DDIs And TDM

Question 1

What is the definition of a drug - drug interaction?

Answer 1

When 2+ drugs interact affecting the toxicity and efficacy of each other.

Question 2

What are the two ways that we can categorise drug - drug interactions?

Answer 2

• their mechanism (ie whether they are pharmaceutical (ie due to incompatibilities, manufacturing, storage , dispensing, admin), pharmacokinetics (ie impacting ADME of the other drug) , or pharmacodynamic (doesn’t affect ADME but will impact toxicity).
• their outcome - ie whether the interaction is beneficial or deleterious.

Question 3

What is a pharmacokinetic DDI?

Answer 3

An interaction between drugs in which one will impact the ADME of the other one.

Question 4

Give an example of drugs that interact with a beneficial outcome?

Answer 4

• Carbidopa and L - dopa
• Tazobactam and piperacillin

Question 5

Discuss the ways that DDIs may impact absorption of a drug?

Answer 5

The drug may impact the rate and extent of absorption by impacting :
1. Gastric emptying —> reduced GE will slow absorption
2. Dissolution or pH —> drugs admin after PPI or antacids - may not remain unionised …
3. GIT motility - eg opioids reduce it - will reduce rate of absorbtion as it may take longer for drug to now go to SI, anti cholineergic drugs also have an impact
4. Complexation —> complexation of the drug to something else -> increase rate of elimination and clearance and thus less of them will be absorbed if drug
5. 1st pass met —> extensive 1stPmet will reduce the (n) of drug absorbed onto systemic circulation from SI ofc.

Question 6

How do DDI impact distribution of a drug?

Answer 6

They may change the extent of plasma or tissue protein binding.
- ie some drugs may compete for the same binding site - where the one with a >er affinity will bind.
- ie often both drugs are highly bound to the protiens —-> this will change the therapeutic response and toxicity.

This will obs impact VoD
- drug that highly bound and has >er affinity for plasma proteins will have reduced VoD compared to the other one that has been displaced (free)

Question 7

How do DDIs impact metabolism?

Answer 7

1. One of the drugs could either INDUCE or INHIBIT the hepatic metabolising enzymes
2. The effect of this will depend on how important metabolism is for the drug where a prodrug, if under the action of an inhibitor, will have reduced action and v little therapeutic action.

Question 8

Describe how inhibition of metabolic/ hepatic enzymes by a drug will impact the action of the other drug?

Answer 8

• inhibition of metabolism may increase plasma conc —> may crease the risk of toxicity and thus may result in us admin a LOWER DOSE

There may be issues with :
- competitive inhibition or non competitive inhibition
- whether inhibition of the enzyme is reversible (where removal of the inhibitor will allow for normal metabolism of the drug) or irreversible where ( metabolism of the drug will require synthesis of new enzymes as those bound have been permanently inhibited by the other drug).

Question 9

Discuss how induction of metabolising enzymes by one drug will affect the therapeutic activity of the other drug?

Answer 9

Increasing induction of metabolism will result in >er hepatic clearance of the drug AND reduced CSS
We will thus need to increase the dose.

Question 10

Inducing metabolic enzymes with a drug - will this effect be rapid or gradual?

Answer 10

• gradual onset of

Question 11

After removal of an enzyme inducer, how long will it take for metabolic enzymes to go back to their regular baseline level of action?

Answer 11

2 - 3 weeks

Question 12

Predict how we will need to change the dosing of a drug after induction or inhibition of metabolic enzymes by another drug?

Answer 12

• inhibition —> will need to reduce the dose to avoid ACCUMULATION + TOXICITY
• induction —> will need to increase the dose to avoid subpar CSS and to achieve therapeutic levels.

We will need to readjust the dose ofc and monitor levels once the inducer and inhibitor drugs are removed.

Question 13

How do drugs that impact efflux/ influx cell transports affect PK of the other drugs?

Answer 13

• they may alter absorbtion and excretion
• those that increase efflux of drugs from systemic circulation - increase excretion and Inhibit absorbtion of the drug

Question 14

Where are cell transporters found?

Answer 14

Intestines, brain, BBB, renal tubes, heptatocytes etc.

Question 15

Give an example of an efflux transporter and its effects when drugs that amplify their expression are used?

Answer 15

Pgp!
- found in the intestines , renal tubules, brain etc
When amplified by some drugs we see :
- decreased intestinal absorption
- increased renal excretion
- decreased uptake in the brain

Competition, induction, inhibition are all possible effects of the PGP

Question 16

Describe how a DDI may impact on drug excretion?

Answer 16

DDI may impact :
- renal excretion
- bile excretion

Question 17

Describe how a DDI may impact renal excretion?
(Excretion)

Answer 17

1. Drugs may change the urine pH where drugs that are more acidic ——> excreted faster in basic urine (bc ionised and cant be re absorbed into blood) and thise that are more basic are faster excreted in acidic urine.
2. DDI may induce completion for active tubular secretion sites —> tubular secretion is how drugs go into renal tubules to be removed.
   - thus by increasing secretion of drugs we may get more removal of these drugs.
   - this may occur by inhibiting renal excretion (removed from tubules - back into blood) ie probenecid which helps ppl with renal impairment —-> will help prevent tox and accumulation).
   Aspirin and MTX - aspirin increased conc of MTX by inhibiting tubular secretion of MTX (thus more of it in the blood stream and thus Nephrotoxicity as its not cleared).

Question 18

What is therapeutic drug monitoring?

Answer 18

This involves using knowledge of PK, PD and pharmaceutics to look at the drug concentration of a patient in order to individualise treatment and adjust the dosing regimen.

Question 19

When would we monitor a drug?

Answer 19

• after initiation
• after retitrated the dose

Question 20

What is the rationale for drug monitoring - ie how is it beneficial? Why should we do it?

Answer 20

It can help us identify common issues with dosing regimens! Such as :
- the wrong drug - may be indicated by plasma/blood conc being either within the therapeutic window/ higher end.
** the wrong dose** - may see below or above the therapeutic window! However before we make any clinical decisions you MUST CHECK PX ADHERENCE 1st!
** adherence issues **
** drug toxicity vs disease progression ** —-> px may be getting worse, however may be due to v drug conc being low and the drug not having an adequate response. It also may be that the dose is fine and the disease is just getting more virulent.

Question 21

TDM is not recommended in the the BNF for ALL drugs. Which drug classes is it usually recommended for?

Answer 21

1. Antibiotics ( aminoglycosides ie gentamicin -> hearing damage)
2. Anti - epileptics (ie Sodium Valp, V acid, phenytoin)
3. Immunosuppressants
4. Cytotoxicity drugs (ie MTX)
5. Lithium and TCA
6. Bronchodilators
7. Cardiovascular drugs (digoxin)

Question 22

What 3 characteristics do most drugs that are monitored fit into?

Answer 22

• narrow therapeutic effects
• variable pK profile (ie there is a poor correlation between plasma conc and dose)
• those that are used in high risk patients (px with multimorbidites, or those on polypharmacy).

Question 23

What sampling considerations do we need to make when doing monitoring of drugs?

Answer 23

• the timing - we usually sample blood when CSS is reached
• what we are sampling (ie blood, plasma, serum)
• free vs total drug concentration —> we usually look at total concentration
• if we are sampling the metabolic or the unchanged version of the drug

Question 24

Why do we need to consider where we sample the drug concentration?

Answer 24

Whether we sample the blood, serum or plasma will affect how we collect the sample, the stability of the sample and the storage of the samples.

Question 25

Why do we need to consider the timing of collecting our sample for TDM?

Answer 25

As mentioned, we usually obtain the sample when the drug has reached CSS however if we are :
1. Monitoring for efficacy - obtain at css as we should’ve have obtained the css before dosing.
2. Monitoring for toxicity -> obtain the sample when we expect it will be at highest conc
3. Monitoring a drug with a LONGGG t1/2 or multiple compartment PK - sample at 6 - 8 hrs after dosing as it may take a while to reach Css

Question 26

When do sample drugs at concs that are NOT the css?

Answer 26

When sampling aminoglycoside or vancomycin

Question 27

Do we sample the free or total concentration?

Answer 27

Usually the total concentration of the drug - however we do the free one if the drug is highly bound to plasma protiens.

This requires separation of the free and bound drug.

Question 28

3 ways we can separate free and bound drug if we need to sample free drug (ie say high protien binding)?

Answer 28

• equilibrium dialysis
  Ultrafiltration
• ultracentrifugation

Question 29

What will affect the extent to which a drug is protein bound and in turn whether we sample free or total drug concentration?

Answer 29

• medical conditions - ie renal or hepatic diseases
• drug interactins

Question 30

Why do we need to consider whether we sample the metabolite or the unchanged drug?

Answer 30

• because in some cases the metabolite is the pharmaceutical API not the pro/ unchanged drug.
• it also may be the metabolite contributing to ADRs and tox

Question 31

Which two analytical techniques can we use to sample metabolites / unchanged drugs when monitoring ?

Answer 31

• immunoassays - fast :), however risk for cross reactivity :( AND reagents needed for specific drugs are not always available :(
• liquid chromatography —> slower, bc it requires method validation, sills, accuracy etc :(, however, we can measure both the metabolite and the unchanged sample at the same time :)