Drug drug interactions Flashcards
Types of drug-drug interactions:
- Pharmacodynamic interactions
- Pharmacokinetic interactions – affecting either:
- -> Drug Absorption
- -> Drug-plasma protein binding
- -> Drug metabolism – most common!
- -> Drug transport
- -> Renal excretion
Relevance of drug drug interactions:
- Metabolic DDIs most common
- Inhibition or induction of CYP enzymes
- Often associated with CYP3A4
- Increasing role of transporters in DDIs
- Range from large effect to none – in drugs with a narrow therapeutic index can have a minimal DDI but can have a large impact
- Withdrawal of drugs from the market due to severe DDIs
- –> terfenadine, mibefradil (CYP3A4)
- -> cerivastatin (CYP2C8/OATP1B1)
- Unpredictable unless CYP/transporter is known for a drug of interest (victim drug)
Modifiers of drug metabolism :
Types of interactions:
- INDUCTION - increased synthesis or activity of metabolic enzymes
- Slow effect, involves enzyme turnover
- Can lead to lack of therapeutic effect - INHIBITION – inactivation or less enzyme available
Reversible (competitive and non-competitive)
- Enzyme-inhibitor complex is formed
- Enzyme activity is recovered after removal of the inhibitor
Irreversible
- Drug/modifier inactivates enzyme by covalently binding to it
- Design of in vitro studies more complex
- Non-recoverable unless new enzyme is synthesized!
Clinical consequences of inhibition and induction DDIs:
Inhibition:
- AUC ratio = AUC+inhibitor / AUCcontrol
Metabolising rate: decreases
Drug concentration: increases
Drug effect: Potentiated – often associated with SE’s
Clinical action: Reduce dose or avoid co-administration
Clinical consequences of inhibition and induction DDIs:
Induction:
Metabolising rate: increases
Drug concentration: decreases
Drug effect: reduced
Clinical action: Increased dose
Drug development and managing drug drug interactions.
FDA drug drug interaction guidance.
- CYP enzymes listed for routine in vitro metabolic DDI screening in drug development: CYP1A2, -2B6, -2C8, -2C9, -2C19, - 2D6 and CYP3A
- [I]/Ki rank order across different CYP enzymes gives priority in performing subsequent clinical studies
- Lower Ki = more potent inhibitor
- Different predictive models used to evaluate clinical DDI risk
- -> Basic (1+ [I]/KI to predict AUC ratio), static and PBPK models
- -> Cut-off values defined to trigger follow up clinical metabolic DDI study
- Drugs also tested for their ability to inhibit major transporters
- Findings have labelling implications!
[I] – inhibitor concentration at the active site of enzyme or transporter
Ki – inhibition constant, measured in vitro
What is the purpose of clinical metabolic and transporter DDI studies?
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 – that will lead into the drug label and HCP
Classification of an investigational drug as a CYP inhibitor
Strong: > 5-fold increase in AUC of a sensitive index substrate (midazolam as cyp3a4 probe)
Moderate: 2 to 5-fold increase in AUC
Weak: 1.25 to 2-fold increase in AUC
AUC ratio = AUC(+inhibitor) / AUC control
PBPK modelling extensively used in drug development to predict DDI risk in a mechanistic manner:
- 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
Labelling based on:
a) Clinical trials
b) Simulations in virtual subjects using PBPK modelling
Clinical example of reversible inhibition drug drug interaction.
Clinical consequences of CYP3A4 inhibition (ketoconazole)
Terfenadine LEFT – victim drug
Antihistaminic, but cardiotoxic at
higher concentrations
Fexofenadine RIGHT
– active metabolite, Antihistaminic, NO cardiotoxicity
Inhibitng CYP3A4 (ketoconazole) consequences:
- 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
Grape fruit juice- drug interactions. Mechanism:
- 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.
Irreversible inhibition as a cause of clinical drug drug or drug food interactions.
Co-administration of grapefruit juice and CYP3A4 substrates can:
- Reduce Inhibition of metabolism and elimination of the ‘victim’ drug
- Increased plasma concentrations and F of the ‘victim’ drug
- May result in increased toxicity and adverse drug effects
Magnitude of GFJ interactions is comparable to many DDI’s
Induction drug drug interactions consequences:
- 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 - increase in metabolism of co-administered drug
1. Selectivity – unique to microsomal drug metabolising enzymes. Effect of smoking on CYP1A2 – increased clozapine clearance
2. Adaptive response to xenobiotics
Phenobarbital therapeutic use and enzymes affected:
Epileptic drug
- UGT1A
- CYP3A4, -3A5, -2C9, -2B6
Rifampicin therapeutic use and enzymes affected:
Antibiotic
- UGT1A
- CYP3A4, -3A5, -2C9, -2B6
Phenytoin, Carbamazepine
therapeutic use and enzymes affected:
Anticonvulsant
- CYP3A4, -3A5, -2C9, -2B6
- UGT2B7 (carbamazepine)
What enzyme is affected by Cigarette smoke:
CYP1A2
Mechanism of induction
- Needs complement of cellular processes - in vitro studies done in hepatocytes, not microsomes!
- Time lag for effect (increased protein synthesis)
- Increased transcription
- Increased translation
- Decreased degradation
Changes in hepatocytes resulting from induction:
- Changes at enzyme level
- Increased Vmax, Km
- Selective therefore CYP spectrum of activity changes - Changes at cellular level
- Increased CYP synthesis and expression levels
- Pronounced proliferation of endoplasmic reticulum - Changes at tissue level
- Induction is not a pathological process, but results in major physiological changes in the liver
- Increased liver size - increase in liver weight, blood and bile flow
Clozapine clearance is increased in patients who are heavy smokers
What change do you expect to see in clozapine Cmax in the case of smoking cessation?
Clozapine Cmax is expected to increase as the enzyme levels return to baseline
The effect will take time (depends on turnover of enzyme)
