19 [first to go]
1A2
2D6
2E1 [last to go]

62
Q

Erythromycin + quinine + cirrhosis DDI?

A
  1. Erythromycin displaces quinine OFF albumin
  2. Erythromycin = 3A4 & Pgp INHIBITOR + Quinine is 3A4 & Pgp SUBSTRATE = INCREASED [quinine]
  3. Cirrhosis: DECREASES albumin production = even more free quinine
    * Cirrhosis = INCREASED [quinine]
    * Erythromycin = INCREASED [quinine]
63
Q

Propranolol + liver disease DDI?

A
  1. Propranolol = HIGH ER drug

2. Cirrhosis = less 1st pass metabolism = HIGHER bioavailability

64
Q

Sofosbuvir + liver disease DDI?

A
  1. Sofosbuvir is metabolized by carboxyesterase-1 = active metabolite
  2. Sofosbuvir is also cleared via Pgp and BCRP transporters
  3. Metabolite is cleared primarily renally

DDI= INCREASED [parent Sofosbuvir]; active metabolite only slightly [increased]

65
Q

Sofosbuvir + renal disease

A

DDI= both [metabolite] & [parent sofosbuvir] INCREASED

66
Q

Outdated “intact nephron theory”

A
  1. Drug renal CL is proportional to CrCl
  2. Non-renal Cl is unaffected by renal impairment
    * *Now we know liver and kidneys affect each other! Renal impairment = solute build up = decrease drug uptake into liver
67
Q

At what GFR are renally-cleared drugs affected?

A

<60 mL/min/m2

68
Q

Fexofenadine + ESRD DDI

A

ESRD reduced non-renal CL of fexofenadine via transporter-mediate mechanisms

69
Q

Midazolam + ESRD

A

ESRD did NOT affect 3A metabolism of Midazolam

70
Q

Clarithromycin + Digoxin + Renal insufficiency (case report only)

A

Clarithryomcyin = 3A4 & Pgp INHIBITOR
Digoxin = 3A4 & Pgp Substrate
Kidney disease = uremic solutes accumulate = decreased transport = digoxin CL is affected

71
Q

Colchicine + Clarithromycin + ESRD DDI?

A

Colchicine is cleared partially renally as unchanged drug, and partially via 3A4 metabolism
Inhibiting BOTH renal AND hepatic clearance = colchicine toxicity!

72
Q

How does inflammation affect drug clearance and DDI potential?

A

Inflammatory disease (RA, sepsis, some cancers) can down-regulate certain drug-metabolizing enzymes or transporters by DECREASING gene transcription

73
Q

Tocilizumab + Simvastatin DDI

A

Tocilizumab reverses inflammation in RA = inhibition of 3A gene expression is removed = GREATER 3A metabolism of Simvastatin = DECREASED simvastatin AUC and possible efficacy

74
Q

Tocilizumab initiation can affect which CYPs? (3)

A

3A4
1A2
2C9

75
Q

Canakinumab initiation can affect which CYP? (1)

A

3A4

76
Q

Cancer/surgery vs ICU in pediatric Pts

A

Cancer/surgery pediatric Pts have HIGHER; 3A4, UGT, and RENAL CL activity than ICU pediatric PTs

PCEUT 510 (12 decks)

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