Transporter-mediated drug-drug interactions

Question 1

Transporter-mediated drug-drug interactions (tDDIs) may occur at:

Answer 1

• Both uptake and efflux transporters (cyclosporine)
  Multiple organs – rosuvastatin - liver (OATP1B1) and intestine (BCRP)
• Transporters and enzyme (gemfibrozil glucuronide – inhibits OATP1B1 and CYP2C8)

Impact on systemic and tissue drug concentration (safety and efficacy)

Question 2

How many membrane transporters?

Answer 2

> 400 membrane transporters identified so far

Question 3

Two major super families of transporters in human genome:

Answer 3

• ATP-binding cassette (ABC)

- Solute carrier (SLC)

Question 4

Most relevant transporters expressed in:

Answer 4

• Epithelia of the intestine, liver and kidney

- Endothelium of the blood–brain barrier

Question 5

OATP - Organic Anion Transporting Polypeptide – OATP1B1 (MAJOR) and OATP1B3 located:

Answer 5

on sinusoidal membrane of hepatocytes

Question 6

OATP1B1 mediates uptake of :

Answer 6

Therapeutic drugs into hepatocytes - statins, repaglinide, valsartan (anionic substrates)

Endogenous compounds - bile acids, bilirubin, thyroxine hormone

Question 7

OATP1B3 – similar in sequence to OATP1B1

Answer 7

• Overlap in substrates with OATP1B1

- Active uptake of glutathione into hepatocytes

Question 8

Clinical relevance of OATP1B1:

Active uptake of statins (acid form!) via OATP1B1:

Answer 8

• Higher liver exposure compared to plasma

- Important for therapeutic effect of statins as this is where statins actually work

Question 9

Expression and activity of OATP1B1 varies between individuals / ethnicities:

Answer 9

SLCO1B1 c.521T>C most relevant SNP

521 CC - decreased OATP1B1 activity, increased risk of myopathy when taking statins

Question 10

Co-administration of OATP1B1 inhibitor:

Answer 10

Decreased active uptake of victim drug into hepatocytes

Increases plasma concentrations of the ‘victim’ drug and risk of adverse reactions

Question 11

Clinical example of OATP1B1 DDI – cyclosporine interaction with rosuvastatin in transplant patients. Mechanism of DDI:

Answer 11

• Cyclosporine inhibits hepatic uptake of statins by OATP1B1 transporter so less gets taken up into hepatocycte and now more is in the systemic circulation

Likelihood of co-medication – very HIGH!
Cardiovascular diseases major problem in long-term transplant recipients

Question 12

Clinical example of OATP1B1 DDI – cyclosporine interaction with rosuvastatin in transplant patients. Consequences:

Answer 12

• Increased plasma concentrations of rosuvastatin
• Safety concern- Impact on drug labelling and recommended initial dose of rosuvastatin
• Similar interaction reported with other statins (atorvastatin, simvastatin)

Question 13

What is the role of efflux transporters in clinically relevant DDIs?

Answer 13

Multiple roles of P-glycoprotein in drug disposition1,2

• Intestinal absorption and bioavailability
• Limits entry of drugs into the CNS
• Biliary and renal excretion of drugs

Question 14

Small number of clinically relevant DDIs can be attributed solely to inhibition of P-gp:

Answer 14

• Overlap in substrates with CYP3A4 (loperamide, vinblastin etc)
• Dual substrates - inhibition of CYP3A4 often the major cause of DDI!

Question 15

Most relevant P-gp DDIs are with digoxin as a substrate:

Answer 15

• Safety concerns due to its narrow therapeutic index
• Recommended probe by FDA for assessing P-gp inhibition
  Dabigatran etexilate or fexofenadine (EMA)

Question 16

Examples of transporter food-drug interaction: Curcumin

Answer 16

• Curcumin (turmeric) inhibits intestinal efflux of sulfasalazine via BCRP.
• Sulfasalazine - anti-inflammatory drug used to treat ulcerative colitis and Crohn’s disease
  Low permeability, low solubility and efficient intestinal BCRP efflux – drug restricted largely to the GI tract
• What is the consequence of inhibition of BCRP? Increased absorption and decreases its exposure to intestinal bacteria (bad as it treats there intestinal disorders)

Question 17

Examples of transporter food-drug interaction: Apple juice

Answer 17

• Apple juice inhibits intestinal uptake via OATP2B1
  Reduced plasma concentrations of aliskiren and fexofenadine when taken with apple juice instead of water
• Complex inhibition interaction via multiple components

Question 18

Evaluation of transporter-mediated PK and DDIs in drug development:

Answer 18

• Drugs tested for their ability to inhibit major transporters
  OATP1B1, OATP1B3, P-gp, BCRP, OATs, OCT2, MATE
  Decision trees to decide on whether to do a clinical transporter DDI study
• Conducting clinical studies to test potential interaction on every transporter (in patient population) is logistically impossible!
• -> Increased use of modelling and simulation (PBPK models)

Question 19

Recent examples of mechanistic modelling of transporter-mediated disposition:

Answer 19

• Transporter-mediated DDIs (simeprevir)
• PK in organ impairment (hepatic impairment – obeticholic acid)
• Extrapolation across ethnic groups (letermovir)

Question 20

Other in vivo methods to investigate risk of transporter DDIs:

Answer 20

1. Clinical studies with cocktails of drug transporter probes (microdosed)
2. Endogenous biomarkers

3. Use of preclinical species  
  Cynomolgus monkey (Shen et al., 2013, Chu et al 2015)

4. Positron emission tomography (PET) imaging

Question 21

Endogenous biomarkers of hepatic and renal transporter:

Answer 21

Many endogenous molecules are substrates of drug transporters coproporhyrin I, bile acids, fatty acids – OATP1B1

Can change in AUC of a biomarker reflect changes in drug’s AUC in DDI? Good as can be done very early stages

Question 22

Required properties of biomarkers:

Answer 22

• Selectivity

- Sensitivity – ability to detect weak/moderate transporter inhibitors

Question 23

Rate of biomarker formation and elimination:

Answer 23

Effect of disease, diet, age, circadian rhythm?

Question 24

Why is CPI the most promising endogenous biomarker for OATP1B?

Answer 24

• CPI is a by-product of haeme synthesis
• Reported interactions with rifampicin and other OAT1B inhibitors
• Increased urinary excretion of CPI in Rotor’s syndrome
• Metabolically stable, excreted in the bile and urine
• Stable inter-occasion baseline and <25% inter-individual variability in subjects with wild type OATP1B1

Question 25

PET imaging to study tissue distribution and transporter DDIs:

Answer 25

• Allows investigation of changes in tissue PK
• Ideal PET tracer:
  Transporter specific
  Metabolically stable
  Amenable to radiolabelling (11C)
• PET tracer administered as a microdose (1-10 µg) in DDI studies

Question 26

Summary:

Answer 26

• Increased recognition of clinical relevance of tDDIs
  Mostly associated with OATP1B1, P-gp
  DDIs with renal transporters (see Renal Elimination lecture)
• Evaluation of changes in drug tissue concentration as a result of tDDI is challenging
  Role of PBPK modelling and PET imagining
• Prospective assessment of DDI risk for drugs that are substrates or inhibitors of multiple transporters and/or enzymes is complex