PK Variability And Patient Groups

Question 1

What are the two types of patient variability that will affect PK of a drug ?

Answer 1

• inter - patient variability
• intra - patient variability

Question 2

What is pharmacokinetics of a drug?

Answer 2

This is the study of ADME - ie how the body will affect the drugs. How the drug is absorbed, distributed, metabolised and excreted by the body.

Question 3

What is intra - patient variability?

Answer 3

This is variations of a drugs PK parameters that result in different plasma concentration - time graphs of the same dose to the same patient.

Question 4

What may cause intra - patient variability?

Answer 4

• the patient taking the drug at the same dose, with or without food (ie fasted - increased abs, fed - decreased absorbtion)
• the patient taking the same drug with one without other drugs? Or with alcohol etc.

The patient is the same, however how they take the drug, ie their environment is what can lead to variability.

Question 5

What is inter - patient variability?

Answer 5

This is the variations of a drugs PK parameters resulting in fairly different plasma conc - time graphs after administration of the same dose of the same drug to different patients

Question 6

LO1 : what are some factors that influence variations in PK after taking drugs?

Answer 6

• genes —> ie px may be fast or slow metabolisers.
• diseases - ie CVD , renal or hepatic impairment
• age and body size - obesity will impact distribution of the drug. (Elderly vs young vs paediatric).
• environmental (ie food or smoking , ie with clozapine).
• pregnancy
• alcohol intake
• if the patient is taking concomitant drugs (ie DDI risk)
• level of patient adherence

Question 7

The Standard Healthy subject used in clinical trials is a 75kg western male. What is the problem with this in regards to PK variability?

Answer 7

How the drug works and the way the body absorbs, distributes, metabolises, eliminates the drug etc is not valid for patients of different ancestry , paediatrics, elderly, diseased, etc.

The results of how the body works on the drug are not representative of a lot of patient groups.

Question 8

Which types of diseases are responsible for large variations in drug PK?

Answer 8

• disease of organs of elimination (ie the kidney and liver)

Question 9

How can diseases of the circulatory system impact the PK parameters of a drug?

Answer 9

Heart failure
- reduced perfusion to organs will reduce absorption at absorption sites.
- distribution is limited or slower in organs that are usually well perfused.
- organs of elimination ie liver have poor hepatic blood flow —> thus metabolism and excretion are reduced - may lead to tox.

Question 10

What is liver disease / hepatic disease?

Answer 10

It’s when the liver function is chronically abnormal - However is not one single condition - it can be autoimmune, inflammatory , infection based etc.
There is no single biomarkers for hepatic disease which can make it difficult to recommend any dosing adjustments.

Question 11

What other organs may be affected by severe cirrhosis of the liver?

Answer 11

The intestines - reduced absorption of orally admin drugs - 1stPmet affected :(
lungs
kidney.

Question 12

The impact of of hepatic disease on PK of a drug will depend on what?

Answer 12

• the disease type
• the extent of liver failure
  eg cirrhosis of the liver, is associated with reduced hepatic clearance - ** ie elimination **

Question 13

How do we classify liver cirrhosis?

Answer 13

Child Pugh classification where we add up the score of each biomarkers and this will indicate the severity of the liver cirrhosis.

Question 14

How does liver disease affect absorption of drugs?

Answer 14

It will increase the BV of some drugs due to :
- the reduced 1stPmetabolsm :) - however this can lead to TOX if xs concentrations of drug
- increased BV as physiological changes due to liver disease may mean the drug bypasses portal circulation and so is not metabolised etc.

This can be very problematic for drugs that are heavily metabolised by the liver —— ie prodrugs, these can thus be ineffective, or those that are hepatically cleared.

Question 15

How does liver disease affect the **distribution **of drugs ?

Answer 15

• liver disease may result in reduced protein levels (ie albumin, alpha - acid glycoprotein) - will impact drugs that are protein bound ( increase free drug concentrations).
• may lead to increased competition for protein sites available and thus displacement - will affect efficacy

Question 16

How will increased competition for protien sites, and displacement etc due to liver disease affect the volume of distribution for albumin - bound drugs?

Answer 16

• will increase VoD as a >er % of them are now free.

Question 17

How else does liver disease affect distribution of the drugs?

Answer 17

• it will impact clearance of drugs —-> ie reduced clearance may result in tox and accumulation.

Question 18

How does liver disease affect metabolism and excretion (via BILE) of drugs?

Answer 18

It depends on how important hepatic metabolism and clearance are for the drug.
If its not that important, ie drug is renally cleared -> there is less of an impact

Those that are cleared by CYP450 enzymes however, will be impacted , with some enzymes being more impacted than others.

Question 19

How does liver disease impact :
- oral bioavailability
- drug clearance
- half life
- volume of distribution

Answer 19

• it will increase BV bc of the lack of 1st pass metabolism and so a >er % of the drug will reach systemic circulation unchanged.
• drug clearance overall will be reduced - however the extent will depend on the rate of drug clearance (ie those with a high rate ,ie 90L/hr will have major reduction vs those with v small ie 6L/hr — small reduction)
• VoD will increase because less drug being cleared thus more available to be distributed.
• half life - will increase , the drug remains in the systemic circulation for longer.

Question 20

Describe the relationship between volume of distribution and drug clearance?

Answer 20

They are inversely proportional
- the >er the VoD, the lesser the drug clearance.
- the <er the VoD, the >er the clearance

Question 21

What considerations should we make when we are adjusting dosing of a drug for liver failure?

Answer 21

• will need to check PK parameters as BNF not v clear - will need to monitor px closely in case of quick adjustments that may need to be made/
• NTI should be used with caution
• extraction ratio of drugs may influence the drug BV. Drugs with a high ER which are usually cleared resulting in low BV, in hepatic impairment are cleared to a lesser extent resulting in high BV being seen
• clearance may be reduced if hepatic blood flow is reduced (this increased Vd)
• patients with hepatic failure ideally should be in trials however - ethics in regards to px experiencing ADRs
• oedema and ascites can lead to increased Vd for hydrophilic drugs

Question 22

Liver failure or cirrhosis will often lead to px developing oedema or cirrhosis - how will this affect the volume of distribution of hydrophilic drug?

Answer 22

Such drugs will show an increased Vd in hepatic impairment.

Question 23

What are 3 major types of renal impairment?

Answer 23

• AKI
• CKD
• renal impairment alongside or due to another condition (co - morbidity).

Question 24

How does renal impairment impact :
- drug clearance of small MW drugs
- clearance of biolgical drugs and high MW drugs
- half life of the drugs
- time taken to reach steady state
- protein binding
- volume of distribution
- hepatic metabolism

Answer 24

• drug clearance of small MW drugs reduces
• large MW drugs or proteins - not really affected as they are not usually cleared renally anyway. However if proteins are present in the urine, this indicates a problem with renal function!
• furthermore, the fragments or metabolite products of large MW drugs may be impacted where they may not be cleared in hepatic impairment.
• half life —> will increase (inverse prop to CL) and also extend the equation to see.
• reduced protein binding - thus increased VoD of protein bound drugs.
• indirect effect on hepatic metabolism - some uremic toxins may reduce hepatic enzyme activity resulting in reduced clearance

Question 25

What are the two main parameters we use to measure hepatic impairment?

Answer 25

• eGFR —-> indicates how good the glomerulus is at filtering blood
• creatinine clearance

Question 26

How do you calculate GFR(absolute)?

Answer 26

EGFR x (BSA/1.73)

Question 27

What is creatinine and what level of it in the blood will indicate renal failure?

Answer 27

• it is a waste product from the breakdown of the protein creatine.
• high levels indicate that it hasn’t been cleared very well and thus the patient is renally impaired.

Question 28

Which GFR value indicates severe kidney failure (ie stage 4)

Answer 28

<30mg/min

Question 29

What is “creatinine clearance”?

Answer 29

Clcr is considered to be a suitable marker for renal function and is used for dosage adaptation in renal impairment.

Question 30

When should we obtain urine sample for creatinine clearance?

Answer 30

• 24 hr urine collection

Question 31

Which equation will give us the CLcr?

Answer 31

Cockcroft and Gault formula.

(140 - age) x weight x constant / serum creatinine.

Question 32

What will influence the decision made in regards to how much dose adjustments should be made for renal failure?

Answer 32

• how important renal clearance is for the drug
• the severity of renal disease (ie “avoid eGFR<30ml/min)

Question 33

Do we increase or decrease the dose of a drug in renal impairment?

Answer 33

Decrease - bc lack of renal excretion due to impairment may result in accumulation and toxicity.

Question 34

Describe the extent to which we adjust the doses of drugs in SEVERE renal disease?

Answer 34

Generally, larger dose adjustments are needed for severe renal impairments - ie in some cases, we may need to omit.

Question 35

In renal impairment we may treat the patient with haemodialysis /dialysis. How will this impact the PK of the drug in a renally impaired patient?

Answer 35

Dialysis ADDS another compartment for the drug to distribute to.
Clearance of the drugs now depend on both the dialysis device, the drug properties and the patient.

Question 36

What types of drugs are implicated when administered to patients with renal impairment who undergo frequent dialysis?

Answer 36

• hydrophilic drugs - likely to accumulate in fluid in machine
• low protein binding
• small Vd drugs

Question 37

Some of the drugs admin to renally impaired patients undergoing dialysis may be lost to the dialysis machine - what may implicate this?

Answer 37

How much drug being lost via dialysis will depend on :
- the surface area of the membrane
- the pore size - larger pores may implicate >er loss

Question 38

Give an example of a drug that accumulates in fatty tissue and how distribution of it will be impacted in obese patients?

Answer 38

• anaesthetics (ie lidocaine) - they are lipophilic drugs - will accumulate in fatty tissue
  In obesity - xs VoD of lipophilic drugs

Question 39

Does extraction ratio change in hepatic / renal impairment?

Answer 39

No - it is intrinsic to the drug however, because of it BV will be affected.
- a drug with low ER is usually not extensively eliminated - now in hepatic impairment - xs BV and can lead to tox
- a drug with a high ER which is extensively cleared and usually has high BV, in hepatic impairment, is not cleared to such an extent and thus BV is increased!

Question 40

How does the VoD of lipophilic and polar (~ hydrophilic) drugs change in obesity?

Answer 40

• lipophilic drugs - increased VoD bc xs fat, adipose tissue is an added compartment for distribution
• polar drugs ie antipyrine will have reduced VoD bc there is a lower body % of water available for polar hydrophilic drugs to distribute to

Question 41

How does obesity impact absorption, distribution, metabolism and excretion of drugs?

Answer 41

A - may impact GI transit time , may change gut microbiota and thus may impact absorbtion of drugs (ie increased GI transit time may lead to >er absorbtion of drugs as the drug may be in contact with absorbing surfaces for longer).

D - >er VoD for lipophilic drugs, <VoD for polar drugs

M - obesity may alter enzymatic activity in the liver - reduced met - potential tox

E - obesity may impaired GFR and renal and hepatic blood flow - thus reduces both types of clearance and extraction - TOX

Question 42

What is the impact of paediatrics on absorption of a drug?

How should we adjust our dosing of medication?

Answer 42

• infants and newborns have :
  Low stomach acid levels, delayed gastric emptying (thus longer time in stomach) and irregular intestinal peristalsis.
• as a result drug absorbtion is much slowerand so we should increase the time interval between each doses

Question 43

What is the impact of paediatrics on distribution of a drug?

How should we adjust our dosing of medication?

Answer 43

Plasma protein binding of drugs is reduced in infants - >er VoD compared to adults

Total body water / body weight decreases in the 1st year of life - thus VoD < essp for hydrophilic drugs due to lack of water to distribute to.

Question 44

What is the impact of paediatrics on metabolism of a drug?

How should we adjust our dosing of medication?

Answer 44

• metabolism of drugs in children varies bc the rate of maturation of the pathways varies in children.
• metabolism depends on how fast the baby’s liver grows, how well perfused it is, bile function etc.

The enzymatic system only matures after 6 months and so we can infer that that overall, the metabolism of drugs in children is much lower than that of adults

We must then reduce the (n) of times we administer, ie we need to space out dosing of a drug to avoid potential toxicity.

Question 45

What is the impact of paediatrics on excretion of a drug?

How should we adjust our dosing of medication?

Answer 45

Tubule function and glom filtration in premature infants and newborns is very underdeveloped - thus we can assume that excretion is low in infants resulting in accum being a potential risk factor.
- becomes normalised for BSA, and GFR can be taken at 6 months however when it has started to mature - GFR reaches adult values at 6 months.

Poor excretion - thus space out dosing and admin very small doses.

Question 46

For some drugs, developing dosing regimens based on PK for paediatric patients is not practical. Why?

Answer 46

• there isnt enough data (ie lack of infants in Clinical Trials
• extensive INTRA (ie same patient) variability in infants.

Question 47

What do we base our judgement for dosing adjustments in children on?

Answer 47

BSA , weight and age

• BSA the most common

Question 48

What is the relationship between BSA and clearance of a drug in children and how does this impact dosing in children?

Answer 48

The higher the BSA (body surface area) : the higher clearance rate.

Question 49

Explain why a a greater maintenance dose/kg is required for smaller and younger children.

Answer 49

Smaller children tend to have higher BSA than adults and larger children and thus faster clearance - thus larger doses are needed.

Question 50

How will elderly age impact the absorption of drugs?

Answer 50

There are lots of physiological changes that will potentially alter absorption, GI motility , pH changes etc however there is little evidence to suggest that its of major consequence?

Question 51

Discuss how distribution of drugs is affected in elderly patients?

Answer 51

• body fat increases from 15 - 30% and so >er distribution of lipophilic drugs.
• possible reduction in protein binding —> decreased albumin (thus reduced bound concentration - possibly more free acidic drug to be distributed).
• changes to perfusion and cardiac output —> will impact distribution (ie reduced CO and perfusion will reduce - reduced dist)
• lean body weight decreases to total body weight

Question 52

How is metabolism affected in elderly patients and how does this impact dosing?

Answer 52

• liver blood flow and liver mass decrease with age.
• thus reduced extraction and so reduced clearance of a drug - could lead to accumulation of
• may need to space out dosing or reduce the dose given to the patient

Question 53

How is elimination affected in elderly patients ?

Answer 53

• GFR reduced due to reduced kidney size, no of nephrons, functioning glom and reduced renal blood flow.

Thus less drug is limited - may need to reduce the dose given for drugs that are largely renally excreted

Question 54

How is absorption of drugs impacted in pregnant women and how does this impact dosing?

Answer 54

These have been observed in pregnant women :
- delayed gastric emptying
- prolonged GI transit
- reduced motility

This ultimately slows the rate of drug absorption in pregnant women

Furthermore, gastric pH increases - may impact pH dependant release drugs - may not be ionised for absorbtion!

Vomiting and nausea may also reduce the (n) of absorption that occurs - may need larger dose or more frequent dosing.

Question 55

How is distribution of drugs impacted in pregnant women and how does this impact dosing?

Answer 55

• increased blood flow, reduced albumin and alpha - acid glycoprotein and so increased free acidic and basic drug conc ——-> this may increase the risk of ADRS!!!!!!!!
• increased body weight links to increased ECF and Intravascular volumes which may affect the distribution of hydrophilic drugs (>er Vd) but also lipophilic drugs due to increased body fat.

Question 56

How is metabolism of drugs impacted in pregnant women and how does this impact dosing?

Answer 56

Oestrogen and progesterone induce and inhibit CYP metabolising enzymes —> thus increase or decrease drug concentrations and thus may need to dose adjust.

Drugs with a higher ER may be metabolised to a greater extent due to increased blood flow in pregnancy resulting in lower plasma concentrations.

Question 57

How is elimination of drugs impacted in pregnant women and how does this impact dosing?

Answer 57

• increased renal blood flow in pregnancy - increased ER of kidney —> >er renal excretion of hydrophilic drugs
• for drugs that are eliminated after metabolism , adjustment needs to be made to consider the impact of pregnancy on both metabolic and renal clearance.

Question 58

Explain how a drug may cross from the mother to the infant during breast feeding and the implications.

Answer 58

Breast tissue - more acid, has a lower pH compared to blood.
Basic drugs that were unionised in blood can cross via endothelial cells (permeable) can thus become ionised in the breast tissue, however cannot go back to the blood.
They may accumulate in the breast tissue and get into the milk which the baby will drink - if the baby has immature hepatic metabolism and renal elimination it may accumulate and cause toxicity.

Question 59

Which kinds of drugs are less likely to be passed into milk during feeding?

Answer 59

Large macromolecules and biologicals