drug-drug interactions

Question 1

what are the types of drug-drug interactions? DDI

Answer 1

1. pharmacodynamic interactions

2. pharmcokinetic interactions

Question 2

what can pharmacokinetic interactions affect?

Answer 2

• drug absorption
• drug plasma protein binding
• drug metabolism - most common
• drug transport
• renal excretion

Question 3

what is metabolic DDIs?

Answer 3

 Inhibition or induction of CYP enzymes
 Often associated with CYP3A4
 Increasing role of transporters in DDIs, can be a combination which makes it difficult to predict
 Range from large effect to none – in drugs with narrow therapeutic windows can have a minimal DDI but with a large impact

Question 4

which drugs have been withdrawn from the market due to severe DDIs?

Answer 4

terfenadine, mibefradil (CYP3A4)
 cerivastatin (CYP2C8/OATP1B1)
 Unpredictable unless CYP/transporter is known for a drug of interest – victim drug. Is it a substrate or an inhibitor

Question 5

what are the types of modifers of drug metabolism?

Answer 5

1. induction

2. inhibition

Question 6

what is induction?

Answer 6

increase synthesis or activity if metabolic enzymes
 Admin certain drugs which cause an induction of the metabolic enzymes
 Slow effect, involves enzyme turnover
 Can lead to lack of therapeutic effect – may have greater elimination of a drug

Question 7

what is inhibition?

Answer 7

inactivation or less enzyme available

Question 8

what are the two types of inhibiton?

Answer 8

reversible

irreversible

Question 9

what is reversible inhibition?

Answer 9

Reversible (competitive and non-competitive)
 Enzyme-inhibitor complex is formed
 Enzyme activity is recovered after removal of the inhibitor.

Question 10

what is irreversible inhibition/

Answer 10

Irreversible
 Drug/modifier inactivates enzyme by covalently binding to it
 Design of in vitro studies more complex
 Non-recoverable unless new enzyme is synthesized!

Question 11

what is the clinical consequences of inhibiton and induction/

Answer 11

Control phase is drug given on its own
With inhibitor- there is an increase in plasma conc
Modifiers (perpetrators) – drug, dietary or environmental chemicals. Inhibitor
Victim drug – affected by the interaction

Question 12

what is the AUC ratio?

Answer 12

AUC ratio = AUC+inhibitor / AUCcontrol

Question 13

what happens during inhibition?

Answer 13

metabolising rate = decreases
drug conc = increases
drug effect = potentiated
clinical action = reduce dose or avoid co admin

Question 14

what happens during induction?

Answer 14

metabolising rate = increases
drug conc = decreases
drug effect = reduced
clinical action = increase dose

Question 15

which CYP enzymes are listed for routine invitro screening during drug development?

Answer 15

CYP1A2, -2B6, -2C8, -2C9, -2C19, - 2D6 and CYP3A

Question 16

what does Ki more in respect to DDI?

Answer 16

The lower the Ki the more potent you inhibitor. The higher the i/ki means you sare more likely to get a DDI

Question 17

what is the purpose of clinical metabolic DDI studies?

Answer 17

To determine:
 Whether investigational drug changes PK of other drugs
 Whether other drugs change the PK of the investigational drug
 Magnitude of change in PK parameters
 Clinical significance of the observed DDI
 Appropriate management strategy for clinically significant DDI – need to provide this that will feed into drug label and help healthcare professionals

Question 18

what is the classifciation of drug as a CYP inhibitor/

Answer 18

Strong: > 5-fold increase in AUC of a sensitive index substrate (midazolam
CYP3A4 probe, if you see an increase it is linked to inhibition)
Moderate: 2 to 5-fold increase in AUC
Weak: 1.25 to 2-fold increase in AUC

Question 19

what does PBPK modelling achieve/

Answer 19

 Simulate [I] at the relevant site of interaction
 Assess the effect of multiple inhibitors
 Predict the effect of multiple interaction mechanisms
 High confidence in prediction of metabolic DDIs
 Guide the decision on the conduct of specific clinical study and their design
 Labelling impact

Question 20

what are the clinical consequences of CYP3A4 inhibition?

Answer 20

 QT prolongation and severe cardiac arrhythmia (‘Torsades de points’)
 Black box warning issued!
 Withdrawal from the US market in 1997, no longer available for prescription in the UK
 Fexofenadine is still available as it has better safety profile – not cardiotoxic but has some similar pharmacological properties

Question 21

what is the interaction with grapefruit?

Answer 21

 Identified by chance – F of felodipine increased 3x when orange juice was replaced by grapefruit
 Corresponding cardiovascular changes observed

Question 22

what is the mechansims of action for grape fruit juice for drug interaction?

Answer 22

 Irreversible inhibition of intestinal CYP3A4 by furanocoumarins (bergamottin and 6’,7’-dihydroxybergamottin)
 Present in the peel and other fruits
 Less effect seen with Seville orange, cranberry and pomegranate juices
 Grapefruit juice effect also suggested on P-gp, OATP1A2 and OATP2B1
 Standard dose has minimal effect on hepatic CYP3A4
 No effect if drug is given i.v.

Question 23

what is the irreversible inhibition of co-admin of grapefruit juice and CYP3A4?

Answer 23

Reduce inhibition of metabolism and elimination of the ‘victim’ drug
  plasma concentrations and F of the ‘victim’ drug
 May result in increased toxicity and adverse drug effects
 New enzyme needs to be synthesised so recovery takes time
 Magnitiude of GFJ interaction is comparable to many drugs -DDI

Question 24

what is induction drug-drug interactions?

Answer 24

 Increased enzyme activity, upregulation of expression, translational activation
Net effect: de novo synthesis, i.e., more enzyme made!
 Autoinduction – drug increases its own metabolism (carbamazepine)
 Heteroinduction -  in metabolism of co-administered drug