#1 Inter-Individual Variability in Drug-Disposition and DDIs Flashcards
The following are examples of \_\_\_\_\_\_\_\_ PATIENT factors that affect a drugs PK/PD: Age Pregnancy Renal Function Liver Function Pharmacogenetics Disease
INTRINSIC
The following are examples of \_\_\_\_\_\_\_ factors that affect a drugs PK/PD: Drug-Food interactions Drug-Drug interactions Environment Medical Practice Regulatory Smoking
EXTERNAL
The age at which children gain most of their CYP2D6 enzyme function?
12 months
Neonates and infants (INCREASED/DECREASED) GFR?
DECREASED
Neonates and infants have (INCREASED/DECREASED) renal transporter activity?
DECREASED
Renal function is HIGHLY variable in neonates and infants depending on if they are ________ or ________?
ill
Premature
T/F
Many of the p450s such as 2D6 and 2C19 aren’t expressed at birth
T
What is the age-dependent PK of Lansoprazole (2C19) in Neonates and infants?
CL/F increases during the first year; presumably because of hepatic 2C19 expression
Before birth you have a lot of _____ and some 3A5, after 5 months 3A4 starts to take over and is highest in adulthood.
3A7
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?
Phenobarbital
What are TWO reasons why there is DECREASED drug clearance in the ELDERLY?
- Decreased enzyme activity [P450s and Glucoronidation]
2. Decreased Renal Clearance [reduced renal function]
What is the only blood chemistry measurement of liver enzyme function (UGT1A1)?
Total bilirubin
In end stage liver disease which CYP enzymes MAINTAIN function longer?
2E1
2D6
In end stage liver disease what CYP enzymes will have decreased function?
1A2
2C19
3A4
[lesser extent = UGT & Sulfotransferases]
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. MRP3
**(Probably wont need to know this level of detail)
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 **
B. BSEP, MRP4, NTCP, OATP1B1
**(Probably wont need to know this level of detail)
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 **
C. MATE1, MRO2, OATP2B, Pgp
**(Probably wont need to know this level of detail)
Patients with HEP C have an INCREASE in which enzymes?
**
MATE1
**(Probably wont need to know this level of detail)
Patients with HEP C will have a DECREASE in which enzymes?
**
BESP, MRP2, NTCP, OATP1B3, OCT1, Pgp **(Probably wont need to know this level of detail)
Patients with HEP C will have NO CHANGE in which enzymes?
**
BCRP, MR3, OATP1B1, OATP1B2 **(Probably wont need to know this level of detail)
Glomerular Disease (filtration) affects drugs with moderate [HIGH/LOW] plasma protein binding that are efficiently filtered; [HIGH/LOW]
LOW protein binding
HIGH free fraction
What is the most common cause of Acute Interstitial Nephritis (AIN)?
DRUGS! Especially:
antimicrobials
NSAIDS
Serum creatinine is not an accurate indication of renal function especially in people with [MORE/LESS] muscle mass?
LESS muscle mass
[ex = elderly people]
The Crockcroft Gault [UNDER/OVER] estimates clearance in obese patients/
OVERESTIMATES
The MDRD is more accurate than the CG-equation but estimates clearance in patients with?
HIGHER kidney function
Historically, renal dosing has been based on the intact nephron theory.
What does this assume?
- Renal drug clearance is proportional to CrCl
- Non-renal clearance is NOT affected by renal impairment
Assumptions = NOT TRUE
_______syndrome (typically refers to DECREASED renal function in patients with severe liver dysfunction but severe renal dysfunction can result in SEVERE liver failure)
Hepato-renal syndrome
At what GFR does drug disposition of renally cleared drugs start be considered SIGNIFICANTLY altered?
60 mL/min
How did ESRD affect
Fexofenadine & Midazolam?
- REDUCED non-renal clearance (transporter mediated) of fexofenadine
- NO effect on Midazolam 3A4 clearance
T/F
Clarithromycin had no effect on Digoxin clearance either in regular patients or renal disease patients?
FALSE
- No effect in healthy subjects
- Elevated Digoxin levels in patients with renal failure given clarithromycin by 3-4 fold increase
What is the DDI effect of colchicine and clarithromycin in patients with renal disease?
FATAL colchicine toxicity
Chronic inflammation in someone with something like Rheumatoid Arthritis tends to have [HIGHER/LOWER] p450 levels and thus [HIGHER/LOWER] clearance?
LOWER p450 levels
LOWER clearance
=
INCREASED drug levels
Inflammatory disease can downregulate drug metabolizing enzymes and transporters via DECREASING ________?
Gene transcription
What happens when you treat RA with anti-cytokine therapy ?
The repression of p450 enzymes (3A4) goes away and p450 levels and clearance increase = drug levels DROP
Which cytokine inhibits P450 creation (3A4)?
IL-6
This drug was shown to ultimately lower levels of simvastatin due to inhibition of IL-6; leading to more P450 synthesis
Tocilizumab
The most significant interactions between inflammation and drug clearance involve drugs metabolized by which enzymes?
3A4
2C9
1A2
Clearance is INCREASED with the resolution of inflammatory condition
This drug INCREASE adalimumab exposure by 79%
Methotrexate
This increases trastuzumab exposure by 150%
Paclitaxel
This dug didn’t show much interaction with digoxin in healthy renal patients, but renal failure patients saw digoxin toxicity
Clarithromycin
This population has LESS muscle mass so CrCl is LESS reliable
Elderly
Tocilizumab inhibits this messenger
IL-6
This cytokine inhibits P450 creation/synthesis
IL-6
This drug was shown to ultimately lower levels of simvastatin due to inhibition of IL-6; leading to more P450 synthesis
Tocilizumab
T/F
Tocilizumab’s effect on IL-6 is similar to inductor effects?
FALSE
This drug increase adalimumab exposure by 79%
Methotrexate
This drug increases trastuzumab exposure by 150%
Paclitaxel
This form of kidney damage is usually caused by antimicrobials and NSAIDS
AIN (acute interstitial nephritis)
This drug didn’t show much interaction with digoxin in healthy renal patients, but renal FAILURE patients saw digoxin toxicity
Clarithromycin
What is the 2D6 variability with AGE?
Very MINIMAL in newborns: gradually INCREASES over 1 year to adult levels
What is the 3A7 variability with AGE?
HIGH in neonates, then DECLINES until 1 yo
What is the 3A4 variability with AGE?
LOW at birth, INCREASES until adulthood
1A2 variability with AGE?
INCREASES until pre-teen years
What is the 2C9 variability with AGE?
INCREASES a TON in the first 0-2 weeks of life, then pretty stable thereafter
Lansoprazole + Infants
Interaction?
Infants 2C19 enzyme hasn’t kicked in yet = super HIGH lansoprazole AUC
3 CYPS that get to adult levels QUICKLY after birth?
2C9
2C8
2D6
2 CYPs that get to adult levels SLOWLY after birth?
3A
2B6
Liver disease:
Child-Pugh Scoring
A = 5-6 pts B = 7-9 pts C = 10-15 pts
Liver biomarkers:
ALT
Tells you acute liver injury only does NOT tell you anything about liver metabolism
Liver biomarkers:
Bilirubin
Tells you DRUG metabolism in liver
Which CYPs DECREASE in activity when you have worsening liver disease?
2C19 [first to go]
1A2
2D6
2E1 [last to go]
Erythromycin + quinine + cirrhosis DDI?
- Erythromycin displaces quinine OFF albumin
- Erythromycin = 3A4 & Pgp INHIBITOR + Quinine is 3A4 & Pgp SUBSTRATE = INCREASED [quinine]
- Cirrhosis: DECREASES albumin production = even more free quinine
* Cirrhosis = INCREASED [quinine]
* Erythromycin = INCREASED [quinine]
Propranolol + liver disease DDI?
- Propranolol = HIGH ER drug
2. Cirrhosis = less 1st pass metabolism = HIGHER bioavailability
Sofosbuvir + liver disease DDI?
- Sofosbuvir is metabolized by carboxyesterase-1 = active metabolite
- Sofosbuvir is also cleared via Pgp and BCRP transporters
- Metabolite is cleared primarily renally
DDI= INCREASED [parent Sofosbuvir]; active metabolite only slightly [increased]
Sofosbuvir + renal disease
DDI= both [metabolite] & [parent sofosbuvir] INCREASED
Outdated “intact nephron theory”
- Drug renal CL is proportional to CrCl
- 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
At what GFR are renally-cleared drugs affected?
<60 mL/min/m2
Fexofenadine + ESRD DDI
ESRD reduced non-renal CL of fexofenadine via transporter-mediate mechanisms
Midazolam + ESRD
ESRD did NOT affect 3A metabolism of Midazolam
Clarithromycin + Digoxin + Renal insufficiency (case report only)
Clarithryomcyin = 3A4 & Pgp INHIBITOR
Digoxin = 3A4 & Pgp Substrate
Kidney disease = uremic solutes accumulate = decreased transport = digoxin CL is affected
Colchicine + Clarithromycin + ESRD DDI?
Colchicine is cleared partially renally as unchanged drug, and partially via 3A4 metabolism
Inhibiting BOTH renal AND hepatic clearance = colchicine toxicity!
How does inflammation affect drug clearance and DDI potential?
Inflammatory disease (RA, sepsis, some cancers) can down-regulate certain drug-metabolizing enzymes or transporters by DECREASING gene transcription
Tocilizumab + Simvastatin DDI
Tocilizumab reverses inflammation in RA = inhibition of 3A gene expression is removed = GREATER 3A metabolism of Simvastatin = DECREASED simvastatin AUC and possible efficacy
Tocilizumab initiation can affect which CYPs? (3)
3A4
1A2
2C9
Canakinumab initiation can affect which CYP? (1)
3A4
Cancer/surgery vs ICU in pediatric Pts
Cancer/surgery pediatric Pts have HIGHER; 3A4, UGT, and RENAL CL activity than ICU pediatric PTs
