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
