Week 10 - Metabolic DDIs and Transporter DDIs Flashcards
Explain the mechanism of drug-drug interactions (DDI) with metabolising enzymes
Occurs when co-administer 2 or more drugs
- common enzyme affected is CYP3A4 = common type of DDI
- victim drug = drug affected by DDI
Pharmacokinetic interactions occur
- absorption, distribution, metabolism, renal excretion, drug-plasma protein binding can be affected
Enzyme levels are altered by irreversible inhibitors (degradation) AND inducers (↑ synthesis)
What are the requirements for assessing the DDI risk in drug development
Monitoring is required for:
- drugs with narrow therapeutic index e.g. digoxin
- patients that have renal or hepatic impairment
- these are major organs for elimination
- elderly patient
- more likely to take multiple drugs
- anticoagulants, antihypertensives, anti diabetics
What is inhibition metabolic DDI
Inactivation or less of the metabolic enzyme
- can be reversible or irreversible
- results in ↓ metabolic elimination = ↑ drug conc. in plasma
= ↑ F = ↑ toxicities and ADRs
SOLUTION: reduce dose of victim drug OR avoid co-administration
Reversible (competitive / non-competitive)
- drug binds to enzyme (enzyme-inhibitor complex formed) = enzyme is inactivated
- removal of inhibitor = enzyme activity is recovered
Irreversible
- drug inhibits enzyme by covalently bonding
- casuses enxyme degradation
- NOT recoverable (when drug is removed) unless synthesise new enzymes
- recovery is slower than reversible as enzyme (protein) conc. decreased, need to synthesise more
What is induction metabolic DDI
Increased synthesis or activity of the metabolic enzyme
- have ↑ metabolic elimination of drug = ↓ drug plasma conc.
- ↓ plasma conc. of victim drug = ↓ therapeutic effects
- SOLUTION: increase dose of victim drug
Autoinduction - drug ↑ its OWN metabolism
- e.g. Carbamazepine
Heteroinduction - drug ↑ metabolism of a co-administered drug
Cigarette smoke = inducer of CYP1A2
What is the mechanism of induction
- ↑ transcription = ↑ mRNA
- ↑ translation of enzyme / ↑ synthesis
- ↑ enzymes = ↑ enzyme activty = ↑ metabolism
What are clinical consequences of CYP inhibition / induction DDIs
DDIs are evaluated using AUC ratio
- AUC ration = AUC(+ inhibitor) ÷ AUC(control)
- compare AUC of victim drug alone and victim drug + perpetrator (inhibitor or inducer)
- compare AUC curves to see how many folds it has changed by
- AUC gives insight to exposure of drug to body + clearance rate
e.g. if AUC for victim drug + perpetrator is higher Han AUC for victim drug = perpetrator is an inhibitor
Common CYP enzymes (we screen for DDIs)
- CYP1A2
- CYP3A4 / CYP3A5
- CYP2D6
Use PBPK model to investigate
Testing CYP3A4
- use Midazalom (CYP3A4) substrate
- can be inhibited by Ketocanazole (inhibits terfenadine)
- causes TDP, prolonged QT interval
- can be inhibited by grapefruit juice (inhibits statins, CCB)
- juice irreversibly binds to intestinal enzyme
- inhibitor is in peel of fruit, use more peel in juice = ↑ effect
What is the purpose of DDI studies
Test drugs against metabolic enzymes + drug transporters
- can use PBPK model to investigate
- a simulation which provides predictions of DDIs
- if we make findings they will influence labelling
- Discover if investigational rug is inducer or inhibitor (PK)
- Magnitude of PK changes
- Clinical significance of DDI
- Determine management strategy for DDI
- minimise risk but keep efficacy of drug
Lower Ki (inhibition constant) = drug is more potent inhibitor
[I] = inhibitor conc.
When [I] ÷ Ki if ratio is greater = ↑ of DDis
Clinical and simulation trials influence labelling
Classification of DDIs
Strong - ≥ 5-fold increase in AUC (of the victim drug)
Moderate - 2 - 5 fold increase
Weak - 1.25 - 2 fold increase
NOT all DDIs are harmful, some can be beneficial
- e.g. combination drugs with ritonavir (used in HIV drugs)
What are the effects of transporter mediated drug-drug interactions (tDDIs)
- tDDIs impact the systemic + tissue drug conc.
= safety and efficacy - perpetrator drug interacts with uptake + efflux transporters
- transporters are found in liver, small intestines, kidneys - need to asses likelihood of 2 drugs being co-adminstered
- one drug could be an inhibitor
List the main drug transporters, their function and clinical relevance
ABC Transporters = efflux
Movement of drug out of cell into blood or bile (liver)
- BCRP
- p-GP
SLC Transporters = uptake
Movement of drug into cell, tissue or organ from blood
- OAT
- OCT
What is the clinical relevance of uptake transporter DDIs
OAT:
OATP1B1
- cyclosporine inhibits hepatic transporter = rosuvastatin + other statins = statin remains in plasma = can have side effects (myopathy)
- lower statin dose to solve problem
- inb=hibted by rifampicin
OATP2B1
- inhibited by apple juice
= ↓ plasma conc. of drug = reduced effect
What is the clinical relevance of efflux transporter DDIs
p-GP
- effluxes drug from enterocytes into intestinal lumen
- involved in biliary + renal excretion
- inhibition of CYP3A4 major DDI (as they have similar substrates)
- effluxes digoxin, use digoxin to investigate
BCRP
- contributes biliary excretion
- affects intestinal
- inhibited strongly by curcumin (food)
What methods are used to investigate transporter-mediated DDI risks in drug development
- PBPK Model
- test OATP1B1, OATP1B3, OCTs, OATs, p-GP, BCRP, MATE
- virtual simulation
- administer many drugs at same time to evaluate multiple transporters at once - PET Imaging
- Allows investigation in changes in tissue expose
- PET tracer needs to be: transporter specific, metabolically stable and can be radio labelled
- generates an image showing distribution of molecule before + after inhibitor - Endogenous Biomarkers
- biomarkers need to be selective + sensitive (towards specific transporter + detect strength of inhibition)
- Allow you to evaluate activity of renal + hepatic transporters
- monitor biomarkers + see if there’s changes in presence of inhibitor
- CPI is a OATP1B1 biomarker
