Drug Drug Interactions Flashcards
Significance of DDIs in current pharmacy?
- metabolic DDIs are most common, often CYP3A4 based
- increasing role of transporters in DDIs
Examples of drugs that have been removed from the market due to metabolic DDIs?
terfenadine and mibefradil (CYP3A4)
cerivastatin (CYP2C8 and OATP1B1)
What types of metabolic drug interactions are there?
Induction and inhibition
What is induction interaction?
increased synthesis or activity of metabolic enzymes
- slow effect, involves enzyme turnover
- can lead to lack of therapeutic effect
What is reversible inhibition interaction?
competitive or non-competitive - complex between enzyme and inhibitor is formed. enzyme activity recovered after removal of the inhibitor
What is irreversible inhibition interaction?
drug/modifier covalently binds to the enzyme and inactivates it
not recoverable, new enzyme must be synthesised
Clinical consequences of induction?
- increased metabolism rate
- reduced drug concentration
- reduced drug effect
- need to increase dose
Clinical consequences of inhibition?
- decreased metabolism rate
- increased drug concentration
- increased drug effect
- need to decrease dose or avoid co-administration
Terminology used for drugs that cause DDIs?
Victim drug
Modifier is known as the perpetrator
What is Ki?
Inhibition constant (affinity of the inhibitor to the enzyme)
lower value is higher potency
How to determine Ki?
[E][I]/[EI]
What is Km?
the concentration of the substrate when the reaction rate is equal to half of the maximal rate
determinant of binding affinity - lower value is higher potency
What is the effect of inhibition dependent on?
- Ki value
- concentration of inhibitor
- inhibition mechanism
Effects on the reaction when enzyme inhibition is competitive? According to Michaelis-Menton
inhibitor causes changes in the binding affinity - increases Km
Effects on the reaction when enzyme inhibition is non-competitive? According to Michaelis-Menton
Reduces the enzyme activity (Vmax)
What is the FDA DDI guidance?
- list of routine screening for certain CYP enzymes
- determine [I]/Ki rank to give order or priority for further studies
- [I]/Ki cutoff values that require further testing through basic, static and PBPK models
- drugs also tested for their ability to inhibit transporters
Why is all the DDI testing important?
Labelling once approved - e.g. imbrutimib has label based on simulation and clinical trials
What do clinical metabolic and transporter DDI studies look to determine?
- whether the investigational drug changes PK of other drugs
- whether other drugs change the PK of the investigational drug
- magnitude of change in the PK parameters
- clinical significance of the observed DDI
- appropriate management strategy for DDI
How are drugs classified as CYP inhibitors? As a function of what?
Strong (>5 fold increase)
Moderate (2-5 fold increase)
Weak (1.25-2 fold increase)
function of AUC of the sensitive index substrate
How is AUC ratio calculated?
AUC + inhibitor / AUC control
Clinical example of terfenadine - severe DDI
Terfenadine metabolised to fexofenadine by CYP3A4
Terfenadine is cardiotoxic at higher concentrations, fexofenadine is not. Both antihistamines.
When given with ketoconazole (CYP3A4 inhibitor) - severe cardiac effects, black box warning issued. no longer available in UK and US
By what mechanism does grapefruit juice inhibit CYP enzymes?
furanocoumarins irreversibly inhibit intestinal CYP3A4
varies by type of juice, can have different quantities of the compounds
How else may grapefruit juice cause DDIs?
effect suggested on Pgp, OATP1A2 and OATP2B1
How can you avoid the effects of grapefruit juice?
iv drug - only affects intestinal CYP3A4, hepatic effect is very minimal
Consequences of grapfruit juice and CYP3A4 substrates co-administration?
- inhibition of metabolism of the victim drug
- increased plasma concentrations and bioavailability of the victim drug
- possible toxicity and adverse effects
Mechanism of ritonavir being used as a booster for HIV protease inhibitors ?
Ritonavir is a potent inhibitor of CYP3A4 which metabolises other protease inhibitors - boost drug levels
- reduces pill burden
- reduces dose of other inhibitors required
What is the recent significance of transporter DDIs?
physchem properties of newer drugs mean we rely more on transporters - disposition of a large number of drugs is significantly modulated by transporters
- impact on sustemic and tissue drug concentration (safety and efficacy concerns)
Where can transporter DDIs occur? Examples?
- both uptake and efflux transporters (cyclosporine can inhibit both)
- multiple organs - liver (OATP1B1) and intestine (BCRP)
- transporters and enzyme (gemfibrozil glucuronide inhibits OATP1B1 and CYP2C8)
What are the two major superfamilies of transporters in humans?
ATP-binding cassettes (generally efflux) (ABC) Solute carrier (generally uptake) (SLC)
Where are the most clinically relevant transporters expressed?
- epithelia of the intestine, liver and kidney
- endothelium of the blood brain barrier
Which transporters are currently screened in drug develpoment?
OATP1B1, OATP1B3, P-gp, BCRP, OATs, OCT2, MATE
Examples of DDIs with OATPs?
Cyclosporine and statin (huge increased AUC and Cmax of statin) Rifampicin and glyburide Rifampicin and Bosentan Lopinavir/ritonavir and Bosentan Lopinavir/ritonavir and Rosuvastatin
Where are the OATPs located?
Sinusoidal membrane of hepatocytes
What types of drugs are substrates of the OATPs?
Anionic, poor passive diffisuion/permeability
Which molecules does OATP1B1 mediate the uptake of?
statins, repaglinide, valsartan
endogeneous compounds - bile acids, bilirubin, thyroxine
Which molecules does OATP1B3 mediate the uptake of?
- overlap in 1B1 substrates
- active uptake of glutathione into hepatocytes
- expressed in some cancer tissues
What are the two forms of statin?
Lactone (prodrug for some statins) and the acid
Lactone is very lipophilic so well absorbed. acid form required to be taken up into hepatocytes
What is the clinical relevance of OATP1B1 and statins?
- active uptake of acid form, so higher conc in liver than plasma (important for the effect of statins, as they affect synthesis inside the hepatocyte)
How does expression/activity of OATP1B1 vary between individuals?
largely - allelic variants (T & C) cause different polymorphisms
TT and TC form are semi similar, CC form has reduced OATP1B1 activity, which leads to higher plasma concentrations of the drug. Increased risk of myopathy
Consequences of co-administration of OATP1B1 substrate and inhibitor?
Decrease active uptake of victim drug into hepatocytes, so a) less therapeutic effect and b) higher plasma concnetrations increases risk of adverse effects
What happens as a consewuence of single/mulitple rifampicin dosing?
- single dose inhibits OATP1B1 - often used in clinical studies to determine interaction
- multiple dose causes induction of CYP3A4
What is the clinical relevance of the cyclosporine/statin interaction?
very high likelihood of co-medication, CV disease is a major problem in long-term transplant recipients
Role of P-gp in drug disposition?
- intestinal absorption and bioavailabilty (intestinal efflux)
- limits entry of drugs into the CNS
- biliary and renal excretion of drugs
Clinical relevance of P-gp interactins?
- very small number of clinically relevant DDIs are attributed solely to P-gp
- overlap in CYP3A4 substrates
What are the most significant P-gp DDIs?
Digoxin
- very narrow therapetuic index so even 2 fold increase can be v dangerous
- digoxin is used as a clinical probe for tesitng P-gp inhibition in clinical studies (other suggested probes are dabigatran etexilate or fexofenadine)
Role of BCRP in drug disposition?
Expressed in intestinal epithelium and liver - attenuates intestinal absorption of drugs with poor permeability, and contributes to biliary excretion
Examples of transporter drug-food interactions?
Curcumin (in turmeric) inhibits intestinal efflux of sulfasalazine via BCRP. drug has poor permeability which is desired as it is needed to act in the GI tract on crohns and UC - so inhibition of efflux will reduce efficacy
apple juice inhibits intestinal uptake via OATP2B1 (e.g. aliskiren, fexofenadine)
Example of transporter DDIs on PD not PK?
Metformin and famotidine
AUC profile was the same for sole and co-administration, yet glucose lowering ability was much lower when coadministered. effect on tissue distribution that meant less metformin in the liver tissue so less effect
Recent examples of moedlling of transporter mediated disposition?
- transporter mediated DDIs in semeprevir
- PK in organ impairment (hepatic impairment and obeticholic acid)
- extrapolation across ethnic groups (from causacian to japanese with letermovir)
How can risk of transporter DDIs be studied in vivo?
- a cocktail of transporter probes
- endogeneous biomarkers
- preclinical species (e.g. cynomolgus monkey, similar genetics)
- PET imagine for tissue distribution
Role of endogeneous biomarkers of hepatic and renal transporter studies?
many endogenous compounds are substrates of transporters
theory that the AUC of a biomarker can reflect changes in a drugs AUC - you would see changes in the biomarker concentrations if your new drug inhibits a transporter
Endogenous substrates of OATP1B1/1B3?
Coproporphyrin I, bile acids, fatty acids
Endogenous substrates of OCT2/MATE1?
Creatinine
Endogenous substrates of OAT1?
Taurine
Required properties of a molecule to be a biomarker?
- selective for a transporter
- sensitive to weak/moderate transporter inhibitors
What factors canaffect the rate of biomarker formation and elimination?
Disease status, diet, age, circadian rhythm maybe
would require a baseline profile in patients as variability can be significant
Role of PET imaging in investagting transporter DDIs?
allows investigation of changes in tissue PK/distribution
Properties of the ideal PET tracer?
- transporter specific
- metabolically stable
- amenable to radiolabelling
How does PET tracing work when investigating DDIs?
PET tracer administered as a microdose and distribution monitored as baseline than in presence if drug being investigated
Role of metabolites in DDIs?
the majority of prescribed rugs have circulating metabolites (82% of CYP inhibitors)
- plasma conc of metabolites can be higher than that of parent compounds
- some metaolites are reported to inhibit
Examples of metabolites thought to inhibit?
- N-desmthyl of diltiazem - inhibit metabolic enzymes
- AM1 of cyclosporine - inhibit uptake transporters
Current FDA guidance on investigating metabolites?
defined criteria on when investigation of metabolites on CYPs/transporters is required
